Components to elevated
of the hem.odynamic response cerebrospinal fluid pressure
Richard E. Brashear, Pao-lo Yu, Ph.D. Indianapolis,
M.D.
Ind.
Elevation of cerebrospinal fluid (CSF) pressure to levels usually exceeding mean systemic blood pressure is followed by what is frequently called the Cushing reflex.’ The increased vascular pressures and cardiac output occurring with the reflex have been well described.*-’ Since intracranial pressures may increase to over 100 mm. Hg with severe brain injury5 and intracranial pressures up to 160 mm. Hg have been described in patients with subarachnoid hemorrhage,6 significant elevations of intracranial pressure have clinical importance. We have previously demonstrated that increasing CSF pressure to 200 mm. Hg significantly increased cardiac output, heart rate, stroke volume, aortic pressure, pulmonary artery pressure, wedge pressure, right atria1 pressure, pulmonary capillary blood volume, and pulmonary diffusing capacity.‘. 8 These changes were attributed to a massive alpha- and beta-adrenergic stimulation. Beta-adrenergic blockade prevented an increase in cardiac output and heart rate but did not alter the response of increased vascular pressures to elevated CSF pressure. Alpha-adrenergic blockade prevented an increase in vascular pressures during elevated CSF pressure but did not prevent the increase in cardiac output. Two distinct adrenergic components were thus identified but it was unclear if the components were humorally or neurogenically mediated. A subsequent study provided evidence for a circulating beta adrenergic agonist during elevated ,CSF pressure.9 The From Center,
the Department Indianapolis,
of
Medicine,
Received
for publication
Dec. 8, 1976.
Accepted
for publication
Feb. 10, 1977.
Reprint requests: Richard cine, Indiana University Indianapolis, IN 46202.
52
Indiana
University
Medical
Ind.
E. Brashear, M.D., Department of MediMedical Center, 1100 West Michigan St.,
present study was undertaken to clarify the origin of these alpha- and beta-adrenergic effects during elevated cerebrospinal fluid pressure. Methods
Mongrel dogs (21 -+-3 kilograms, mean k SD) were anesthetized with pentobarbital, 30 mg./Kg. intravenously. Ventilation with periodic hyperinflation was controlled through a cuffed endotracheal tube with a Harvard constant volume ventilator, end-tidal CO, was monitored and maintained between 5.0 to 5.5 per cent, and the animals were paralyzed with intravenous gallamine triethiodide, 2.0 mg. /Kg. For clarification, the various subgroups studied with elevated CSF pressure are outlined as follows: Group I. An initial six dogs studied acutely after bilateral adrenalectomy and ganglionic blockade with hexamethonium. Group II. Six dogs studied 17 + 2 days after adrenalectomy. Group III. Twelve dogs studied with an isolated and perfused gracilis muscle preparation and beta adrenergic blockade. Group III A. Four studied with intact adrenals with the muscle preparation denervated. Group III B. Four studied 18 ? 1 days after adrenalectomy with the muscle preparation denerva ted. Group III C. Four studied 18 ? 2 days after adrenalectomy with muscle preparation innervated. Group IV. Six dogs with an isolated, perfused, and denervated gracilis muscle preparation, alpha-adrenergic blockade, and intact adrenals. Groups I and II were studied as previously described.x. y Cardiac catheters were placed in the main pulmonary artery, right atrium, and wedge
January,
1978, Vol. 95, No. 1, pp. 52-59
Response
position through the jugular veins and in the ascending aorta just distal to the aortic valve through the carotid artery. Pressures were measured at end expiration and heart rate was determined from the pressure tracing. Cardiac outputs were done in duplicate by the indicator-dilution technique and expressed as milliliters per minute per kilogram of body weight and stroke volume as milliliters per beat per kilogram. Central blood volume was determined from the main pulmonary artery to ascending aorta. Mean pressures were used to calculate vascular resistance. Systemic vascular resistance (units) = systemic artery pressure - right atria1 pressure (mm. Hg)/cardiac output (ml./min. per kilogram). Pulmonary vascular resistance (units) = pulmonary artery pressure - wedge pressure (mm. Hg)/cardiac output (ml./min. per kilogram). Arterial blood pH, Po2, and Pco, were determined by conventional electrodes (Instrumentation Laboratory, Inc.). Cerebrospinal fluid pressure was elevated as previously described using a pressure reservoir of saline (37’ C.), buffered with NaHCO,J to pH 7.4, connected to a needle in the cisterna magna.7-9 After control period values were obtained, the CSF pressure was increased to 100 mm. Hg and measurements were obtained after 5 and 10 minutes. The CSF pressure was then increased to 200 mm. Hg, the determinations repeated after 5 and 10 minutes, and the CSF pressure was returned to control period levels. The previously mentioned determinations were repeated 10 minutes after CSF pressure was returned to control values. In Group I, the animals were studied immediately after bilateral adrenalectomy and ganglionic blockade obtained with intravenous hexamethonium chloride, 5 mg. of base per kilogram in a concentration of 25 mg./ml., infused over 5 minutes. Completeness of ganglionic blockade was determined by observing mean systemic blood pressure during 30 seconds of bilateral common carotid artery occlusion. Hydrocortisone sodium succinate was given, 50 mg. intramuscularly at onset of adrenalectomy and 100 mg. intravenously during the remainder of the study. Performing the elevated CSF pressure study immediately after adrenalectomy resulted in protracted experiment of 4 to 5 hours. Subsequently, in Groups II and III, bilateral adrenalectomy was performed through a midline
American
Heart
Journal
to elevated
CSF pressure
incision with sterile technique, meticulous di’ssection, and hemostasis. Dogs were maintained after adrenalectomy with 12.5 mg. cortisone acetate and 1 mg. desoxycorticosterone acetate intramuscularly each day. On the day when the dogs were subsequently studied with elevated CSF pressure, 14 to 19 days post-adrenalectomy, they received a 25 mg. intravenous bolus of hydrocortisone sodium succinate and an additional 25 mg. in 50 ml. of saline infused during the remaining study. The amount of steroid was considered to reasonably approximate the amount that would be elaborated during severe stress by an animal with intact adrenals. The isolated perfused gracilis muscle was prepared in the dog as previously described.“‘. ” Briefly, the gracilis muscle was completely exposed and isolated except for minimal lateral and medial tendinous connections and the gracilis artery and vein. The obturator nerve was sectioned in the denervated muscle preparations. Heparin, 5 mg./Kg., was given intravenously and a polyethylene catheter (PE 90) was inserted in the gracilis artery and connected to a constant volume flow rate pump (Holter Pump, Model 911). The contralateral femoral artery was cannulated for inflow to the pump and flow rate (11.5 & 2.8 ml. per minute, mean + SD) was adjusted so gracilis perfusion pressure approximated systemic blood pressure. Pressure was monitored in the tubing between the femoral artery and perfusion pump permitting the inflow pressure to the pump to be kept constant at control levels, regardless of increases in femoral artery pressure, by using a screw resistor. After stabilization of the muscle perfusion pressure, the propranolol or phenoxybenzamine were infused. The 12 dogs (Group III) with beta-adrenergic blockade and the isolated perfused gracilis muscle preparation received propranolol, 0.5 mg./Kg. in 30 ml. saline over 5 minutes prior to obtaining control values and an additional 0.25 mg./Kg. in 30 ml. over the remainder of the study. Four were studied with intact adrenals and denervated muscle preparation (Group III A). Four were studied after adrenalectomy with denervated muscle preparation (Group III B). Four were studied after adrenalectomy with the muscle preparation innervated (Group III C). At the conclusion of the study, the completeness of beta blockade was demonstrated with intravenous isoproterenol (0.01 mg. in 20 ml. saline over 2
53
Brashear
and
Yu
k& 100
fouIll 100
--OMIN a00 mm
10 Mm 200
10 Mm POST
1. per
blockade;
minutes) demonstrating no change in heart rate, systemic blood pressure, or gracilis muscle resistance. The six alpha-adrenergic blockade animals (Group IV), all with intact adrenals and an isolated, denervated, and perfused gracilis muscle preparation, received phenoxybenzamine hydrochloride (courtesy Smith, Kline, and French Co., Philadelphia ), 3 mg. /Kg. in 25 ml. saline over 60 minutes prior to obtaining values and an additional 1 mg./Kg. in 25 ml. over the remainder of the study. At the conclusion, the completeness of alpha blockade was demonstrated with norepinephrine base, 0.01 mg. in 20 ml. saline intravenously over 2 minutes, demonstrating no change in heart rate, systemic blood pressure, or gracilis muscle resistance.
54
lO?dm 100
Hg
cent change from control during elevated Group II-adrenalectomy. Abscissa indicates minutes post indicates time after CSF pressure returned P < 0.05 level. Fig.
u--u5MlN ml
5buN zoo mln
10 Mm am3
10 MIN POST
Kg
CSF pressure. Group I-adrenalectomy and ganglionic duration and magnitude of elevated CSF pressure, 10 to control values. Asterisk indicates change significant at
The significance of the change from the control period to each of the subsequent periods was determined by Dunnett’s t test at the 5 per cent level.‘2 Results
The results are presented in Figs. 1 and 2. In Group I animals, studied acutely after adrenalectomy and ganglionic blockade, control aortic pressure (92 t 8 mm. Hg, mean + SD) only changed 10 minutes after CSF pressure was returned to control values. Control cardiac output (123 & 15, ml./min. per kilogram) increased significantly (P < 0.05) at 5 minutes of 200 mm. Hg CSF pressure and 10 minutes after CSF pressure returned to control levels. Control systemic vascular resistance (0.759 + 0.097 units/
January,
1978, Vol. 95, No. 1
Response to elevated CSF pressure
GROUP GROUP
Ill A III B
GROUP GROUP
RI C IV
----II 5lmN 100
10 Mm 100
5mN 200 mm
10 Mm 200
10 Mm POST
Hg
Fig. 2. Per cent change from control in gracilis muscle study. Group III-beta-adrenergic blockade; A-intact adrenals, denervated muscle; B-adrenalectomy, denervated muscle; C-adrenalectomy, innervated muscle. Group IV-alpha-adrenergic blockade, intact adrenals, denervated muscle. Abscissa and asterisk same as in Fig. 1.
kilogram) decreased significantly at 10 minutes 100 mm. Hg and 5 minutes and 10 minutes of 200 mm. Hg CSF pressure. Control right atria1 (-1 f 1 mm. Hg) and wedge (1 & 3 mm. Hg) pressures showed essentially no change but control pulmonary artery pressure (13 f 2 mm. Hg) increased slightly but significantly during 5 minutes 200 mm. Hg CSF pressure and 10 minutes after release of CSF pressure. Control heart rate (111 + 8 beats/minute) increased significantly 10 minutes after release of CSF pressure. There were no significant changes compared to the control period for any parameter after 5 or 10 minutes of CSF pressure 100 mm. Hg in Group II. In Group II, control aortic pressure (126 + 5 mm. Hg), pulmonary artery pressure (11 1 3 mm. Hg), wedge pressure (3 +- 4 mm. Hg), cardiac output (177 f 41 ml./min. per kilogram), stroke volume (0.99 + 0.17 ml./beat per kilogram), and central blood volume fl5.2 +- 2.2 ml/Kg.) increased significantly (P < 0.05) at 5 and 10 minutes of CSF pressure 200 mm. Hg. Group II also demon-
American Heart Journal
strated a significant decrease from control systemic vascular resistance (0.758 ? 0.183 units/ Kg.) at 10 minutes of 200 mm. Hg and after release of CSF pressure. Group II demonstrated no significant changes in pulmonary vascular resistance or heart rate while a change in right atria1 pressure was significant but small. In Group II, the animals were weighed daily after the adrenalectomy and the weight decreased 1 + 1 kilogram prior to the elevated CSF pressure study. Serum electrolytes were determined on the day of the CSF study and were sodium 144 f 1, potassium 4.4 + 0.3, and chloride 108 +- 4 mEq./L. There were no changes during CSF pressure 100 mm. Hg in the beta-adrenergic blockade dogs (Fig. 2) with the perfused gracilis muscle preparations (Group III). In the animals with intact adrenals and denervated muscle (Group III A), the control aortic pressure (131 + 5 mm. Hg) increased significantly during 5 and 10 minutes of CSF pressure 200 mm. Hg. The resistance of the perfused gracilis muscle increased significantly
55
Brashear
and
Yu
from the control period during 5 and 10 minutes of CSF pressure 200 mm. Hg, respectively. In these animals with intact adrenals, it is of particular interest that 21 it 17 seconds (mean t SD) were required for mean aortic pressure to increase to 200 mm. Hg after CSF pressure was increased to 200 mm. Hg. In contrast, 48 t 11 seconds elapsed before any detectable increase from control was noted in the denervated gracilis muscle perfusion pressure and 4.6 -t 3.6 minutes elapsed before the gracilis muscle perfusion pressure reached a maximum. In the animals with beta-adrenergic blockade, denervated gracilis muscle preparation, and adrenalectomy (Group III B), control aortic pressure (131 + 4 mm. Hg) increased significantly during 5 minutes CSF pressure 200 mm. Hg. There was no significant change in the resistance of the denervated gracilis muscle. In Group III C (beta-adrenergic blockade, adrenalectomy, innervated gracilis muscle), control aortic pressure (125 + 19 mm. Hg) increased significantly during 5 minutes CSF pressure 200 mm. Hg. Gracilis muscle resistance increased significantly during 5 and 10 minutes CSF pressure 200 mm. Hg. The aortic pressure and gracilis muscle resistance began to increase about the same time (18 to 30 seconds) after CSF pressure was increased to 200 mm. Hg. Aortic pressure usually reached a maximal value in 14 to 64 seconds whereas the gracilis muscle resistance showed a progressive increase over 3 to 4.5 minutes up to 10 minutes. Group IV, alpha-adrenergic blockade and intact adrenals, aortic pressure demonstrated a significant decrease during 5 and 10 minutes of CSF pressure 200 mm. Hg from 105 -+ 13 mm. Hg in the control period. There was no change in resistance of the gracilis muscle. Arterial blood for all dogs in the control period demonstrated pH 7.39 + 0.03, PaCO, 40 + 3 mm. Hg, and PaO, 87 + 7 mm. Hg. At the conclusion of 10 minutes CSF pressure 200 mm. Hg, arterial blood showed pH 7.33 +- 0.04, PaCO, 41 * 5 mm. Hg, and PaO, 83 t 8 mm. Hg. Discussion
Cushing, in 1901,’ demonstrated a pressor response to elevated intracranial pressure. Subsequent investigators considered several mechanisms including a humoral vasopressor in the chick,“‘ cerebral ischemia,‘, 14venoconstriction,‘”
56
neurohumoral stimulation with a phasic response of systemic blood pressure in dogs and rabbits,‘” myocardial inotropic response,” and shunting.‘” Mechanical compression of the rat brain produces a pressor response not altered by adrenalectomy or bilateral cervical vagotomy.“’ A receptive area in the lower brainstem possibly mediates the Cushing response.“’ In 1970, the Cushing response (reflex) was clearly separated into alpha- and beta-adrenergic components.i: This study was initiated to determine the etiology of these alpha and beta effects. The animals with the denervated and perfused gracilis muscle preparation, beta-adrenergic blockade, and intact adrenals (Group III A) demonstrated an increase in resistance of the gracilis muscle preparation indicating a circulating vasoconstrictor of skeletal muscle. The aortic pressure also increased significantly and could be caused by either a humoral agonist or neurogenic stimulation. The significant time lag between aortic pressure elevation and elevation of the gracilis muscle perfusion pressure is indicative of a circulating vasoconstrictor that is delayed by the external pump that perfuses the gracilis muscle preparation. In contrast, the animals with the denervated, perfused gracilis muscle preparation, betaadrenergic blockade, and no adrenals (Group III B) demonstrated an increased aortic pressure but no change in gracilis muscle perfusion pressure or resistance. Therefore, the adrenals appear to be the source of the alpha-adrenergic agonist affecting the denervated gracilis muscle since any increase in resistance of the gracilis muscle is absent in the adrenalectomized dog with betaadrenergic blockade. The increase in aortic pressure in both Group III A and B is probably neurogenic and nonadrenal in origin. The neurogenic component of the Cushing reflex is demonstrated in Group III C (no adrenals, beta-adrenergic blockade, and innervated gracilis muscle). In contrast to the lack of change in the denervated gracilis muscle resistance in Group III B, Group III C demonstrated a marked increase in gracilis muscle resistance. Group I, animals with ganglionic blockade studied acutely after adrenalectomy, demonstrated changes similar to those previously reported in animals with intact adrenals, ganglionic blockade, and alpha-adrenergic block-
January,
1978, Vol. 95, No. 1
Response to elevated CSF pressure
ade.9 There was no increase in aortic pressure during elevated CSF pressure but cardiac output increased and systemic vascular resistance decreased indicating the’ presence of a circulating beta-adrenergic agonist independent of the adrenals. The previous study also indicated a circulating beta-adrenergic agonist but the adrenals were intact.” The decrease in control blood pressure was consistent with the lowering of blood pressure found in rats and rabbits with combined chemical sympathectomy and adrenalectomy.21 A marked increase in cardiac output and aortic pressure occurred 10 minutes after CSF pressure was returned to control levels, this was noted previously9 in dogs with systemic hypotension during the increased CSF pressure. Dogs can survive 25 minutes of cerebral ischemiaZ2 and a marked reactive hyperemia occurs with reperfusion of the brain2” that may wash out vasoactive substances.2’. 25 Group II (adrenalectomized animals) demonstrated the expected8 alpha- and beta-adrenergic effects (increase in vascular pressures, cardiac output, stroke volume) during CSF pressure of 200 mm. Hg and, therefore, excluded the adrenals as the only participant in the Cushing reflex. Other investigators have noted that adrenalectomy in rats does not blunt the rise in blood pressure evoked by brainstem lesions.26 Group I, acute adrenalectomy and ganglionic blockade, demonstrated the beta-adrenergic effect of increased cardiac output and decreased systemic resistance but essentially no alphaadrenergic effect. This implies the alphaadrenergic effect is lacking because of neurogenic blockade or absent adrenal secretions. Group II, adrenalectomy only, demonstrated that both the alpha- and beta-adrenergic effect occurred during elevated CSF pressure and indicated the alphaadrenergic stimulation is dependent on an intact sympathetic nervous system but is independent of the adrenal. The beta-adrenergic effect seems independent of both an intact sympathetic nervous system and the adrenals. Since the alphaadrenergic effect of increased aortic pressure was absent in Group I (adrenalectomy and ganglionic blockade) and present in Group II (adrenalectomy), it is probably neurogenically mediated. Group I (studied acutely after adrenalectomy) is not comparable to Group II (studied 17 + 2 days after adrenalectomy), but Group I did demonstrate a beta-adrenergic response of increased
American Heart Journal
cardiac output and decreased peripheral resistance similar to that in animals previously studied with intact adrenals, ganglionic blockade, and alpha-adrenergic blockade.” Therefore, the Cushing reflex consists of a dual mechanism for the alpha-adrenergic component. First, the adrenals are necessary to provide a vasoconstrictor agonist that affects denervated skeletal musculature (Group III A). Secondly, a neurogenically mediated component is present since the alpha-adrenergic effect of increased systemic blood pressure will occur in the adrenalectomized animal with intact sympathetic nervous system (Group II) but will not occur in the adrenalectomized animals with ganglionic blockade (Group I). Also, in the adrenalectomized dog, the innervated muscle (Group III C) responded dramatically to elevated CSF pressure with no response in the denervated preparation (Group III B). The expected beta-adrenergic effect”. 9 of elevated cerebrospinal fluid pressure, increased cardiac output or decreased systemic vascular resistance, seems independent of the adrenals and the sympathetic nervous system because it is detectable in adrenalectomized dogs, with or without ganglionic blockade (Groups I and II). Preliminary studies demonstrated responsiveness of the denervated gracilis muscle preparation to isoproterenol. Since gracilis muscle resistance did not change with elevated CSF pressure in animals with intact adrenals and alpha-adrenergic blockade (Group IV), it is assumed no significant circulating vasodilator (beta-adrenergic effect) of the denervated skeletal muscle vasculature is present. However, total systemic vascular resistance decreased in Group I (adrenalectomy and ganglionic blockade) and also in animals previously studied with intact adrenals, with and without ganglionic blockade, and alpha-adrenergic blockade.g This probably reflects dilation of vascular beds other than skeletal muscle. With alpha-adrenergic blockade, the beta-adrenergic effect may only represent withdrawal of peripheral alpha-adrenergic vasoconstrictor tone. However, a beta-adrenergic effect occurred in Group I during ganglionic blockade in the absence of specific alpha-adrenergic blockade. The specific origin of a circulating betaadrenergic agonist is open to speculation. It is probably not neuronally released since Glick and co-workersZ7 have shown that neuronally released
57
Brashear
and
Yu
norepinephrine does not have access to betaadrenergic receptors in contrast to injected norepinephrine. Although the reuptake of neuronally released norepinephrine may be inhibited by phenoxybenzamine,‘” it is doubtful this permits access of neuronally released norepinephrine to beta-adrenergic receptors. It is also possible some autonomic pathways are invulnerable to ganglionic blockade. An adrenal source seems excluded by the present study but brain amine+‘- “i or nonadrenal chromaffin tissue might be a consideration. A dopaminergic response is an unlikely explanation for the Cushing response since alpha- and beta-adrenergic antagonists are relatively ineffective in blocking this response.“’ Parasympathetic activity is reasonably excluded since gallamine triethiodide has significant vagolytic effects.:“‘. .‘I Intravenous propranolol in dogs, 0.2 to 0.25 mg./ Kg. effectively blocks changes induced by isoproterenol. id. .{.IHowever, in addition to beta-receptor blocking properties, propranolol has nonspecific effects that would be similar in Group III A, B, and C..“. :i,
The presence of a nonadrenal circulating beta agonist that increases cardiac output and decreases peripheral vascular resistance is indicated by these studies. Also, the Cushing reflex involves an adrenal alpha-adrenergic component affecting skeletal muscle resistance and another alpha-adrenergic component dependent on an intact sympathetic nervous system. REFERENCES
1.
2.
3.
4.
5.
6.
Cushing, H.: Concerning a definite regulatory mechanism of the vasomotor center which controls blood pressure during cerebral compression, Johns Hopkins Hosp. Bull. 12:290, 1901. Ducker, T. B., and Simmons, R. L.: Increased intracranial pressure and pulmonary edema, J. Neurosurg. 28:118, 1968. Gonzalez, N. C., and Overman, J.: Cardiopulmonary responses to uniformly elevated CSF pressure, J. Trauma 13:727, 1973. Richardson, T. Q.. Fermoso, d. D., and Pugh, G. 0.: Effect of acutely elevated intracranial pressure on cardiac output and other circulatory factors, J. Surg. Res. 5:318, 1965. Troupp, H., and Vapalahti, M.: Intraventricular pressure in the final stages of a severe brain injury, Acta Neurochir. 25:189, 1971. Nornes, H., and Magnes, B.: Intracranial pressure in patients with ruptured saccular aneurysm, J. Neurosurg. 36:537,
Summary
The cardiovascular effects of elevated cerebrospinal fluid (CSF) pressure were studied in adrenalectomized dogs with and without ganglionic blockade. A significant increase in vascular pressures and cardiac output, occurred in those without ganglionic blockade but was absent or markedly blunted in those with ganglionic blockade. This indicated that an intact sympathetic nervous system was required for the pressor response to elevated cerebrospinal fluid pressure but the adrenals were not required. A betaadrenergic effect was noted in dogs with ganglionic blockade and adrenalectomy. The effects of elevated CSF pressure were also studied using a perfused gracilis muscle preparation in 12 animals with beta-adrenergic blockade, with and without adrenalectomy. Animals with intact adrenals and denervated gracilis muscle showed an increase in aortic pressure and gracilis muscle resistance. Adrenalectomized animals with innervated gracilis muscle demonstrated an increase in aortic pressure and gracilis muscle resistance. Elevated CSF pressure with intact adrenals and alpha-adrenergic blockade demonstrated a decrease in aortic pressure but no change in gracilis muscle resistance.
58
7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
1972.
Brashear, R. E., and Pamintuan, R. L.: Increased pulmonary diffusing capacity and elevated cerebrospinal fluid pressure, d. Appl. Physiol. 30:844, 1971. Brashear, R. E., and Ross, J. C.: Hemodynamic effects of elevated cerebrospinal fluid pressure: Alterations with adrenergic blockade, J. Clin Invest. 49:1324, 1970. Brashear, R. E., and Ross, J. C.: Circulating beta adrenergic stimulator during elevated cerebrospinal fluid pressure. Arch. Intern. Med. 127:748, 1971. Ballard, D. R., Abboud, F. M., and Mayer, H. E.: Release of a humoral vasodilator substance during neurogenic vasodilatation, Am. d. Physiol. 219:14X, 1970. Heitz, D. C., and Brody, M. J.: Possible mechanism of histamine release during active vasodilatation, Am. J. Physiol. 228:13X, 1975. Winer, B. J.: Statistical principles of experimental design, New York, 1962, McGraw-Hill Book Company, p. 89. Rodbard, S., Reyes, M., Mininni, G., et al.: Neurohumoral transmission of the pressor response to intracranial compression, Am. J. Physiol. 176:341, 1954. Guyton, A. C.: Acute hypertension in dogs with cerebral ischemia, Am. J. Physiol. 154:45, 1948. Brown, F. K.: Cardiovascular effects of acutely raised intracranial pressure, Am. J. Physiol. 185:510, 1956. Rodbard, S., and Stone, W.: Pressore mechanisms induced by intracranial compression, Circulation 12:883, 1955.
17.
18.
Ducker, T. B., Simmons, R. L., and Anderson, R. W.: Increased intracranial pressure and pulmonary edema III. The effect of increased intracranial pressure on the cardiovascular hemodynamics of chimpanzees, J. Neurosurg. 29:475, 1968. Berman, I. R., and Ducker, T. B.: Pulmonary, somatic, and splanchnic circulatory responses to increased intracranial pressure, Ann. Surg. 169:210, 1969.
January,
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95, No.
1
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19.
20.
21. 22. 23.
24.
25.
26.
27.
Chen, H. I., Sun, S. C., and Chai, C. Y.: Pulmonary edema and hemorrhage resulting from cerebral compression, Am. J. Physiol. 224:223, 1973. Doba, N., and Reis, D. J.: Localization within the lower brainstem of a receptive area mediating the pressor response to increased intracranial pressure (the Cushing response), Brain Res. 47:487, 1972. Chalmers, J. P.: Brain amines and models of experimental hypertension, Circ. Res. 36:469, 1975. Neely, W. A., and Youmans, J. R.: Anoxia of canine brain without damage, J.A.M.A. 183: 1085, 1963. Zimmer, R., Lang, R., and Oberdorster, G.: Post-ischemic reactive hyperemia of the isolated perfused brain of the dog, Pflugers Arch. 328:332, 1971. Ramwell, P. W., and Shaw, J. E.: Spontaneous and evoked release of prostaglandins from cerebral cortex of anesthetized cats, Am. J. Physiol. 211:125, 1966. Vogt, M.: Release from brain tissue of compounds with possible transmitter function: Interaction of drugs with these substances, Br. J. Pharmacol. 37:325, 1969. Doba, N., and Reis, D. J.: Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat, Circ. Res. 32:584, 1973. Glick, G., Epstein, S. E., Wechsler, A. S., et al: Physiological differences between the effects of neuronally released and blood-borne norepinephrine on beta
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28.
29. 30.
31.
32.
33.
34.
to elevated
CSF pressure
adrenergic receptors in the arterial bed of the dog, Circ. Res. 21:217, 1967. Boerth, R. C., Ryan, M. J., and Brody, M. J.: Pharmacologic blockade of reflex vasodilatation: Effects on postulated neurohumoral mechanisms, J. Pharmacol. Exp. Ther. 172:52, 1970. Lefkowitz, R. J.: Beta-adrenergic receptors: recognition and regulation, N. Engl. J. Med. 295:323, 1976. Hughes, R.: Haemodynamic effects of tubocurarine, gallamine and suxamethonium in dogs, Br. J. Anaesth. 42:928, 1970. Rathbun, F. J., and Hamilton, J. T.: Effect of gallamine on cholinergic receptors, Can. Anaes. Sot. J. 17:574, 1970. Bergamaschi, M., Shanks, R. G., Caravaggi, A. M., et al: A comparison of the cardiovascular actions of four adrenergic P-receptor blocking agents in resting conscious dogs, AM. HEART J. 82:338, 1971. Nakano, J., and Kusakari, T.: Effect of beta adrenergic on the cardiovascular dynamics, Am. J. Physiol. 210:833, 1966. Barrett, A. M.: A comparison of the effects of (+ )propranolol and ( + )-propranolol in anaesthetized dogs; P-receptor blocking and haemodynamic action, J. Pharm. Pharmacol.-21:241, 1969.
59
of the hem.odynamic response cerebrospinal fluid pressure
Richard E. Brashear, Pao-lo Yu, Ph.D. Indianapolis,
M.D.
Ind.
Elevation of cerebrospinal fluid (CSF) pressure to levels usually exceeding mean systemic blood pressure is followed by what is frequently called the Cushing reflex.’ The increased vascular pressures and cardiac output occurring with the reflex have been well described.*-’ Since intracranial pressures may increase to over 100 mm. Hg with severe brain injury5 and intracranial pressures up to 160 mm. Hg have been described in patients with subarachnoid hemorrhage,6 significant elevations of intracranial pressure have clinical importance. We have previously demonstrated that increasing CSF pressure to 200 mm. Hg significantly increased cardiac output, heart rate, stroke volume, aortic pressure, pulmonary artery pressure, wedge pressure, right atria1 pressure, pulmonary capillary blood volume, and pulmonary diffusing capacity.‘. 8 These changes were attributed to a massive alpha- and beta-adrenergic stimulation. Beta-adrenergic blockade prevented an increase in cardiac output and heart rate but did not alter the response of increased vascular pressures to elevated CSF pressure. Alpha-adrenergic blockade prevented an increase in vascular pressures during elevated CSF pressure but did not prevent the increase in cardiac output. Two distinct adrenergic components were thus identified but it was unclear if the components were humorally or neurogenically mediated. A subsequent study provided evidence for a circulating beta adrenergic agonist during elevated ,CSF pressure.9 The From Center,
the Department Indianapolis,
of
Medicine,
Received
for publication
Dec. 8, 1976.
Accepted
for publication
Feb. 10, 1977.
Reprint requests: Richard cine, Indiana University Indianapolis, IN 46202.
52
Indiana
University
Medical
Ind.
E. Brashear, M.D., Department of MediMedical Center, 1100 West Michigan St.,
present study was undertaken to clarify the origin of these alpha- and beta-adrenergic effects during elevated cerebrospinal fluid pressure. Methods
Mongrel dogs (21 -+-3 kilograms, mean k SD) were anesthetized with pentobarbital, 30 mg./Kg. intravenously. Ventilation with periodic hyperinflation was controlled through a cuffed endotracheal tube with a Harvard constant volume ventilator, end-tidal CO, was monitored and maintained between 5.0 to 5.5 per cent, and the animals were paralyzed with intravenous gallamine triethiodide, 2.0 mg. /Kg. For clarification, the various subgroups studied with elevated CSF pressure are outlined as follows: Group I. An initial six dogs studied acutely after bilateral adrenalectomy and ganglionic blockade with hexamethonium. Group II. Six dogs studied 17 + 2 days after adrenalectomy. Group III. Twelve dogs studied with an isolated and perfused gracilis muscle preparation and beta adrenergic blockade. Group III A. Four studied with intact adrenals with the muscle preparation denervated. Group III B. Four studied 18 ? 1 days after adrenalectomy with the muscle preparation denerva ted. Group III C. Four studied 18 ? 2 days after adrenalectomy with muscle preparation innervated. Group IV. Six dogs with an isolated, perfused, and denervated gracilis muscle preparation, alpha-adrenergic blockade, and intact adrenals. Groups I and II were studied as previously described.x. y Cardiac catheters were placed in the main pulmonary artery, right atrium, and wedge
January,
1978, Vol. 95, No. 1, pp. 52-59
Response
position through the jugular veins and in the ascending aorta just distal to the aortic valve through the carotid artery. Pressures were measured at end expiration and heart rate was determined from the pressure tracing. Cardiac outputs were done in duplicate by the indicator-dilution technique and expressed as milliliters per minute per kilogram of body weight and stroke volume as milliliters per beat per kilogram. Central blood volume was determined from the main pulmonary artery to ascending aorta. Mean pressures were used to calculate vascular resistance. Systemic vascular resistance (units) = systemic artery pressure - right atria1 pressure (mm. Hg)/cardiac output (ml./min. per kilogram). Pulmonary vascular resistance (units) = pulmonary artery pressure - wedge pressure (mm. Hg)/cardiac output (ml./min. per kilogram). Arterial blood pH, Po2, and Pco, were determined by conventional electrodes (Instrumentation Laboratory, Inc.). Cerebrospinal fluid pressure was elevated as previously described using a pressure reservoir of saline (37’ C.), buffered with NaHCO,J to pH 7.4, connected to a needle in the cisterna magna.7-9 After control period values were obtained, the CSF pressure was increased to 100 mm. Hg and measurements were obtained after 5 and 10 minutes. The CSF pressure was then increased to 200 mm. Hg, the determinations repeated after 5 and 10 minutes, and the CSF pressure was returned to control period levels. The previously mentioned determinations were repeated 10 minutes after CSF pressure was returned to control values. In Group I, the animals were studied immediately after bilateral adrenalectomy and ganglionic blockade obtained with intravenous hexamethonium chloride, 5 mg. of base per kilogram in a concentration of 25 mg./ml., infused over 5 minutes. Completeness of ganglionic blockade was determined by observing mean systemic blood pressure during 30 seconds of bilateral common carotid artery occlusion. Hydrocortisone sodium succinate was given, 50 mg. intramuscularly at onset of adrenalectomy and 100 mg. intravenously during the remainder of the study. Performing the elevated CSF pressure study immediately after adrenalectomy resulted in protracted experiment of 4 to 5 hours. Subsequently, in Groups II and III, bilateral adrenalectomy was performed through a midline
American
Heart
Journal
to elevated
CSF pressure
incision with sterile technique, meticulous di’ssection, and hemostasis. Dogs were maintained after adrenalectomy with 12.5 mg. cortisone acetate and 1 mg. desoxycorticosterone acetate intramuscularly each day. On the day when the dogs were subsequently studied with elevated CSF pressure, 14 to 19 days post-adrenalectomy, they received a 25 mg. intravenous bolus of hydrocortisone sodium succinate and an additional 25 mg. in 50 ml. of saline infused during the remaining study. The amount of steroid was considered to reasonably approximate the amount that would be elaborated during severe stress by an animal with intact adrenals. The isolated perfused gracilis muscle was prepared in the dog as previously described.“‘. ” Briefly, the gracilis muscle was completely exposed and isolated except for minimal lateral and medial tendinous connections and the gracilis artery and vein. The obturator nerve was sectioned in the denervated muscle preparations. Heparin, 5 mg./Kg., was given intravenously and a polyethylene catheter (PE 90) was inserted in the gracilis artery and connected to a constant volume flow rate pump (Holter Pump, Model 911). The contralateral femoral artery was cannulated for inflow to the pump and flow rate (11.5 & 2.8 ml. per minute, mean + SD) was adjusted so gracilis perfusion pressure approximated systemic blood pressure. Pressure was monitored in the tubing between the femoral artery and perfusion pump permitting the inflow pressure to the pump to be kept constant at control levels, regardless of increases in femoral artery pressure, by using a screw resistor. After stabilization of the muscle perfusion pressure, the propranolol or phenoxybenzamine were infused. The 12 dogs (Group III) with beta-adrenergic blockade and the isolated perfused gracilis muscle preparation received propranolol, 0.5 mg./Kg. in 30 ml. saline over 5 minutes prior to obtaining control values and an additional 0.25 mg./Kg. in 30 ml. over the remainder of the study. Four were studied with intact adrenals and denervated muscle preparation (Group III A). Four were studied after adrenalectomy with denervated muscle preparation (Group III B). Four were studied after adrenalectomy with the muscle preparation innervated (Group III C). At the conclusion of the study, the completeness of beta blockade was demonstrated with intravenous isoproterenol (0.01 mg. in 20 ml. saline over 2
53
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k& 100
fouIll 100
--OMIN a00 mm
10 Mm 200
10 Mm POST
1. per
blockade;
minutes) demonstrating no change in heart rate, systemic blood pressure, or gracilis muscle resistance. The six alpha-adrenergic blockade animals (Group IV), all with intact adrenals and an isolated, denervated, and perfused gracilis muscle preparation, received phenoxybenzamine hydrochloride (courtesy Smith, Kline, and French Co., Philadelphia ), 3 mg. /Kg. in 25 ml. saline over 60 minutes prior to obtaining values and an additional 1 mg./Kg. in 25 ml. over the remainder of the study. At the conclusion, the completeness of alpha blockade was demonstrated with norepinephrine base, 0.01 mg. in 20 ml. saline intravenously over 2 minutes, demonstrating no change in heart rate, systemic blood pressure, or gracilis muscle resistance.
54
lO?dm 100
Hg
cent change from control during elevated Group II-adrenalectomy. Abscissa indicates minutes post indicates time after CSF pressure returned P < 0.05 level. Fig.
u--u5MlN ml
5buN zoo mln
10 Mm am3
10 MIN POST
Kg
CSF pressure. Group I-adrenalectomy and ganglionic duration and magnitude of elevated CSF pressure, 10 to control values. Asterisk indicates change significant at
The significance of the change from the control period to each of the subsequent periods was determined by Dunnett’s t test at the 5 per cent level.‘2 Results
The results are presented in Figs. 1 and 2. In Group I animals, studied acutely after adrenalectomy and ganglionic blockade, control aortic pressure (92 t 8 mm. Hg, mean + SD) only changed 10 minutes after CSF pressure was returned to control values. Control cardiac output (123 & 15, ml./min. per kilogram) increased significantly (P < 0.05) at 5 minutes of 200 mm. Hg CSF pressure and 10 minutes after CSF pressure returned to control levels. Control systemic vascular resistance (0.759 + 0.097 units/
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1978, Vol. 95, No. 1
Response to elevated CSF pressure
GROUP GROUP
Ill A III B
GROUP GROUP
RI C IV
----II 5lmN 100
10 Mm 100
5mN 200 mm
10 Mm 200
10 Mm POST
Hg
Fig. 2. Per cent change from control in gracilis muscle study. Group III-beta-adrenergic blockade; A-intact adrenals, denervated muscle; B-adrenalectomy, denervated muscle; C-adrenalectomy, innervated muscle. Group IV-alpha-adrenergic blockade, intact adrenals, denervated muscle. Abscissa and asterisk same as in Fig. 1.
kilogram) decreased significantly at 10 minutes 100 mm. Hg and 5 minutes and 10 minutes of 200 mm. Hg CSF pressure. Control right atria1 (-1 f 1 mm. Hg) and wedge (1 & 3 mm. Hg) pressures showed essentially no change but control pulmonary artery pressure (13 f 2 mm. Hg) increased slightly but significantly during 5 minutes 200 mm. Hg CSF pressure and 10 minutes after release of CSF pressure. Control heart rate (111 + 8 beats/minute) increased significantly 10 minutes after release of CSF pressure. There were no significant changes compared to the control period for any parameter after 5 or 10 minutes of CSF pressure 100 mm. Hg in Group II. In Group II, control aortic pressure (126 + 5 mm. Hg), pulmonary artery pressure (11 1 3 mm. Hg), wedge pressure (3 +- 4 mm. Hg), cardiac output (177 f 41 ml./min. per kilogram), stroke volume (0.99 + 0.17 ml./beat per kilogram), and central blood volume fl5.2 +- 2.2 ml/Kg.) increased significantly (P < 0.05) at 5 and 10 minutes of CSF pressure 200 mm. Hg. Group II also demon-
American Heart Journal
strated a significant decrease from control systemic vascular resistance (0.758 ? 0.183 units/ Kg.) at 10 minutes of 200 mm. Hg and after release of CSF pressure. Group II demonstrated no significant changes in pulmonary vascular resistance or heart rate while a change in right atria1 pressure was significant but small. In Group II, the animals were weighed daily after the adrenalectomy and the weight decreased 1 + 1 kilogram prior to the elevated CSF pressure study. Serum electrolytes were determined on the day of the CSF study and were sodium 144 f 1, potassium 4.4 + 0.3, and chloride 108 +- 4 mEq./L. There were no changes during CSF pressure 100 mm. Hg in the beta-adrenergic blockade dogs (Fig. 2) with the perfused gracilis muscle preparations (Group III). In the animals with intact adrenals and denervated muscle (Group III A), the control aortic pressure (131 + 5 mm. Hg) increased significantly during 5 and 10 minutes of CSF pressure 200 mm. Hg. The resistance of the perfused gracilis muscle increased significantly
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from the control period during 5 and 10 minutes of CSF pressure 200 mm. Hg, respectively. In these animals with intact adrenals, it is of particular interest that 21 it 17 seconds (mean t SD) were required for mean aortic pressure to increase to 200 mm. Hg after CSF pressure was increased to 200 mm. Hg. In contrast, 48 t 11 seconds elapsed before any detectable increase from control was noted in the denervated gracilis muscle perfusion pressure and 4.6 -t 3.6 minutes elapsed before the gracilis muscle perfusion pressure reached a maximum. In the animals with beta-adrenergic blockade, denervated gracilis muscle preparation, and adrenalectomy (Group III B), control aortic pressure (131 + 4 mm. Hg) increased significantly during 5 minutes CSF pressure 200 mm. Hg. There was no significant change in the resistance of the denervated gracilis muscle. In Group III C (beta-adrenergic blockade, adrenalectomy, innervated gracilis muscle), control aortic pressure (125 + 19 mm. Hg) increased significantly during 5 minutes CSF pressure 200 mm. Hg. Gracilis muscle resistance increased significantly during 5 and 10 minutes CSF pressure 200 mm. Hg. The aortic pressure and gracilis muscle resistance began to increase about the same time (18 to 30 seconds) after CSF pressure was increased to 200 mm. Hg. Aortic pressure usually reached a maximal value in 14 to 64 seconds whereas the gracilis muscle resistance showed a progressive increase over 3 to 4.5 minutes up to 10 minutes. Group IV, alpha-adrenergic blockade and intact adrenals, aortic pressure demonstrated a significant decrease during 5 and 10 minutes of CSF pressure 200 mm. Hg from 105 -+ 13 mm. Hg in the control period. There was no change in resistance of the gracilis muscle. Arterial blood for all dogs in the control period demonstrated pH 7.39 + 0.03, PaCO, 40 + 3 mm. Hg, and PaO, 87 + 7 mm. Hg. At the conclusion of 10 minutes CSF pressure 200 mm. Hg, arterial blood showed pH 7.33 +- 0.04, PaCO, 41 * 5 mm. Hg, and PaO, 83 t 8 mm. Hg. Discussion
Cushing, in 1901,’ demonstrated a pressor response to elevated intracranial pressure. Subsequent investigators considered several mechanisms including a humoral vasopressor in the chick,“‘ cerebral ischemia,‘, 14venoconstriction,‘”
56
neurohumoral stimulation with a phasic response of systemic blood pressure in dogs and rabbits,‘” myocardial inotropic response,” and shunting.‘” Mechanical compression of the rat brain produces a pressor response not altered by adrenalectomy or bilateral cervical vagotomy.“’ A receptive area in the lower brainstem possibly mediates the Cushing response.“’ In 1970, the Cushing response (reflex) was clearly separated into alpha- and beta-adrenergic components.i: This study was initiated to determine the etiology of these alpha and beta effects. The animals with the denervated and perfused gracilis muscle preparation, beta-adrenergic blockade, and intact adrenals (Group III A) demonstrated an increase in resistance of the gracilis muscle preparation indicating a circulating vasoconstrictor of skeletal muscle. The aortic pressure also increased significantly and could be caused by either a humoral agonist or neurogenic stimulation. The significant time lag between aortic pressure elevation and elevation of the gracilis muscle perfusion pressure is indicative of a circulating vasoconstrictor that is delayed by the external pump that perfuses the gracilis muscle preparation. In contrast, the animals with the denervated, perfused gracilis muscle preparation, betaadrenergic blockade, and no adrenals (Group III B) demonstrated an increased aortic pressure but no change in gracilis muscle perfusion pressure or resistance. Therefore, the adrenals appear to be the source of the alpha-adrenergic agonist affecting the denervated gracilis muscle since any increase in resistance of the gracilis muscle is absent in the adrenalectomized dog with betaadrenergic blockade. The increase in aortic pressure in both Group III A and B is probably neurogenic and nonadrenal in origin. The neurogenic component of the Cushing reflex is demonstrated in Group III C (no adrenals, beta-adrenergic blockade, and innervated gracilis muscle). In contrast to the lack of change in the denervated gracilis muscle resistance in Group III B, Group III C demonstrated a marked increase in gracilis muscle resistance. Group I, animals with ganglionic blockade studied acutely after adrenalectomy, demonstrated changes similar to those previously reported in animals with intact adrenals, ganglionic blockade, and alpha-adrenergic block-
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1978, Vol. 95, No. 1
Response to elevated CSF pressure
ade.9 There was no increase in aortic pressure during elevated CSF pressure but cardiac output increased and systemic vascular resistance decreased indicating the’ presence of a circulating beta-adrenergic agonist independent of the adrenals. The previous study also indicated a circulating beta-adrenergic agonist but the adrenals were intact.” The decrease in control blood pressure was consistent with the lowering of blood pressure found in rats and rabbits with combined chemical sympathectomy and adrenalectomy.21 A marked increase in cardiac output and aortic pressure occurred 10 minutes after CSF pressure was returned to control levels, this was noted previously9 in dogs with systemic hypotension during the increased CSF pressure. Dogs can survive 25 minutes of cerebral ischemiaZ2 and a marked reactive hyperemia occurs with reperfusion of the brain2” that may wash out vasoactive substances.2’. 25 Group II (adrenalectomized animals) demonstrated the expected8 alpha- and beta-adrenergic effects (increase in vascular pressures, cardiac output, stroke volume) during CSF pressure of 200 mm. Hg and, therefore, excluded the adrenals as the only participant in the Cushing reflex. Other investigators have noted that adrenalectomy in rats does not blunt the rise in blood pressure evoked by brainstem lesions.26 Group I, acute adrenalectomy and ganglionic blockade, demonstrated the beta-adrenergic effect of increased cardiac output and decreased systemic resistance but essentially no alphaadrenergic effect. This implies the alphaadrenergic effect is lacking because of neurogenic blockade or absent adrenal secretions. Group II, adrenalectomy only, demonstrated that both the alpha- and beta-adrenergic effect occurred during elevated CSF pressure and indicated the alphaadrenergic stimulation is dependent on an intact sympathetic nervous system but is independent of the adrenal. The beta-adrenergic effect seems independent of both an intact sympathetic nervous system and the adrenals. Since the alphaadrenergic effect of increased aortic pressure was absent in Group I (adrenalectomy and ganglionic blockade) and present in Group II (adrenalectomy), it is probably neurogenically mediated. Group I (studied acutely after adrenalectomy) is not comparable to Group II (studied 17 + 2 days after adrenalectomy), but Group I did demonstrate a beta-adrenergic response of increased
American Heart Journal
cardiac output and decreased peripheral resistance similar to that in animals previously studied with intact adrenals, ganglionic blockade, and alpha-adrenergic blockade.” Therefore, the Cushing reflex consists of a dual mechanism for the alpha-adrenergic component. First, the adrenals are necessary to provide a vasoconstrictor agonist that affects denervated skeletal musculature (Group III A). Secondly, a neurogenically mediated component is present since the alpha-adrenergic effect of increased systemic blood pressure will occur in the adrenalectomized animal with intact sympathetic nervous system (Group II) but will not occur in the adrenalectomized animals with ganglionic blockade (Group I). Also, in the adrenalectomized dog, the innervated muscle (Group III C) responded dramatically to elevated CSF pressure with no response in the denervated preparation (Group III B). The expected beta-adrenergic effect”. 9 of elevated cerebrospinal fluid pressure, increased cardiac output or decreased systemic vascular resistance, seems independent of the adrenals and the sympathetic nervous system because it is detectable in adrenalectomized dogs, with or without ganglionic blockade (Groups I and II). Preliminary studies demonstrated responsiveness of the denervated gracilis muscle preparation to isoproterenol. Since gracilis muscle resistance did not change with elevated CSF pressure in animals with intact adrenals and alpha-adrenergic blockade (Group IV), it is assumed no significant circulating vasodilator (beta-adrenergic effect) of the denervated skeletal muscle vasculature is present. However, total systemic vascular resistance decreased in Group I (adrenalectomy and ganglionic blockade) and also in animals previously studied with intact adrenals, with and without ganglionic blockade, and alpha-adrenergic blockade.g This probably reflects dilation of vascular beds other than skeletal muscle. With alpha-adrenergic blockade, the beta-adrenergic effect may only represent withdrawal of peripheral alpha-adrenergic vasoconstrictor tone. However, a beta-adrenergic effect occurred in Group I during ganglionic blockade in the absence of specific alpha-adrenergic blockade. The specific origin of a circulating betaadrenergic agonist is open to speculation. It is probably not neuronally released since Glick and co-workersZ7 have shown that neuronally released
57
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norepinephrine does not have access to betaadrenergic receptors in contrast to injected norepinephrine. Although the reuptake of neuronally released norepinephrine may be inhibited by phenoxybenzamine,‘” it is doubtful this permits access of neuronally released norepinephrine to beta-adrenergic receptors. It is also possible some autonomic pathways are invulnerable to ganglionic blockade. An adrenal source seems excluded by the present study but brain amine+‘- “i or nonadrenal chromaffin tissue might be a consideration. A dopaminergic response is an unlikely explanation for the Cushing response since alpha- and beta-adrenergic antagonists are relatively ineffective in blocking this response.“’ Parasympathetic activity is reasonably excluded since gallamine triethiodide has significant vagolytic effects.:“‘. .‘I Intravenous propranolol in dogs, 0.2 to 0.25 mg./ Kg. effectively blocks changes induced by isoproterenol. id. .{.IHowever, in addition to beta-receptor blocking properties, propranolol has nonspecific effects that would be similar in Group III A, B, and C..“. :i,
The presence of a nonadrenal circulating beta agonist that increases cardiac output and decreases peripheral vascular resistance is indicated by these studies. Also, the Cushing reflex involves an adrenal alpha-adrenergic component affecting skeletal muscle resistance and another alpha-adrenergic component dependent on an intact sympathetic nervous system. REFERENCES
1.
2.
3.
4.
5.
6.
Cushing, H.: Concerning a definite regulatory mechanism of the vasomotor center which controls blood pressure during cerebral compression, Johns Hopkins Hosp. Bull. 12:290, 1901. Ducker, T. B., and Simmons, R. L.: Increased intracranial pressure and pulmonary edema, J. Neurosurg. 28:118, 1968. Gonzalez, N. C., and Overman, J.: Cardiopulmonary responses to uniformly elevated CSF pressure, J. Trauma 13:727, 1973. Richardson, T. Q.. Fermoso, d. D., and Pugh, G. 0.: Effect of acutely elevated intracranial pressure on cardiac output and other circulatory factors, J. Surg. Res. 5:318, 1965. Troupp, H., and Vapalahti, M.: Intraventricular pressure in the final stages of a severe brain injury, Acta Neurochir. 25:189, 1971. Nornes, H., and Magnes, B.: Intracranial pressure in patients with ruptured saccular aneurysm, J. Neurosurg. 36:537,
Summary
The cardiovascular effects of elevated cerebrospinal fluid (CSF) pressure were studied in adrenalectomized dogs with and without ganglionic blockade. A significant increase in vascular pressures and cardiac output, occurred in those without ganglionic blockade but was absent or markedly blunted in those with ganglionic blockade. This indicated that an intact sympathetic nervous system was required for the pressor response to elevated cerebrospinal fluid pressure but the adrenals were not required. A betaadrenergic effect was noted in dogs with ganglionic blockade and adrenalectomy. The effects of elevated CSF pressure were also studied using a perfused gracilis muscle preparation in 12 animals with beta-adrenergic blockade, with and without adrenalectomy. Animals with intact adrenals and denervated gracilis muscle showed an increase in aortic pressure and gracilis muscle resistance. Adrenalectomized animals with innervated gracilis muscle demonstrated an increase in aortic pressure and gracilis muscle resistance. Elevated CSF pressure with intact adrenals and alpha-adrenergic blockade demonstrated a decrease in aortic pressure but no change in gracilis muscle resistance.
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7.
8.
9.
10.
11.
12.
13.
14.
15. 16.
1972.
Brashear, R. E., and Pamintuan, R. L.: Increased pulmonary diffusing capacity and elevated cerebrospinal fluid pressure, d. Appl. Physiol. 30:844, 1971. Brashear, R. E., and Ross, J. C.: Hemodynamic effects of elevated cerebrospinal fluid pressure: Alterations with adrenergic blockade, J. Clin Invest. 49:1324, 1970. Brashear, R. E., and Ross, J. C.: Circulating beta adrenergic stimulator during elevated cerebrospinal fluid pressure. Arch. Intern. Med. 127:748, 1971. Ballard, D. R., Abboud, F. M., and Mayer, H. E.: Release of a humoral vasodilator substance during neurogenic vasodilatation, Am. d. Physiol. 219:14X, 1970. Heitz, D. C., and Brody, M. J.: Possible mechanism of histamine release during active vasodilatation, Am. J. Physiol. 228:13X, 1975. Winer, B. J.: Statistical principles of experimental design, New York, 1962, McGraw-Hill Book Company, p. 89. Rodbard, S., Reyes, M., Mininni, G., et al.: Neurohumoral transmission of the pressor response to intracranial compression, Am. J. Physiol. 176:341, 1954. Guyton, A. C.: Acute hypertension in dogs with cerebral ischemia, Am. J. Physiol. 154:45, 1948. Brown, F. K.: Cardiovascular effects of acutely raised intracranial pressure, Am. J. Physiol. 185:510, 1956. Rodbard, S., and Stone, W.: Pressore mechanisms induced by intracranial compression, Circulation 12:883, 1955.
17.
18.
Ducker, T. B., Simmons, R. L., and Anderson, R. W.: Increased intracranial pressure and pulmonary edema III. The effect of increased intracranial pressure on the cardiovascular hemodynamics of chimpanzees, J. Neurosurg. 29:475, 1968. Berman, I. R., and Ducker, T. B.: Pulmonary, somatic, and splanchnic circulatory responses to increased intracranial pressure, Ann. Surg. 169:210, 1969.
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19.
20.
21. 22. 23.
24.
25.
26.
27.
Chen, H. I., Sun, S. C., and Chai, C. Y.: Pulmonary edema and hemorrhage resulting from cerebral compression, Am. J. Physiol. 224:223, 1973. Doba, N., and Reis, D. J.: Localization within the lower brainstem of a receptive area mediating the pressor response to increased intracranial pressure (the Cushing response), Brain Res. 47:487, 1972. Chalmers, J. P.: Brain amines and models of experimental hypertension, Circ. Res. 36:469, 1975. Neely, W. A., and Youmans, J. R.: Anoxia of canine brain without damage, J.A.M.A. 183: 1085, 1963. Zimmer, R., Lang, R., and Oberdorster, G.: Post-ischemic reactive hyperemia of the isolated perfused brain of the dog, Pflugers Arch. 328:332, 1971. Ramwell, P. W., and Shaw, J. E.: Spontaneous and evoked release of prostaglandins from cerebral cortex of anesthetized cats, Am. J. Physiol. 211:125, 1966. Vogt, M.: Release from brain tissue of compounds with possible transmitter function: Interaction of drugs with these substances, Br. J. Pharmacol. 37:325, 1969. Doba, N., and Reis, D. J.: Acute fulminating neurogenic hypertension produced by brainstem lesions in the rat, Circ. Res. 32:584, 1973. Glick, G., Epstein, S. E., Wechsler, A. S., et al: Physiological differences between the effects of neuronally released and blood-borne norepinephrine on beta
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28.
29. 30.
31.
32.
33.
34.
to elevated
CSF pressure
adrenergic receptors in the arterial bed of the dog, Circ. Res. 21:217, 1967. Boerth, R. C., Ryan, M. J., and Brody, M. J.: Pharmacologic blockade of reflex vasodilatation: Effects on postulated neurohumoral mechanisms, J. Pharmacol. Exp. Ther. 172:52, 1970. Lefkowitz, R. J.: Beta-adrenergic receptors: recognition and regulation, N. Engl. J. Med. 295:323, 1976. Hughes, R.: Haemodynamic effects of tubocurarine, gallamine and suxamethonium in dogs, Br. J. Anaesth. 42:928, 1970. Rathbun, F. J., and Hamilton, J. T.: Effect of gallamine on cholinergic receptors, Can. Anaes. Sot. J. 17:574, 1970. Bergamaschi, M., Shanks, R. G., Caravaggi, A. M., et al: A comparison of the cardiovascular actions of four adrenergic P-receptor blocking agents in resting conscious dogs, AM. HEART J. 82:338, 1971. Nakano, J., and Kusakari, T.: Effect of beta adrenergic on the cardiovascular dynamics, Am. J. Physiol. 210:833, 1966. Barrett, A. M.: A comparison of the effects of (+ )propranolol and ( + )-propranolol in anaesthetized dogs; P-receptor blocking and haemodynamic action, J. Pharm. Pharmacol.-21:241, 1969.
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