Acta physiol. scand. 1975. 93. 129-134 From the Department of Physiology and Biophysics, University of Lund, Sweden

Circulatory Effects Evoked by ‘Physiological’ Increases of Arterial Osmolality BY JOHANNES JKRHULT, JANHILLMAN and STEFANMELLANDER Received I July 1974

Abstract JARHULT,J., J. HILLMAN and S . MELLANDER. Circulatory effects evoked by ‘physiological’ increases of arterial osmolality. Acta physiol. scand. 1975. 93. 129-1 34. The effects of moderate arterial hyperosmolality ( + 20 mOsm/kg HaO),produced by short term intravenous hypertonic infusion, on vascular resistance in skin, skeletal muscle, intestine, and kidney were analysed in the anesthetized cat. Vascular resistance decreased in all four regions in response to the hypertonicity both before and after regional sympathectomy and the effects were not significantly altered by ,!I-adrcnoceptor blockade. Arterial blood pressure rose during the hypertonic infusion despite the decreased vascular resistance and an unchanged heart rate, indicating an increased stroke volume and cardiac output. Similar increases of arterial osmolality are known to occur in heavy exercise and in hemorrhage. The present results may therefore suggest that blood borne hyperosmolality is a factor which can contribute to the overall cardiovascular adjustments in these situations.

lnvestigations in recent years have demonstrated that hyperosmolality plays important roles in the control of the circulation by influencing vascular tone, transcapillary fluid balance, plasma volume etc. (for ref. see Mellander 1973). The osmolar control of vascular smooth muscle seems of special significance in skeletal muscle and glands, in which a pronounced local tissue hyperosmolality develops during increased activity and contributes to the functional vasodilatation (Mellander et al. 1967, Lundvall 1972, Lundvall and Holmberg 1974). Vascular smooth muscle in several other tissues is known to be responsive to experimental hyperosmolality produced by administration of hypertonic solutions to the blood stream (e.g. Navar et al. 1966, Gazitua et al. 1971, Hauge and B0 1971, Lundvall 1972). The vascular effects of a generalized blood borne hyperosmolality, as induced by intravenous hypertonic infusion, have so far mainly been studied in response to drastic increases of osmolality (e.g. Muirhead et al. 1947, Read et al. 1960, Raizner et al. 1973), which may be considered ‘supraphysiological’. A moderate hyperosmolality (about 20 mOsm/kg H 2 0 above the control level) develops in the arterial blood during whole body exercise due to “delivery of osmols” from the active muscles (Lundvall et a / . 1972) and in hemorrhage due to glucose release from the liver (e.g. Jarhult 1973, 1974). The present study was undertaken to analyse whether such ‘physiological’ blood borne hyperosmolality 9 - 75581 I

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may significantly affect the peripherql circulation. The investigation was performed on cats in which the effects of slow intravenous hypertonic infusions on the vascular resistance function in skin, skeletal muscle, intestine and kidney were analysed before and after regional sympathectomy.

Methods Experiments were performed on 14 cats (mean weight 2.7 kg) anesthetized with a-chloralose (50 mg/kg) after induction with ether supplemented with a small dose of pentobarbital sodium ( 1 5 mg). Arterial pulsatile and mean pressures were monitored (via Statham P23 AC transducers) from the right carotid artery and observations were further made of heart rate (Grass Tachograph, model 7P4 D) and of blood flows from four different tissues: Skin, skeletal muscle, intestine, and kidney. After heparinization, the regional blood flows were measured with optical drop recorder units inserted in the cognate vein of either tissue, other draining vessels being ligated. The venous outflows were returned to the animal via a funnel connected to the right, and sometimes also the left, jugular vein. With this technique the regional venous outflow pressures were kept constant at a value of about 5 mm Hg. Inflow of blood f r o m the funnel was automatically adjusted so as to keep the extracorporeal blood volume small and constant. I n the individual experiment, blood flows from 2 o r 3 regions were measured simultaneously. All parameters were recorded o n a direct writing oscillograph (Grass polygraph). The preparations were as follows: Skin. Recordings of blood flow from the left hind paw were obtained by insertion of the flowmeter in the great saphenous vein at the level of the ankle. All other draining superficial veins were ligated and drainage through deep veins was prevented by the application of a cuff at the ankle which raised tissue pressure to a level slightly exceeding venous outflow pressure. The pads of the paw were carefully ligated t o exclude the majority of the arterio-venous anastomoses; hence observed reactions in the cutaneous circulation can mainly be considered representative of those in 'nutritive' skin resistance vessels. Skeletal musck. Blood flow from the right lower hind leg muscles was recorded with the technique described by Kjellmer (1964). Inlessline. A I5 cm long segment of the jejunum was prepared to permit blood flow recordings according to Folkow e l ul. (1963). Kidney. Blood flow from the left kidney was recorded after cannulation of the main renal vein. The left ovarian or spermatic veins were ligated. The effects of i.v. iso- and hypertonic infusions on vascular resistance in the 4 regions were studied both before and after regional sympathectomy. At the end of each experiment the studied tissues were weighed to permit calculation of blood flow per 100 g tissue. Regional resistance (arterio-venous pressure gradient/ (blood flow/min 100 g tissue)) was determined before (control) and during the infusions and the reactions in the resistance vessels were expressed as per cent change from the control value. Intravenous infusions of isotonic and hypertonic (30 to 50%) solutions of glucose, xylose, and sucrose were administered via the right axillary vein, usually at a rate of 1.0 ml/min. Arterial blood samples were intermittently withdrawn from a T-tube in the arterial catheter and analysed for plasma osmolality with thermistor cryoscopy (Advanced Instruments, Inc.). In 4 expts. observations were made after intravenous administration of propranolol ( I mg/kg b.wt.). - Spread of data is given below as S.E. )I

Results Hyperosmolality in the arterial blood develops relatively rapidly in muscle exercise and hemorrhage, reaching peak levels of 20-25 mOsm/kg HsO above control within 4-6 min in heavy work (Lundvall e t a / . 1972) and in 10-20 min in bleeding (Jarhult 1973). In the present study the intravenous hypertonic infusion rates were adjusted so as to evoke a similar arterial hyperosmolality in 5 min. The experimental protocol was as follows: The animal rested for about 30 min after the completion of the surgery. After this, one isotonic and 2-3 hypertonic infusions of 5 min duration were made, permitting full recovery of the circulatory events between the different infusions. Samples for arterial plasma osmolality determinations were withdrawn in the control period and I , 3, 5, 10 and 20 min after the start of the infusion.

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Fig. 2. Effects of i.v. hypertonic infusion (signal) on the regional blood flow and vascular resistance in intact ( O - - O ) and sympathectornized ( 0 - 0 ) vascular beds of skin, skeletal muscle, intestine, and kidney. Mean va1ueskS.E. are given. The concomitant average changes of arterial osmolality and blood pressure are depicted in Fig. 1.

sympathectomized regions, even if the effects tended to be somewhat less pronounced with intact innervation. It follows that the resistance decrease is a local and not a reflex nervous adjustment, and it most likely can be ascribed to a direct dilator action of hyperosmolality on the resistance vessels (see below). In relative terms, the resistance decrease seemed more pronounced in skin and muscle tissues than in intestine and kidney. The circulatory effects of hypertonic infusion were also analysed after administration of propranolol (4 cats) in a dose (1 mg/kg b.wt.) known to effectively block the beta adrenoceptors. Such blockade did not affect the peripheral dilator responses to hypertonic infusion in these experiments, but the blood pressure responses was depressed by an

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average of 40%. The described dilator effects thus cannot be attributed to possible release of adrenaline from the adrenals.

Discussion The present study has shown that ‘physiological’ increases of the osmolality of the blood, as can occur in exercise or hemorrhage, lead to raised arterial mean and pulse pressure (in agreement with Stainsby and Barclay 1971) and to a decrease of vascular resistance in skin, skeletal muscle, intestine and kidney both before and after regional sympathectomy. Blockade of B-adrenoceptors attenuated the blood pressure response but did not alter the hypertonic effects on vascular resistance. The decreased vascular resistance most likely is due to an active dilator response caused by direct inhibition of vascular smooth muscle tone by hyperosmolality, as evidenced by previous in vivo and in vitro experiments (Mellander et a/. 1967, Johansson and Jonsson 1968, Lundvall 1972). Rheological or other passive effects of the hypertonic infusion may be considered small (see Lundvall 1972), but perhaps not entirely negligible due to an osmotic absorption of extravascular fluid and consequent plasma volume expansion (Lundvall e t a / . 1972, Atkins e t a / . 1973, Jarhult 1973). It may be concluded that moderate (‘physiological’) blood borne hyperosmolality has a significant dilator effect in these four regions of the systemic circulation. Hauge and B0 (1971) have previously shown that such hyperosmolality also evokes a clearcut dilatation of the pulmonary resistance vessels. The raised arterial blood pressure in face of dilatation in four hemodynamically important vascular beds is indicative of an augmented cardiac output, in turn caused by increased stroke volume since heart rate was not much altered. This interpretation is corroborated by previous direct observations of cardiac output and total peripheral resistance by Atkins et al. (1973). The latter authors attributed the cardiac effects mainly to a direct positive inotropic action of hyperosmolality. The present results obtained after interference with B-adrenoceptors suggest that hyperosmolality, in addition, causes an inotropic effect via a moderate excitation of the sympathetic nervous system, an opinion also expressed by Wildenthal et a/. 1969. The latter effect may be mediated through postulated peripheral ‘osmoreceptors’ (Lasser et a/. 1960), or by an action of hyperosmolality on the central nervous system (Holland et al. 1960, Mellander and Hillman 1975). The cardiac effects of hyperosmolality to some extent might also have been due to interference with the FrankStarling mechanism in view of the mentioned osmotic plasma volume expansion. An inhibitory reflex adrenergic effect noted in the initial phase during rapid intravenous infusions of strong hypertonic solutions (Raizner et a/. 1973) was not observed in the present experiments with more moderate hyperosmolality. Circulatory adjustment to stress (e.g. exercise or bleeding) is the integrated net result of simultaneous synergistic or antagonistic influences of different control systems on the heart and the peripheral circulation. The importance of each control system may be best appreciated by studying its selective effects under standardized experimental conditions. The present results, taken together with those of Wildenthal et a/. (1969) and Atkins et al. (1973), suggest that blood borne hyperosmolality is a factor which can contribute to the cardiac adjustments in exercise and hemorrhage; at the same time, the hyperosmolality

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would tend to oppose the reflex adrenergic constriction of the peripheral resistance vessels in these situations. This study was supported by grants from the Swedish Medical Research Council (B75-14X-ZZI0-09A) and from the Faculty of Medicine, University of Lund (53482332-3).

References ATKINS,J. M., K. WILDENTHAL and L. D. HORWITZ, Cardiovascular responses to hyperosmotic mannitol in anesthetized and conscious dogs. Amer. J . fhysiol. 1973. 225. 132-137. and I. WALLENTIN, Studies on the relationship between flow resistance, FOLKOW.B., 0.LUNDGREN capillary filtration coefficient and regional blood volume in the intestine of the cat. A r i a physiol. scancl. 1963. 57. 270-283. GAZITUA, S., J. 8. SCOTT,B. SWINDALL and F. J. HADDY,Resistance responses to local changes in plasma osmolality in three vascular beds. Amer. J . fhysiol. 1971. 220. 384-391. HAUGE,A. and G. Be, Blood hyperosmolality and pulmonary vascular resistance in the cat. Circular. Res. 1971. 28. 371-376. HOLLAND, R. C., J. W. SUNDSTEN and C. H. SAWYER, Effects of intracarotid injections of hypertonic solutions on arterial pressure in the rabbit. Circular. Res. 1959. 7. 712-720. JARHULT, J., Osmotic fluid transfer from tissue to blood during hemorrhagic hypotension. A r i a physiol. scand. 1973. 89. 213-226. JARHULT, J., Role of the sympatho-adrenal system in hemorrhagic hyperglycemia. A r i a physiol. scatd. 1975. 93. 25-33. JOHANSSON, B. and 0.JONSSON,Cell volume as a factor influencing electrical and mechanical activity of vascular smooth muscle. A r i a physiol. srancl. 1968. 72. 456-468. KJELLMER, I., The effect of exercise on the vascular bed of skeletal muscle. Aria physiol. scand. 1964. 62. 18-30.

LASER, R. P., M. R. SCHOENFELD, D. F. ALLENand C. K. FRIEDBERG, Reflex circulatory effects elicited by hypertonic and hypotonic solutions injected into femoral and brachial arteries of dogs. Circular. Res. 1960. 8 . 913-919. LUNDVALL, J., Tissue hyperosmolality as a mediator of vasodilatation and transcapillary fluid flux in exercising skeletal muscle. A r i a physiol. srand. 1972. Suppl. 379. J. and J. HOLMBERG, Role of tissue hyperosmolality in functional vasodilatation in the subLUNDVALL, mandibular gland. A r i a physiol. srand. 1974. 92. 165-174. LUNDVALL, J., S. MELLANDER, H. WESTLING and T. WHITE,Fluid transfer between blood and tissues during exercise. Acta physiol. scan(/. 1972. 85. 258-269. S.,Osmolar control of the circulation. A r i a physiol. scand. 1973. Suppl. 396. 46. MELLANDER, MELLANDER, S. and J. HILLMAN, Circulatory and respiratory effects evoked by hypertonic ventriculocisternal brain perfusion. A r i a physiol. scand. 1975. T o b? published. S. and B. JOHANSSON, Control of resistance, exchange, and capacitance functions in the MELLANDER, peripheral circulation. Pharmacol. Rev. 1968. 20. 117-196. MELLANDER, S.. B. JOHANSSON, S. GRAY,0.JONSSON, J. LUNDVALL and B. LJUNG,The effects of hyperosmolality on intact and isolated vascular smooth muscle. Possible role in exercise hyperemia. Angiologica 1967. 4. 310-322. MUIRHEAD, E. E., R. W. LACKEY, C. A. BUNDEand J. M. HILL,Transient hypotension following rapid intravenous injections of hypertonic solution. Amer. J. Physiol. 1947. I S / . 516-524. NAVAR, L. G., A. C. GUYTON and J. 8. LANOSTON, Effect of alterations in plasma osmolality on renal blood flow autoregulation. Amer. J. Physiol. 1966. 211. 1387-1392. RAIZNER, A. E., J. C. COSTIN,R. P. CROKF,J. B. BISHOP,T. V. ~ N C L E S B Yand N. S. SKINNER. JR., Reflex, systemic, and local hemodynamic alterations with experimental hyperosmolality. Amer. J. Physiol. 1973. 224. 1327-1333. READ,R. C., J. A. JOHNSON, J. A. VICK and M. W. MEYER,Vascular effects of hypertonic solutions. Circulur. Res. 1960. 8. 538-548.

STAINSBY, W. N. and J. K. BARCLAY, Effect of infusions of osmotically active substances on muscle blood flow and systemic blood pressure. Circulai. Res. 1971. 28-29. Suppl. 1. 33-38. K., D. S. MIERZWIAK and J. H. MITCHELL, Acute effects of increased serum osmolality o n WILDENTHAL, left ventricular performance. Amer. J . fhysiol. 1969. 216. 898-904.