Adv. Cardiol., vol. 22, pp. 138-146 (Karger, Basel 1978)

Vasodilators in the Management of Acute Myocardial Infarction STEPHEN E. EpSTEIN, KENNETH M. KENT, JEFFREY S. BORER, ROBERT E. GOLDSTEIN, HOWARD J. SMITH and NORINE L. CAPURRO

Over the past few years vasodilators have been used with increasing frequency in the treatment of the patient with acute myocardial infarction. Two concepts have been instrumental in the development of this approach: one, that vasodilators lead to 'afterload reduction' and thereby enhance the efficiency of the heart as a pump; and two, that vasodilators may actually decrease the intensity of the ischemic insult. It had been demonstrated by several groups working independently that anyone of several vasodilators is hemodynamically beneficial in patients with acute myocardial infarction and left ventricular failure. Thus, nitroprusside, nitroglycerin, and phentolamine each diminish left ventricular filling pressure and usually increase cardiac output under such circumstances [1-6]. However, it was pointed out several years ago that an improvement in hemodynamics did not necessarily reflect reduction in the ischemic insult [7]. This caveat was raised because of the pharmacologic studies carried out over a decade ago suggesting that not all vasodilators acted on the same portions of the vascular tree. Thus, F AM and MCGREGOR [8] showed that dipyridamole was a very potent dilator of the resistance vessels of the coronary tree while nitroglycerin, in contrast, was a more potent dilator of the larger conductance vessels. Such different actions might lead to different effects on ischemic injury. For example, dilation of resistance vessels could exacerbate ischemia by a coronary steal mechanism. Dilation of conductance vessels, on the other hand, could reduce ischemia by diminishing resistance of the vessels supplying collateral channels and thereby enhance collateral flow. In this paper we will present the available information relating to the effects of nitroglycerin on ischemic injury. In addition, we will discuss how the effects of this drug contrast with the effects of another vasodilator, nitroprusside.

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Cardiology Branch, National Heart, Lung and Blood Institute, Bethesda, Md.

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In our initial studies we employed a canine model of acute myocardial ischemia whereby coronary occlusions of 15 min duration were carried out in the presence and absence of intravenously administered nitroglycerin. Coronary occlusion was produced by inflating a balloon cuff previously implanted around the left anterior descending coronary artery. In these experiments we estimated the degree of ischemic injury by measuring ST segment elevation recorded from multiple intramyocardial electrodes implanted at the same preparatory operation. We found that the magnitude of ST segment elevation appearing after coronary occlusion was reduced when nitroglycerin was administered. Moreover, when the blood pressure lowering and reflex tachycardia effects of nitroglycerin were abolished by simultaneous administration of the a-adrenergic agonist methoxamine, further reduction in ST segment elevation occurred [9]. Similar results were obtained in a group of dogs with chronic coronary occlusions produced by ameroid constrictors [10]. These latter studies also showed that when nitroglycerin, given alone, produced excessive reflex tachycardia (greater than 50 % of control), ST segments could actually increase. Such deleterious effects were never observed when methoxamine was administered to abolish the heart rate speeding and blood pressure lowering effects of nitroglycerin. These findings indicated that during acute coronary occlusion in closed chest dogs (which are not in left ventricular failure) (1) nitroglycerin reduces the degree of ischemic injury, (2) the fall in arterial pressure and reflex increase in heart rate produced by the drug oppose its beneficial actions, and (3) abolition of nitroglycerin's peripheral effects by simultaneous administration of an a-adrenergic agonist potentiates its beneficial action. Additional studies were then carried out to determine whether nitroglycerin and methoxamine attenuate the deleterious effects of a 5-hour period of coronary occlusion [11]. In these studies animals were randomized into control and treatment groups 10 min after coronary occlusion, at which time treatment was begun. Nitroglycerin and methoxamine were administered during the entire 5-hour period of coronary occlusion. Infarct size was assessed 24 h after occlusion by gross inspection of the hearts and by measurement of myocardial CPK activity. The control dogs manifested gross evidence of myocardial infarction and hemorrhage with considerable reduction of myocardial CPK activity. In contrast, considerably less gross or biochemical evidence of ischemic damage was evident in the treated dogs. To further delineate the functional significance of these salutary effects of nitroglycerin, we studied the effects of the drug during acute coronary

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occlusion on ventricular fibrillation threshold [12] and on the incidence of spontaneously occurring ventricular fibrillation [13]. In both of these studies treatment resulted in beneficial effects. Thus, the pronounced reduction in fibrillation threshold evident following acute coronary occlusion was substantially minimized by administration of nitroglycerin and further improved when phenylephrine was administered to reverse hypotensive effects of nitroglycerin. Most importantly, the incidence of spontaneously occurring ventricular fibrillation was significantly reduced by therapy. Because of these encouraging results, we studied the effects of nitroglycerin on the degree of ischemic injury occurring during acute myocardial infarction in man [5]. Ischemic injury was estimated by use of precordial electrodes. Diminution in ST segment deviation from baseline was taken as a reflection of a decrease in ischemic injury. Control recordings were obtained for an average of about 40 min; thereafter patients received sublingual nitroglycerin, 1.5-2.5 mg, over 5-7 min. Nitroglycerin administration resulted in an average reduction in mean systemic arterial pressure of 21 mm Hg. Approximately 10 min (5-18 min) after the start of nitroglycerin administration, the fall in systemic arterial pressure was totally abolished with intravenous phenylephrine. Observations were then continued for approximately 50 min, during which time arterial pressure was maintained at the pretreatment level. 7 of the 12 patients studied had pulmonary capillary wedge pressures that were less than 15 mm Hg and comprised the nonfailure subgroup. The remaining 5 patients had mean pulmonary wedge pressures between 15 and 35 mm Hg and comprised the left ventricular failure subgroup. In patients without left ventricular failure, nitroglycerin reduced mean pulmonary wedge pressure from 11 to 5 mm Hg (p < 0.02) and mean systemic arterial pressure from 99 to 82 mm Hg. Mean heart rate increased from 89 to 95 beats/min (n. s.). There were no consistent changes in the sum of ST segment deviations (EST) following nitroglycerin alone: EST increased in 1 patient, decreased in 4 and was unchanged in 1. In contrast, when arterial pressure reduction was abolished and heart rate returned to control levels by simultaneous administration of phenylephrine, EST fell to values below control levels in each patient: the mean reduction was 36 % (p < 0.05). Moreover, in each patient EST was lower than it had been during therapy with nitroglycerin alone. These results obtained in patients without left ventricular failure are remarkably similar to the findings observed in our dogs with multivessel coronary occlusions [10], which also were not in left ventricular failure. In both studies, nitroglycerin alone did not produce consistent effects on ischemic injury. But when its hypotensive and reflex

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tachycardia effects were eliminated by simultaneous administration of a vasoconstrictor, ischemic injury uniformly improved. In contrast to its effects in the subgroup without failure, nitroglycerin alone uniformly reduced ST segment abnormalities (average reduction, 23 %; p < 0.05) in those patients with left ventricular failure. This decrease in ischemic injury was associated with an average 26 mm Hg fall in mean systemic arterial pressure and a 15 mm Hg fall in pulmonary arterial wedge pressure. The average heart rate for the group as a whole did not change with nitroglycerin. The addition of phenylephrine to nitroglycerin in these patients tended to reduce the beneficial effect of nitroglycerin when given alone. Thus, our studies in man suggest that in patients without left ventricular failure administration of nitroglycerin alone often reduces, but occasionally increases, ischemic injury. Ischemic injury is more consistently reduced in such patients when phenylephrine is added to reverse the fall in arterial pressure and the reflex cardioacceleration induced by nitroglycerin. In contrast, in patients with left ventricular failure, nitroglycerin alone reduces ischemic injury. In these patients, the addition of phenylephrine in a dose sufficient to abolish the nitroglycerin-induced fall in arterial pressure usually partially reverses the beneficial effects of nitroglycerin. Although the precise role of simultaneous administration of an a-adrenergic agonist with nitroglycerin in patients with failure still must be defined, there have now been several reports, in addition to our own, demonstrating a beneficial effect of nitroglycerin on ischemic injury. Each group to date has used the precordial mapping technique to estimate changes in the intensity of the ischemia. Thus, FLAHERTY et al. [4] and COME et al. [14] demonstrated that nitroglycerin given alone to patients with acute myocardial infarction reduced ST segment abnormalities. These investigators gave the drug intravenously. Similar results were found with sublinugal nitroglycerin by CmARIELLO et al. [15] and AWAN et al. [16]. To determine the mechanisms of action of the beneficial effects of nitroglycerin during acute myocardial infarction, we measured myocardial blood flow after acute coronary occlusion in closed-chest sedated dogs [17,18]. Myocardial blood flow was measured with radioactive microspheres and myocardial flow within the center of the infarct was used as an index of collateral blood flow. In summary, collateral blood flow, measured 10 min after acute coronary occlusion, was severely depressed when compared to flow to nonischemic myocardium. 30 min after occlusion collateral flow was little changed in the control dogs; in contrast, collateral flow in the treated dogs increased from an average of about 15 to 25 ml/min/IOO g, or about 70%.

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Hence, during acute coronary occlusion nitroglycerin is capable of augmenting flow to ischemic myocardium in dogs through collateral channels. The possibility of a direct influence of nitroglycerin on human coronary collateral channels was suggested by studies performed at the time of coronary artery surgery in patients with coronary artery disease [19]. In these patients, retrograde pressure and flow was measured from a catheter inserted into a vein graft after it had been attached to the coronary artery distal to the site of complete occlusion. Since no antegrade flow was present, any flow collected or pressure measured provided an index of coronary collateral function. Hence, reduction in ischemic injury by nitroglycerin can be attributable to several effects the drug has on factors relating to the balance between myocardial oxygen demand (MV0 2) and myocardial oxygen supply. Nitroglycerin decreases myocardial tension in systole and diastole by reducing both left ventricular volume and pressure. The decrease in systolic wall tension leads to a favorable effect on ischemia by reducing MV02; the decrease in diastolic wall tension contributes to a reduction in resistance to flow through coronary collateral channels, an effect that could increase blood flow to ischemic myocardium. In addition, nitroglycerin probably increases collateral flow to ischemic myocardium by a direct action on coronary collateral vessels. Little information is available relating to the longer-term effects of nitroglycerin on collateral flow when the drug is given acutely during myocardial infarction. However, the results of a recent study suggest possible long-term beneficial effects. The details and complete results of this investigation will be reported in a separate communication [20]. In brief, acute coronary occlusion was carried out in closed-chest dogs. Half of the dogs were treated with nitroglycerin for I h. Arterial pressure and heart rate were maintained at control levels by periodic injections of methoxamine. After I h of treatment, drug infusion was discontinued, while coronary occlusion was maintained for the entire 5 h of the study. Collateral flow was measured by the microsphere technique. We found that after 1 h nitroglycerin increased collateral flow from 14 to 27 mlJminJl00 g. Of great interest, however, was the further observation that this acute increase in collateral flow was present even at termination of study, 4 h after discontinuation of drugs. Hence, short-term treatment with nitroglycerin results in a sustained increase in collateral flow. This may occur as a result of intrinsic collateral function being stimulated by nitroglycerin administration. Alternatively, treatment may maintain cell viability for the critical period necessary for normal mechanisms to bring about a spontaneous enhancement of collateral function.

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Finally, we would like to discuss the concept that not all vasodilators have similar actions on various portions of the vascular bed. The interesting studies performed over a decade ago by F AM and MCGREGOR [8] demonstrated that when the effects of nitroglycerin and dipyridamole were compared, nitroglycerin had a major action in dilating the larger conductance vessels of the coronary arterial tree, while dipyridamole had a major effect in dilating the more distal coronary resistance vessels, or arterioles. The authors pointed out that if the arterioles of a nonischemic bed are dilated by a drug, this may result in a redistribution of flow such that less blood is delivered to ischemic areas through collateral beds and a greater percentage to the now dilated nonischemic bed. We demonstrated similar differences when we compared the effects of nitroglycerin and nitroprusside. Dose-response curves to the drugs were performed in an open chest model in which retrograde flow and peripheral coronary pressure were measured [21]. It was found that when given intravenously, nitroglycerin had a more potent dilating effect on coronary collateral channels than did nitroprusside. In contrast, nitroprusside was a more potent dilator of both systemic and coronary arterioles. This implies that for a given reduction in systemic arteriolar resistance, nitroglycerin would result in a greater beneficial effect on coronary collateral resistance. In addition, these results raise the possibility that nitroprusside, by dilating the distal coronary arterioles, could predispose to a coronary steal situation. We subsequently performed studies compatible with such an hypothesis. Thus, in collaboration with Dr. ALAN PEARLMAN, nitroglycerin or nitroprusside was given at doses producing equivalent falls in arterial pressure to nonfailure dogs during acute coronary occlusion [22]. Nitroglycerin resulted in a decrease in ST segment elevation, while nitroprusside caused a significant increase, suggesting a deleterious effect of nitroprusside. Similar results were found in a recent study by CHIARIELLO et al. [15]. These investigators found that in dogs subjected to acute coronary occlusion, ST segment elevation was increased by nitroprusside, but decreased by nitroglycerin. They also found similar divergent effects on coronary collateral flow; nitroprusside decreased flow to the ischemic area while nitroglycerin enhanced it. In addition, although the number of patients they studied was small, these investigators found analogous effects when treating acute myocardial infarction in man. Thus, precordial ST segment elevation increased in some patients treated with nitroprusside, but decreased in all patients treated with nitroglycerin. It should be pointed out that the potential of nitroprusside to produce a deleterious effect on ischemic injury may not be realized often in the clinical

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setting. Thus, vasodilators usually are not administered to patients unless they are in left ventricular failure. In patients with failure, the increased left ventricular filling pressure and volume may raise myocardial wall tension to a level that critically reduces the caliber of those collateral vessels and capillaries perfused by severely narrowed coronary arteries. In such circumstances, the diminution in wall tension resulting from the large reduction in filling pressure and volume caused by nitroprusside may outweigh the deleterious effects the drug might produce on the coronary arterial tree. Indeed, it was recently reported [23] that while nitroprusside had deleterious effects on myocardial blood flow, myocardial ischemia, and left ventricular function in dogs that were either not in left ventricular failure or had only incipient failure, the drug lowered left ventricular diastolic pressure and increased myocardial flow in the region of distribution of the occluded LAD after failure was induced with propranolol and volume overload. In summary, these studies provide evidence that pharmacological intervention, in particular nitroglycerin infusion, can reduce infarct size. Although the mechanisms of action appear complex, they probably relate to a decrease in myocardial oxygen demands and an increase in collateral flow. It also seems apparent that conclusions derived from these studies cannot be directly applied to other vasodilators in that such drugs are not a homogeneous group of compounds. Rather, each 'vasodilator' must be evaluated independently as to whether or not it is capable of both improving hemodynamic function and decreasing ischemic injury.

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glycerin plus phenylephrine administered during acute myocardial infarction in man. New Eng. J. Med. 293: 1008 (1975). KELLY, D. T.; DELGADO, C. E.; TAYLOR, D. R.; PrrT, B., and Ross, R. S.: Use of phentolamine in acute myocardial infarction associated with hypertension and left ventricular failure. Circulation 47: 729 (1973). EpSTEIN, S. E.: Hypotension, nitroglycerin, and acute myocardial infarction. Circulation 47: 217 (1973). FAM, W. M. and MCGREGOR, M.: Effect of nitroglycerin and dipyridamole on regional coronary resistance. Circulation Res. 22: 649 (1968). SMITH, E. R.; REDWOOD, D. R.; MCCARRON, W. E., and EpSTEIN, S. E.: Coronary artery occlusion in the conscious dog. Effects of alterations in arterial pressure produced by nitroglycerin, hemorrhage, and alpha adrenergic agonists on the degree of myocardial ischemia. Circulation 47: 51 (1973). MYERS, R. W.; SCHERER, J. L.; GOLDSTEIN, R. A.; GOLDSTEIN, R. E.; KENT, K. M., and EpSTEIN, S. E.: Effects of nitroglycerin and nitroglycerin-methoxamine during acute myocardial ischemia in dogs with pre-existing multivessel coronary occlusive disease. Circulation 51: 632 (1975). HIRSHFELD, J. W.; BORER, J. S.; GOLDSTEIN, R. E.; BARRETT, M. J., and EpSTEIN, S. E.: Reduction in severity and extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion. Circulation 49: 291 (1974). KENT, K. M.; SMITH, E. R.; REDWOOD, D. R., and EpSTEIN, S. E.: Beneficial electrophysiologic effects of nitroglycerin during acute myocardial infarction. Am. J. Cardiol. 33: 513 (1974). BORER, J. S.; KENT, K. M.; GOLDSTEIN, R. E., and EpSTEIN, S. E.: Nitroglycerininduced reduction in the incidence of spontaneous ventricular fibrillation during coronary occlusion in dogs. Am. J. Cardiol. 33: 517 (1974). COME, P.; FLAHERTY, J.; WEISFEHLDT, M.; GREENE, L.; BECKER, L., and PITT, B.: Reversal of the benefical effects of intravenous nitroglycerin in patients with acute myocardial infarction by phenylephrine. New Engl. J. Med. 293: 1003 (1975). CHIARIELLO, M.; GOLD, H. K.; ZEINBACH, R. C. ; DAVIS, M. A., and MAROKO, P. R.: Comparison between the effects of nitroprusside and nitroglycerin on ischemic injury during acute myocardial infarction. Circulation 54: 766 (1976). AWAN, N. A.; AMSTERDAM, E. A.; ZAKARRADDIN, V.; DEMARIA, A. N.; MILLER, R. R., and MASON, D. T.: Reduction of ischemic injury by sublingual nitroglycerin in patients with acute myocardial infarction. Circulation 54: 761 (1976). CAPURRO, N. L.; KENT, K. M., and EpSTEIN, S. E.: Effects of intracoronary and intravenous nitroglycerin on coronary collateral function. J. Pharmac. expo Ther. 199: 262 (1976). SMITH, H. J.; GOLDSTEIN, R.A.; KENT, K. M.; AAMODT, R., and EpSTEIN, S. E.: Reduction of ischemia by nitroglycerin and methoxamine: mechanisms of action (submitted for publication). GOLDSTEIN, R. E.; STINSON, E. B.; SCHERER, J.L.; SENINGEN, R. P.; GREHL, T. M., and EpSTEIN, S. E.: Intraoperative coronary collateral function in patients with coronary occlusive disease: nitroglycerin responsiveness and angiographic correlation of nitroglycerin and methoxamine. Am. J. Cardiol. 39: 679 (1977).

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CAPURRO, N. L.; KENT, K. M.; SMITH, H. J.; AAMODT, R., and EpSTEIN, S. E.: Acute coronary occlusion: prolonged increase in collateral flow following brief administration of nitroglycerin and methoxamine. Am. J. Cardiol. 39: 679 (1977). CAPURRO, N. L.; KENT, K. M., and EpSTEIN, S. E.: Comparison of nitroglycerinnitroprusside, and phentolamine-induced changes in coronary collateral function in dogs. J. clin. Invest. (in press). PEARLMAN, A. S.; ENGLER, R. L.; GOLDSTEIN, R .A.; KENT, K. M., and EpSTEIN, S. E.: Relative effects of nitroglycerin and nitroprusside on acute myocardial ischemia in dogs with pre-existing multivessel coronary constrictions (submitted for publication). LEJEMTEL, T. H.; NELSON, G. R.; SONNENBLICK, E. H., and KIRKS, E. S.: Preload and afterload changes induced by nitroprusside: beneficial and detrimental effects on ischemia Circulation 54: supp!. II, p. 69 (1976).

S. E. EpSTEIN, MD, Chief, Cardiology Branch, National Heart, Lung and Blood Institute, Building 10, Room 7B-15, Bethesda, MD 20014 (USA)

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Vasodilators in the management of acute myocardial infarction.

Adv. Cardiol., vol. 22, pp. 138-146 (Karger, Basel 1978) Vasodilators in the Management of Acute Myocardial Infarction STEPHEN E. EpSTEIN, KENNETH M...
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