Beneficial electrophysiologic effects of nitroglycerin during acute myocardial infarction

EXPERIMENTAL STUDIES

Beneficial Electrophysiologic

Effects of Nitroglycerin

During Acute Myocardial Infarction

KENNETH

M. KENT,

MD,

ELDON

R. SMITH,

DAVID

R. REDWOOD,

STEPHEN

PhD

MD’

E. EPSTEIN,

MD MD

Bethesda, Maryland

From the Cardiology Branch, National Heart and Lung Institute, Bethesda, Md. Manuscript accepted October 24, 1973. Current address: Department of Medicine, Victoria General Hospital, Halifax, Nova Scotia. Address for reprints: Kenneth hf. Kent, MD, Cardiilogy Branch, National Heart and Lung Institute. Bldg. 10, Room 78-15. Bethesda, Md. 20014. l

Nitroglycerin reduces ischemic injury after experimental coronary occlusion. To determine whether it also has the potential of protecting the heart against the development of serious ventricular arrhythmias, the effects of nitroglycerin on electrical stability of acutely ischemic myocardium were determined in open chest dogs. Electrical stability of the ventricle was assessed by measuring ventricular fibrillation threshold before and after acute myocardial ischemia was produced by occlusion of the left anterior descending coronary artery. Ventricular flbrillation threshold was measured in a random manner under conditions of nonischemia, ischemia, ischemia plus nitroglycerin, and simultaneous infusion of phenylephrine to maintain mean systemic arterial pressure at control levels. Heart rate was kept constant at 120 beats/min by destruction of the atrioventricular node and use of ventricular pacing. In the absence of ischemia ventricular fibrillation threshold was 77 f 5 milliamperes (ma), a value unaffected by either nltroglycerln or phenylephrine. After 6 minutes of acute myocardlal ischemia, ventricular fibrillation threshold was reduced to 30 f 6 ma (P
Despite the long-standing use of nitroglycerin in the treatment of angina pectoris, it is generally accepted that the drug should not be used to treat ischemic pain caused by acute myocardial infarction. This concept is based on the belief that the nitroglycerin-induced decrease in arterial pressure and reflex increase in heart rate might exacerbate the ischemic insult. The demonstration that hypotension (induced either by hemorrhage1 or reflexly by stimulation of the carotid baroreceptors2) and an increase in heart rate3 augment the degree of ischemic injury occurring during experimental acute coronary occlusion appears to support this view. Recently, the concept that nitroglycerin is contraindicated in acute myocardial infarction has been challenged by the finding that during experimental coronary occlusion, nitroglycerin actually diminishes the intensity of ischemia’ and the area of infarcted myocardium.* If these beneficial effects are of physiologic significance, and if the pro-

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FIGURE 1. Ventricular fibrillation threshold (lvF) in 5 dogs under condiiins of nonischemia, ischemia, ischemia with nitroglycerin (TNG) infusion, and ischemia with nitroglycerin and phenylephrine (@e hi). Heart rate (HR) was kept constant by ventricular pacing. &A = mean systemic arterial pressure.

curred. Ventricular fibrillation threshold was defined as the current (in milliamperes) required to produce fibrillation This procedure was similar to that previously described.5 Ventricular defibrillation was accomplished within 30 seconds after the initiation of fibrillation by a direct current shock (capacitor-discharged) applied to the heart through two 6 cm electrodes. Ventricular fibrillation threshold was determined under four conditions: (1) in the absence of ischemia, (2) during ischemia (5 minutes after occlusion of the left anterior descending coronary artery), (3) during ischemia when nitroglycerin was being administered, and (4) during ischemia with simultaneous administration of nitroglycerin and phenylephrine. When nitroglycerin was administered it was given before coronary occlusion as a single injection of 300 pug followed by a constant infusion of 200 bg/min. When phenylephrine was administered it was given after the effects of the nitroglycerin infusion had stabilized and was infused at a rate sufficient to maintain systemic arterial pressure at control levels. The interventions were randomized, and each was separated by a 1 hour period. (We recently demonstrated5 that ventricular fibrillation threshold during acute myocardial ischemia under control conditions of arterial pressure and heart rate was unchanged over a time course similar to that used here.) The effects on ventricular fibrillation threshold in the absence of ischemia of nitroglycerin alone, phenylephrine alone and the combination of nitroglycerin and phenylephrine were determined in two dogs. Statistical analysis was performed by Student’s t test for paired data. Results are expressed as mean f 1 standard error of the mean.

Results pen&y for arrhythmias to develop during coronary occlusion is related to the degree of associated myocardial ischemia, nitroglycerin might also counteract the diminution of electrical stability in ischemic myocardium.5 In this study we tested this hypothesis by determining the effect of nitroglycerin on the vulnerability of the ventricle to fibrillation during experimental acute myocardial ischemia.

Methods Mongrel dogs weighing from 15 to 18 kg were anesthetized with sodium pentobarbital, 30 mg/kg intravenously, and studied in the supine position. The heart was exposed through a transverse thoracotomy and an adjustable ligature was placed around the left anterior descending coronary artery approximately 2 cm from its origin. Heart rate and systemic arterial pressure were recorded continuously. Heart rate was kept constant at 120 beats/min with ventricular pacing after induction of complete heart block by the injection of 1 ml of 10 percent formalin into the region of the atrioventricular (A-V) node. Ventricular fibrillation threshold was assessed by delivering a train of pulses, each 2 msec in duration and separated by 8 msec, through a bipolar platinum electrode sutured to the left ventricle outside of the region of subsequent ischemia. The train of pulses was delivered during the ventricular vulnerable period, starting 80 msec after ventricular activation and continuing for 50 msec after the end of the T wave in lead II of the electrocardiogram. The current was increased by four milliampere (ma) steps (measured with a Hewlett-Packard current probe and displayed on a storage oscilloscope) until ventricular fibrihation oc-

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Systemic Arterial Pressure Occlusion of the left anterior descending coronary artery at a heart rate of 120 beats/min did not induce any changes in systemic arterial pressure. Administration of nitroglycerin (300 pg intravenously foilowed by an infusion of 200 pg/min) caused mean systemic arterial pressure to decrease from 80 f 6 to 61 f 3 mm Hg (P X0.05). Infusion of phenylephrine during administration of nitroglycerin restored arterial pressure to control values. Ventricular Fibrillation Threshold Nonischemia: Ventricular fibrillation threshold averaged 77 f 5 ma in the five experimental animals. In two additional control animals nitroglycerin and phenylephrine were administered separately and in combination in the doses previously described. In the first of these two animals under control conditions the fibrillation threshold was 62 ma, during infusion of nitroglycerin alone 60 ma (systemic arterial pressure decreased 20 percent), during infusion of phenylephrine alone 68 ma (arterial pressure increased 10 percent) and with the combined administration of nitroglycerin and phenylephrine 66 ma (arterial pressure unchanged). In the second animal the fibrillation threshold under control conditions was 76 ma, during infusion of nitroglycerin alone 70 ma (arterial pressure decreased 22 percent), during infusion of phenylephrine alone 80 ma (arterial pressure increased 16 percent) and with the combined adminis-

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tration of nitroglycerin and phenylephrine 74 ma (arterial pressure unchanged). Effects of ischemia: Ventricular fibrillation threshold decreased 61 percent from control (nonischemic) values 5 minutes after occlusion of the left anterior descending coronary artery. The fibrillation threshold was lowered from an average of 77 f 5 to 30 f 6 ma (P X0.01, Fig. 1). Effects of nitroglycerin during acute myocardial ischemia: When nitroglycerin was infused during coronary occlusion ventricular fibrillation threshold increased 83 percent from the level reached during &hernia in the absence of nitroglycerin (Fig. 1). The improvement occurred despite a 24 percent reduction in mean arterial pressure. Thus, fibrillation threshold averaged 30 f 6 ma during myocardial &hernia under control conditions and 55 f 3 ma during ischemia when nitroglycerin was infused (P <0.005). Effects of nitroglycerin and phenylephrine during acute myocardial ischemia: When the nitroglycerin-induced reduction in arterial pressure was prevented by the simultaneous administration of phenylephrine, ventricular fibrillation threshold during acute myocardial ischemia increased even further to 75 f 6 ma (Fig. 1). This value was not significantly different from the control (nonischemia) fibrillation threshold (mean difference 2 f 8 ma).

Discussion The results of our investigation demonstrate that nitroglycerin increases the electrical stability of acutely ischemic myocardium, as manifested by a decreased vulnerability of the heart to the development of ventricular fibrillation in response to an electrical stimulus. Moreover, this beneficial electrophysiologic effect is potentiated when the nitrate-induced hypotension is prevented by the simultaneous administration of phenylephrine, an alpha receptor agonist. The potential efficacy of combination therapy appears considerable, since the decrease in electrical stability that occurred during ischemia was completely reversed by simultaneous administration of nitroglycerin and phenylephrine. The absolute values for the ventricular fibrillation threshold in these experiments were considerably higher than those previously reported from our laboratory5 and by others6v7 in anesthetized open chest dogs. The only difference between this preparation and those of previous studies, in which fibrillation thresholds were lower, was that in the studies described here the A-V node was destroyed by formalin in order to induce heart block. The latter was required to achieve slower heart rates than those usually obtained in pentobarbital-anesthetized dogs. The mechanism responsible for the increased threshold for fibrillation caused by the induction of heart block is unknown. However, there are several possible explanations. The formalin injection in the A-V nodal region could have interrupted sympathetic nerve fibers to the ventricular conducting system. Stimulation of these fibers is known to decrease the ventricu-

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lar fibrillation threshold.8 Destruction of the A-V nodal region also could have destroyed some of the particularly vulnerable areas of the conducting system. The elucidation of the exact mechanism responsible for the increased ventricular fibrillation threshold in animals with heart block requires further study. Mechanism of effect of nitroglycerin on ventricular fibrillation threshold: How nitroglycerin reverses the ischemia-induced decrease in electrical stability cannot be determined precisely from the results of our investigation. Nitroglycerin increased fibrillation threshold only in the presence of &hernia. Thus, it is unlikely that its actions were due to a nonspecific membrane-stabilizing effect although such direct effects could be demonstrable only in ischemic tissue. Alternatively, the beneficial electrophysiologic effect could have resulted from a favorable change in the balance between myocardial oxygen supply and demand within the ischemic zone. This mechanism would be operative if nitroglycerin reduced oxygen demands of the ischemic tissue by altering heart rate, wall tension and myocardial contractile state. However, the beneficial effects of nitroglycerin were observed even when heart rate and arterial pressure were kept constant, and under these conditions reduction of myocardial contractility also would have been unlikely. Thus, if nitroglycerin caused a significant decrease in myocardial oxygen consumption under the conditions of our study, it could have done so only by causing greater venodilatation than could be reversed by phenylephrine. This change would decrease ventricular volume, diminish myocardial wall tension and thereby decrease myocardial oxygen consumption. Finally, nitroglycerin could have favorably altered the balance between myocardial oxygen supply and demand by increasing blood flow to the ischemic area. Nitroglycerin has been shown in the dog to be capable of dilating large coronary arteries, increasing retrograde coronary flow during coronary occluSion, and increasing coronary pressure distal to the site of an occluded coronary artery.9 Winbury et al.‘O have shown an increase in endocardial PO2 and a favorable redistribution of blood toward ischemic myocardium after administration of nitroglycerin. Recent studies from our laboratory I1 have demonstrated that nitroglycerin has the capacity to decrease resistance to collateral flow in patients undergoing coronary bypass surgery. The increase in ventricular fibrillation threshold after administration of nitroglycerin is not necessarily equivalent to a decreased propensity for the spontaneous development of serious ventricular arrhythmias and ventricular fibrillation. However, data presented elsewhere in this issue l2 suggest that this is the case. Clinical implications: Recently, additional data have been reported that suggest a role for nitroglycerin in the therapy of acute myocardial infarction. For example, the degree of ischemic injury occurring during experimental acute coronary occlusion is di-

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minished by nitroglycerin, and this effect is further enhanced when the reduction in arterial pressure is prevented by the infusion of an alpha adrenergic agonist.’ Later studies have shown that the extent of myocardial infarction (quantitated by measuring the depression of myocardial creatine phosphokinase activity) produced by 5 hours of occlusion of the left anterior descending coronary artery is considerably less in dogs treated by an infusion of nitroglycerin and methoxamine than in a control group.4 In addition, Gold et a1.13 administered nitroglycerin sublingually to a group of patients with acute myocardial infarction. In some of the patients with persistent refractory left ventricular failure, nitroglycerin resulted

in a reduction in pulmonary capillary wedge pressure and an increase in cardiac output. Similar results were obtained by Franciosa et a1,14 who infused the vasodilator, sodium nitroprusside, in patients with acute infarction. The results of our investigation, which demonstrate that nitroglycerin also enhances electrical stability, add another dimension to the potential beneficial role of nitroglycerin in acute myocardial infarction. Thus, although it is not certain whether our data are applicable to the clinical situation, they suggest that nitroglycerin may be uniquely valuable in the treatment of acute myocardial infarction by reducing the degree of ischemic injury and the incidence of serious ventricular arrhythmias.

References 1. Smith ER, Redwood DR. McCarron WE, et al: Coronary occlusion in the conscious dog. Circulation 47~51~57, 1973 2. Thtbautt GE, Farnham OS, Myers RW, et al: Increased myocardial ischemia caused by reflexly induced hypotension during coronary occlusion in the conscious dog (abstr). Clin Res 21:454, 1973 3. Redwood DR, Smith ER, Epstein SE: Coronary artery occlusion in the conscious dog. Circulation 46:323-332, 1972 4. Hlrshhdd JW, Borer JS, Goldstein RE, et al: Reduction in extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion (abstr). Clin Res 21: 426, 1973 5. Kent KM, Smtth ER. Redwood DR, et al: Electrical stability of acutely ischemic myocardium. Circulation 47:291-296. 1973 6. Han J: Ventricular vulnerabiiii during acute coronary occlusion. Am J Cardiol 24:857-864. 1969 7. Spear Jf, Moore EN, Gerstenblith G: Effect of lidocaine on the ventricular fibrillation threshold in the dog during ischemia and premature contractions. Circulation 46:65-73, 1972 8. Han J, Garcia JP, Moe OK: Adrenergic effects on ventricular

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vulnerability. Circ Res 145 16-524, 1964 9. Fam WM, McGregor M: Effect of nitroglycerin and dipyridamole on regional coronary resistance. Circ Res 22:649-659, 1968 10. Winbury MY, Howe BB, Weiss HR: Effects of nitroglycerin and dipyridamole on epicardial and endocardial oxygen tension. Further evidence of redistribution of myocardial blood flow. J Pharmacol Exp Ther 176:184-199, 1971 11. Gotdstein RE, Sthson EB, Epsteln SE: Effects of nitroglycerin on coronary collateral function in patients with coronary occlusive disease (abstr). Am J Cardiol 31:135, 1973 12. Borer JS, Kent KM, Gotsteln RE, et al: Nitroglycerin-induced reduction in the incidence of spontaneous ventricular fibrillation during coronary occlusion in dogs. Am J Cardiol 33:517-520. 1974 13. Gold HK, Leinbach RC, Sanders CA: Use of sublingual nitroglycerin in congestive failure following acute myocardial infarction. Circulation 46:839-845, 1972 14. Franctosa JA, Gulha NH, Limas CJ, et al: Improved left ventricular function during nitroprussic infusion in acute myocardial infarction. Lancet 1:650-657, 1972