- Email: [email protected]
Nitroglycerin-induced reduction in the incidence of spontaneous ventricular fibrillation during coronary occlusion in dogs
Nitroglycerin-Induced
Reduction in the Incidence of
Spontaneous Ventricular Fibrillation During Coronary Occlusion in Dogs
JEFFREY
S. BORER,
MD
KENNETH
M. KENT,
MD,
ROBERT
E. GOLDSTEIN,
STEPHEN
E. EPSTEIN,
PhD MD
MD.
Bethesda, Maryland
Previous investigations have demonstrated that nitroglycerin reduces ischemk injury and enhances ventricular electrical stabtffty during coronary occlusion in dogs. These beneficial effects were potenttated by preventing drug-induced hypotension wtth alpha adrenergk agontsts. To determine whether nitroglycerin can prevent spontaneous post-occluston ventricular fibrillation, 27 open chest dogs w&e asslgned in random fashion to two groups-control (saline infusion) and nttrogfycerin-treated (0.45 mg intravenous bolus infusion followed by 0.3 mg/ min continuous infusion). Afler 10 minutes of lnfuskn the lefl anterior descending and septal coronary arteries were occluded at thetr origins. Hypotensive effects of nitroglycerin were prevented by Intermittent intravenous doses of methoxamlne; mean arterial pressure and heart rate in control and treated animals were thus IndWngulshabk. lnfuskns continued until ventricular fibrtflatkn occurred or 30 minutes elapsed. Twelve of 13 control dogs died wtth ventrkular Hbrillatkn; only 7 of 14 nitrogtycerln-treated dogs died (P
The use of nitroglycerin traditionally has been avoided in the presence of acute myocardial infarction because of the fear that nitroglycerin-induced hypotension and tachycardia might exacerbate the ischemit insult. Recently, however, nitroglycerin was found to reduce the degree of ischemic injury and to increase the threshold at which ventricular fibrillation could be induced electrically during experimental acute coronary occlusion14; both of these salutary effects were enhanced if nitroglycerin-induced hypotension was prevented by administration of an alpha adrenergic agonist. In this investigation we have determined whether nitroglycerin is capable of inhibiting the spontaneous occurrence of ventricular fibrillation during acute coronary occlusion in dogs when drug-induced hypotension is prevented with methoxamine. From the Cardickgy Branch, National Heart and Lung Institute, Bethesda, Md. 20014. Manuscript accepted January 16, 1974. Address for reprints: Jeffrey S. Borer, MD, Cardii Branch, National Heart and Lung InMute, Bldg. 10, Room 7515, Bethesda, Md. 20014.
Methods Twenty-seven male dogs weighing 16 to 25 kg were randomized into control and nitroglycerin-treated groups. Each dog was anesthetized with intravenously administered sodium pentobarbital (35 mg/kg). A catheter was intraduced into the femoral artery for pressure recording and into a limb vein
April 1974
The American Journal of CARDfCLOGY
Vohmm 33
517
t4lmoavoERlN
lr4mmoN
OF VENTfWULAR
FBFtlLLATKIN-BORE8
for drug administration. Standard subcutaneous electrodes were inserted for recording the electrocardiogram. The heart was exposed through a left thoracotomy during positive pressure ventilation. The left anterior descending and septal coronary arteries were dissected free at their origins. Arterial hemoglobin oxygen saturation and pH were then determined and the respirator adjusted so that oxygen saturation was at least 91 percent, and pH was between 7.42 and 7.52. All dogs had sinus rhythm. Each dog in the treated group received an initial intravenous bolus infusion of 0.45 mg of nitroglycerin followed by a continuous intravenous infusion of 0.3 mg/min. The infusion solution was prepared by dissolving nitroglycerin tablets (Lilly) in normal saline solution in quantities permitting an infusion rate of 0.5 ml/min. Methoxamine, an alpha adrenergic agonist, was administered intermittently to maintain mean arterial pteskure at the pre-nitroglycerin level. Each control dog received an infusion of normal saline solution, also at a rate of 0.5 ml/min. After 10 minutes of infusion, the left anterior descending and septal coronary arteries were simultaneously clamped at their origins; the clamp was suspended by sutures from an overlying crossbar so that traction on the coronary arteries was relatively constant despite respiratory movements. The clamp was carefully placed so as to avoid occluding either the left main or left circumflex coronary arteries. To ensure that such inadvertent occlusion had not occurred, after each experiment the heart was removed with the clamp in place and the coronary arteries were probed, opened and inspected. Mean arterial pressure and the electrocardiogram were recorded continuously. After occlusion, each experiment continued until the dog died with ventricular fibrillation, or until 30 minutes had elapsed without ventricular fibrillation. This duration of observation was chosen since preliminary experiments with this model demonstrated that if fibrillation did not develop within 30 minutes after occlusion, it did not develop during a subsequent hour of observation either in control or nitroglycerin-treated dogs. The rate of administration of methoxamine as well as nitroglycerin was identical in treated dogs that experienced ventricular fibrilhtion and in treated survivors. Statistical analysis of the difference in incidence of ventricular fibrillation in control and treated groups was performed with the use of the Fisher Exact Test. Comparison of blood pressure and heart rate was performed with the Student t test.
Results Before infusion, no significant differences in mean arterial pressure or heart rate existed between control and treated dogs. Mean arterial pressure in control dogs was 120 f 5 mm Hg and in treated dogs 128 k 6 mm Hg. Heart rate in control dogs was 166 f 7 beats/min and in treated dogs was 170 f 6 beats/min. Moreover, during the course of occlusion, no significant differences developed between the control and treated dogs that were alive at any given assessment point. Arterial pressure remained relatively constant in each dog for the duration of the experiment, except for transient fluctuations associated with arrhythmias which, when ventricular fibrillation did not supervene, were only of a few seconds’ duration. Among the treated dogs, no significant differences in h&art rate or blood pressure were discernible during the course of the experiments when comparing the dogs that died with those that survived.
518
Aplll974
The American Journal of CARDIOLOGY
Volume 33
ET AL.
Ventricular fibrillation occurred in 12 of 13 control dogs but in only 7 of 14 treated dogs (P dO.05, Fig. 1). No dog had ventricular fibrillation after surviving more than 18.5 minutes of occlusion, and most (15 of 19) died between 11 and 18.5 minutes after occlusion. No dog had atrioventricular dissociation during the course of the experiment. Discussion The results of this investigation demonstrate that nitroglycerin (its hypotensive effects obviated by simultaneous administration of methoxamine) markedly diminishes the incidence of ventricular fibrillation occurring spontaneously in an experimental model of acute myocardial infarction. These results are in accord with and extend our previous studies3p4 demonstrating that nitroglycerin, alone or with phenylephrine, significantly increases the threshold at which ventricular fibrillation can be induced electrically during coronary occlusion in dogs. Mechanisms of beneficial action of nitroglycerin: The mechanisms by which nitroglycerin and
methoxamine reduce the prevalence of ventricular fibrillation are unknown. Nitroglycerin alone, and in combination with methoxamine, decreases the degree of myocardial ischemia occurring during experimental coronary occlusion.lp2 It appears likely that such an effect is responsible for enhanced survival. This conclusion is reinforced by our previous findings that nitroglycerin increases ventricular fibrillation threshold in the presence of ischemia but does not do so when ischemia is absent. It is unclear, however, whether nitroglycerin reduces ischemia by decreasing oxygen demand of the heart, increasing blood flow to ischemic areas, or both. The actions of nitroglycerin alone on the prevalence of spontaneous ventricular fibrillation during
14-
12 -
1 2
0
No VFfl
VF
-
2-
0
CONTR L
TNG 8 METHOXAMINE FtGURE 1. Ventricular fibrillation after coronary artery occlusion. Drug administration in treated (TNG & Methoxamine) group and saline infusion in control group were begun 10 minutes before coronary occlusion.
coronary occlusion is yet to be determined. That this agent contributes markedly to the decrease in ventricular fibrillation observed when both nitroglycerin and methoxamine are administered, however, is suggested by the finding that nitroglycerin itself increased ventricular fibrillation threshold during acute myocardial ischemia.3*4 When the hypotensive effects of nitroglycerin were abolished by simultaneous administration of another alpha adrenergic agonist (phenylephrine), a further increase in ventricular fibrillation threshold was observed. Moreover, we have found no significant reduction in the incidence of spontaneous postocclusion fibrillation after the administration of phenylephrine alone, in amounts sufficient to raise mean arterial pressure to levels associated with significant reduction in ischemit injury (unpublished observations). Thus, the results of the previous studies, in conjunction with those of this investigation, indicate that nitroglycerin can inhibit the development of ventricular fibrillation occurring during experimental acute coronary occlusion and that this effect is potentiated by preventing the reduction in arterial pressure that this drug might cause. The dog model of ischemia-induced ventricular fibrillation used in the present investigation differs
considerably from models used in other studies. In such models, although wide fluctuations exist, the incidence of early ventricular fibrillation has generally been far lower than in the present model, whereas hemodynamic abnormalities have often been prominent. Thus, although occlusion of the left main coronary artery leads almost uniformly to ventricular fibrillation, this intervention usually causes hypotension and cardiogenic shock.5-7 When the circumflex coronary artery is occluded in the open chest dog, the cumulative incidence of ventricular fibrillation is about 33 percent. 5spgIn the closed chest dog, the incidence has been approximately 60 percent, but the range from study to study is extensive (0 to 75 percent) and severe hypotension is a frequent complicating feature.7*8J0-12 Approximately 30 percent of more than 750 closed and open chest dogs studied have had fibrillation within 30 minutes after proximal occlusion of the left anterior descending coronary artery5~8~gJ3-18;in combined small series about 10 percent of dogs had early fibrillation after occlusion of the septal artery.5p1g*20 The incidence of ventricular fibrillation after occlusion of the right coronary arIn this study, the septal corotery is 10 percent. 5,7pg,21 nary artery was systematically occluded together with the left anterior descending coronary artery. Both vessels were occluded proximal to any branches.
This intervention led to incidence of ventricular fibrillation of 92 percent in the control group. In more recent studies from our laboratory in which the same model has been used, the cumulative incidence of fibrillation in untreated animals has been 87 percent (71 of 82). Changes in blood pressure and heart rate after occlusion have been relatively slight in virtually all studies, and are comparable to those reported here. Moreover, our data indicate that the model can be influenced by therapeutic interventions, despite the ischemic insult and high rate of ventricular fibrillation. Hence, this model of acute infarction appears to have particular advantages for evaluating interventions that are capable of reducing the incidence of spontaneous ventricular fibrillation during the early phase of acute myocardial infarction. Clinical implications: The applicability of our findings to acute myocardial infarction in man is unknown. The protective effects of nitroglycerin on the occurrence of ventricular fibrillation were demonstrated in dogs with acute coronary occlusion but with otherwise normal coronary arteries and normal myocardium. It is possible that nitroglycerin does not exert similar effects when long-term multivessel disease is present. Moreover, other workers22 have demonstrated that the mechanism of ventricular fibrillation is different early after coronary occlusion than it is several hours later. Thus, although our results suggest potential benefit from nitroglycerin (with methoxamine) during the early phase of acute myocardial infarction in man (when most arrhythmic deaths OCCUP~*~~), the drug may not have similar effects later in the course of infarction. There is now an impressive body of experimental evidence demonstrating that during acute coronary occlusion nitroglycerin decreases ischemic injury, enhances electrical stability of the ventricle and, as our study has shown, reduces the incidence of spontaneously occurring ventricular fibrillation. Clinical studies25 indicate that during the course of acute myocardial infarction associated with left ventricular failure in man, administration of nitroglycerin can result in hemodynamic improvement. Thus, these experimental and clinical studies suggest that the general reluctance to administer nitroglycerin during acute myocardial infarction should he reconsidered since the drug may be of unique therapeutic value in this condition. Acknowledgment We gratefully acknowledge the expert technical assistance of Mr. Richard McGill and Mr. William Parker.
References 1. Smith ER, Redwood DR, McCarron WE, et al: 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 myocardttl ischemia. Circulatfon 4751-57, 1973
2. Hlrshfeld JW, Borer JS, Goldeteln RE, et al: Reduction in severity and extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion. Circulatiin 49:291-297,1974 3. Borer JS, Kent KM, Goldafeln RE, et al: Nitroglycerin-induced
April 1974
The American Journal of CARBKXGGY
Vehane 33
919
AL.
4.
5. 6.
7.
6.
9. 10.
11.
12.
13.
14.
520
enhancement of ventricular electrlll stability and reduction in the lnckfsnce of spontaneous ventricular flbrfllation during coronary occfusbn in dogs (abstr). Circulation 48:suppl IV:IV-126, 1973 Kent KM, Sdth ER. Redwood DR, et al: Beneficial electro physic effects of nitroglycerin during acute myocardiil infarct&n. Am J Cardiol33:513-516.1974 Porter W’R On the results of ligation of the coronary arteries. J Fhysfoll5:121-136, 1694 Hefnbecker P, Barton WA: An effective method for the development of collateral circulation to the myocardium. Ann Surg 114:166-190, 1941 APert JB, Leadl JR: Effect of the level of ligature on mot-talky follow@ ligation of the circumflex coronary artery in the dog. Am Heart J 39273-276, 1950 Memhg GW, McEechem CG, Hall GE: Reflex coronary spasm fo6owfng sudden occlusion of other coronary branches. Arch Intern Med 64~661-674.1939 sndth FM The ligation of coronary arteries with electrocardiographic study. Arch Intern Med 22:8-27, 1918 Khan MI, Hadton Jl, Manning GW: protective effect of beta abenerglc blockade in experimental coronary occlusion in conscious dogs. Am J Cardbl30:832-837, 1972 Paeyk S, Boor CM, Khourl EM, et al: Systemic and coronary effects of coronary artery occlusion in the unanesthetized dog. Am J Fhyslol220:646-654, 1971 SkeKon RB, Gergeiy N, Yanntng GW, et al: Mortalii studies in experlmental coronary occlusion. J Thorac Cardiovasc Surg 44390-96.1962 Herds AS: Factors which determine prognosis in experimental coronary occlusion. In, Sudden Cardiac Death (Surawicz B, Pellegrin ED, ed). New York, Grune 8 Stratton, 1964, p 1 IO-121 BtePhen~~ SE, Cole RK, Parrish TF, et al: Ventricular fibrillation during and after coronary artery occlusion: incidence and protection afforded by various drugs. Am J Cardiol 577-87, 1960
rrprH 1974
The Amerkan
Journal of CARDIOLOGY
15. Gchewr 0, Grea L, Btum L: Hemodynamlc studies in experimental coronary ocdusbn: IV. Stellate ganglbnectomy experiments. Am Heart J 14669-676.1937 16. Fe5 HI, Klltr LN, Moore RA, et al: The electrocardiographic changes in myocardlal lschemla: I. The effects of ligation of the feft anterior descending coronary artery with and without occlusion of the inferior vena cava. Am Heart J 6522-535, 1931 17. Johnrt~n FD, HI6 IGW, wlbon FN: The form of the electrocardiogram in experimental myocardial infarction. II. The early effects produced by ligation of the anterior descending branch of the left coronary artery. Am Heart J 10:889-902,1935 18. Harris RR, Hwsey R: The electrocardiographic changes following coronary artery llgation in dogs. Am Heart J 12:724-735, 1936 19. DonaM D, t&x HE: The canine septal coronary artery: an anatomic and electrophysbbgic study. Am J Physiol 176: 143154.1954 20. wibon FN, Httl KIW, John&on TD: The form of the electrocardii ogram in experimental myocardiil infarction: I. Septal infarcts and the origin of the preliminary deflections of the canine levocardiogram. Am Heart J 9596-615, 1934 21. Hfll fGW, Johnson FD, Wtteon FM The form of the electrocardiogram in experimental myocardiil infarction: V. The later effects produced by ligation of the right coronary artery. Am Heart J 16:309-320.1936 22. 6oherte9 RJ, Lazrara R, Abellelra JL, et al: Mechanisms of early and late arrhythmias due to myocardiil ischemia and infarction (abstr). Circulation 46:suppl IMI-59, 1972 23. Lown B, Rubemvan W: The concept of pm-coronary care. Mod Cone Cardtovasc Dls 39:97-102. 1970 24. Pentrldge JF, Geddee JS: A mobile intensive-care unit in the management of myocardtl infarction. Lancet 2:271-273, 1967 25. odd HK, Lelnbech RC, Sandem CA: Use of sublingual nitroglycerin in congestive heart failure following acute myocardial infarction. Ciiculatbn 46:639-845, 1972
Volume 33
Reduction in the Incidence of
Spontaneous Ventricular Fibrillation During Coronary Occlusion in Dogs
JEFFREY
S. BORER,
MD
KENNETH
M. KENT,
MD,
ROBERT
E. GOLDSTEIN,
STEPHEN
E. EPSTEIN,
PhD MD
MD.
Bethesda, Maryland
Previous investigations have demonstrated that nitroglycerin reduces ischemk injury and enhances ventricular electrical stabtffty during coronary occlusion in dogs. These beneficial effects were potenttated by preventing drug-induced hypotension wtth alpha adrenergk agontsts. To determine whether nitroglycerin can prevent spontaneous post-occluston ventricular fibrillation, 27 open chest dogs w&e asslgned in random fashion to two groups-control (saline infusion) and nttrogfycerin-treated (0.45 mg intravenous bolus infusion followed by 0.3 mg/ min continuous infusion). Afler 10 minutes of lnfuskn the lefl anterior descending and septal coronary arteries were occluded at thetr origins. Hypotensive effects of nitroglycerin were prevented by Intermittent intravenous doses of methoxamlne; mean arterial pressure and heart rate in control and treated animals were thus IndWngulshabk. lnfuskns continued until ventricular fibrtflatkn occurred or 30 minutes elapsed. Twelve of 13 control dogs died wtth ventrkular Hbrillatkn; only 7 of 14 nitrogtycerln-treated dogs died (P
The use of nitroglycerin traditionally has been avoided in the presence of acute myocardial infarction because of the fear that nitroglycerin-induced hypotension and tachycardia might exacerbate the ischemit insult. Recently, however, nitroglycerin was found to reduce the degree of ischemic injury and to increase the threshold at which ventricular fibrillation could be induced electrically during experimental acute coronary occlusion14; both of these salutary effects were enhanced if nitroglycerin-induced hypotension was prevented by administration of an alpha adrenergic agonist. In this investigation we have determined whether nitroglycerin is capable of inhibiting the spontaneous occurrence of ventricular fibrillation during acute coronary occlusion in dogs when drug-induced hypotension is prevented with methoxamine. From the Cardickgy Branch, National Heart and Lung Institute, Bethesda, Md. 20014. Manuscript accepted January 16, 1974. Address for reprints: Jeffrey S. Borer, MD, Cardii Branch, National Heart and Lung InMute, Bldg. 10, Room 7515, Bethesda, Md. 20014.
Methods Twenty-seven male dogs weighing 16 to 25 kg were randomized into control and nitroglycerin-treated groups. Each dog was anesthetized with intravenously administered sodium pentobarbital (35 mg/kg). A catheter was intraduced into the femoral artery for pressure recording and into a limb vein
April 1974
The American Journal of CARDfCLOGY
Vohmm 33
517
t4lmoavoERlN
lr4mmoN
OF VENTfWULAR
FBFtlLLATKIN-BORE8
for drug administration. Standard subcutaneous electrodes were inserted for recording the electrocardiogram. The heart was exposed through a left thoracotomy during positive pressure ventilation. The left anterior descending and septal coronary arteries were dissected free at their origins. Arterial hemoglobin oxygen saturation and pH were then determined and the respirator adjusted so that oxygen saturation was at least 91 percent, and pH was between 7.42 and 7.52. All dogs had sinus rhythm. Each dog in the treated group received an initial intravenous bolus infusion of 0.45 mg of nitroglycerin followed by a continuous intravenous infusion of 0.3 mg/min. The infusion solution was prepared by dissolving nitroglycerin tablets (Lilly) in normal saline solution in quantities permitting an infusion rate of 0.5 ml/min. Methoxamine, an alpha adrenergic agonist, was administered intermittently to maintain mean arterial pteskure at the pre-nitroglycerin level. Each control dog received an infusion of normal saline solution, also at a rate of 0.5 ml/min. After 10 minutes of infusion, the left anterior descending and septal coronary arteries were simultaneously clamped at their origins; the clamp was suspended by sutures from an overlying crossbar so that traction on the coronary arteries was relatively constant despite respiratory movements. The clamp was carefully placed so as to avoid occluding either the left main or left circumflex coronary arteries. To ensure that such inadvertent occlusion had not occurred, after each experiment the heart was removed with the clamp in place and the coronary arteries were probed, opened and inspected. Mean arterial pressure and the electrocardiogram were recorded continuously. After occlusion, each experiment continued until the dog died with ventricular fibrillation, or until 30 minutes had elapsed without ventricular fibrillation. This duration of observation was chosen since preliminary experiments with this model demonstrated that if fibrillation did not develop within 30 minutes after occlusion, it did not develop during a subsequent hour of observation either in control or nitroglycerin-treated dogs. The rate of administration of methoxamine as well as nitroglycerin was identical in treated dogs that experienced ventricular fibrilhtion and in treated survivors. Statistical analysis of the difference in incidence of ventricular fibrillation in control and treated groups was performed with the use of the Fisher Exact Test. Comparison of blood pressure and heart rate was performed with the Student t test.
Results Before infusion, no significant differences in mean arterial pressure or heart rate existed between control and treated dogs. Mean arterial pressure in control dogs was 120 f 5 mm Hg and in treated dogs 128 k 6 mm Hg. Heart rate in control dogs was 166 f 7 beats/min and in treated dogs was 170 f 6 beats/min. Moreover, during the course of occlusion, no significant differences developed between the control and treated dogs that were alive at any given assessment point. Arterial pressure remained relatively constant in each dog for the duration of the experiment, except for transient fluctuations associated with arrhythmias which, when ventricular fibrillation did not supervene, were only of a few seconds’ duration. Among the treated dogs, no significant differences in h&art rate or blood pressure were discernible during the course of the experiments when comparing the dogs that died with those that survived.
518
Aplll974
The American Journal of CARDIOLOGY
Volume 33
ET AL.
Ventricular fibrillation occurred in 12 of 13 control dogs but in only 7 of 14 treated dogs (P dO.05, Fig. 1). No dog had ventricular fibrillation after surviving more than 18.5 minutes of occlusion, and most (15 of 19) died between 11 and 18.5 minutes after occlusion. No dog had atrioventricular dissociation during the course of the experiment. Discussion The results of this investigation demonstrate that nitroglycerin (its hypotensive effects obviated by simultaneous administration of methoxamine) markedly diminishes the incidence of ventricular fibrillation occurring spontaneously in an experimental model of acute myocardial infarction. These results are in accord with and extend our previous studies3p4 demonstrating that nitroglycerin, alone or with phenylephrine, significantly increases the threshold at which ventricular fibrillation can be induced electrically during coronary occlusion in dogs. Mechanisms of beneficial action of nitroglycerin: The mechanisms by which nitroglycerin and
methoxamine reduce the prevalence of ventricular fibrillation are unknown. Nitroglycerin alone, and in combination with methoxamine, decreases the degree of myocardial ischemia occurring during experimental coronary occlusion.lp2 It appears likely that such an effect is responsible for enhanced survival. This conclusion is reinforced by our previous findings that nitroglycerin increases ventricular fibrillation threshold in the presence of ischemia but does not do so when ischemia is absent. It is unclear, however, whether nitroglycerin reduces ischemia by decreasing oxygen demand of the heart, increasing blood flow to ischemic areas, or both. The actions of nitroglycerin alone on the prevalence of spontaneous ventricular fibrillation during
14-
12 -
1 2
0
No VFfl
VF
-
2-
0
CONTR L
TNG 8 METHOXAMINE FtGURE 1. Ventricular fibrillation after coronary artery occlusion. Drug administration in treated (TNG & Methoxamine) group and saline infusion in control group were begun 10 minutes before coronary occlusion.
coronary occlusion is yet to be determined. That this agent contributes markedly to the decrease in ventricular fibrillation observed when both nitroglycerin and methoxamine are administered, however, is suggested by the finding that nitroglycerin itself increased ventricular fibrillation threshold during acute myocardial ischemia.3*4 When the hypotensive effects of nitroglycerin were abolished by simultaneous administration of another alpha adrenergic agonist (phenylephrine), a further increase in ventricular fibrillation threshold was observed. Moreover, we have found no significant reduction in the incidence of spontaneous postocclusion fibrillation after the administration of phenylephrine alone, in amounts sufficient to raise mean arterial pressure to levels associated with significant reduction in ischemit injury (unpublished observations). Thus, the results of the previous studies, in conjunction with those of this investigation, indicate that nitroglycerin can inhibit the development of ventricular fibrillation occurring during experimental acute coronary occlusion and that this effect is potentiated by preventing the reduction in arterial pressure that this drug might cause. The dog model of ischemia-induced ventricular fibrillation used in the present investigation differs
considerably from models used in other studies. In such models, although wide fluctuations exist, the incidence of early ventricular fibrillation has generally been far lower than in the present model, whereas hemodynamic abnormalities have often been prominent. Thus, although occlusion of the left main coronary artery leads almost uniformly to ventricular fibrillation, this intervention usually causes hypotension and cardiogenic shock.5-7 When the circumflex coronary artery is occluded in the open chest dog, the cumulative incidence of ventricular fibrillation is about 33 percent. 5spgIn the closed chest dog, the incidence has been approximately 60 percent, but the range from study to study is extensive (0 to 75 percent) and severe hypotension is a frequent complicating feature.7*8J0-12 Approximately 30 percent of more than 750 closed and open chest dogs studied have had fibrillation within 30 minutes after proximal occlusion of the left anterior descending coronary artery5~8~gJ3-18;in combined small series about 10 percent of dogs had early fibrillation after occlusion of the septal artery.5p1g*20 The incidence of ventricular fibrillation after occlusion of the right coronary arIn this study, the septal corotery is 10 percent. 5,7pg,21 nary artery was systematically occluded together with the left anterior descending coronary artery. Both vessels were occluded proximal to any branches.
This intervention led to incidence of ventricular fibrillation of 92 percent in the control group. In more recent studies from our laboratory in which the same model has been used, the cumulative incidence of fibrillation in untreated animals has been 87 percent (71 of 82). Changes in blood pressure and heart rate after occlusion have been relatively slight in virtually all studies, and are comparable to those reported here. Moreover, our data indicate that the model can be influenced by therapeutic interventions, despite the ischemic insult and high rate of ventricular fibrillation. Hence, this model of acute infarction appears to have particular advantages for evaluating interventions that are capable of reducing the incidence of spontaneous ventricular fibrillation during the early phase of acute myocardial infarction. Clinical implications: The applicability of our findings to acute myocardial infarction in man is unknown. The protective effects of nitroglycerin on the occurrence of ventricular fibrillation were demonstrated in dogs with acute coronary occlusion but with otherwise normal coronary arteries and normal myocardium. It is possible that nitroglycerin does not exert similar effects when long-term multivessel disease is present. Moreover, other workers22 have demonstrated that the mechanism of ventricular fibrillation is different early after coronary occlusion than it is several hours later. Thus, although our results suggest potential benefit from nitroglycerin (with methoxamine) during the early phase of acute myocardial infarction in man (when most arrhythmic deaths OCCUP~*~~), the drug may not have similar effects later in the course of infarction. There is now an impressive body of experimental evidence demonstrating that during acute coronary occlusion nitroglycerin decreases ischemic injury, enhances electrical stability of the ventricle and, as our study has shown, reduces the incidence of spontaneously occurring ventricular fibrillation. Clinical studies25 indicate that during the course of acute myocardial infarction associated with left ventricular failure in man, administration of nitroglycerin can result in hemodynamic improvement. Thus, these experimental and clinical studies suggest that the general reluctance to administer nitroglycerin during acute myocardial infarction should he reconsidered since the drug may be of unique therapeutic value in this condition. Acknowledgment We gratefully acknowledge the expert technical assistance of Mr. Richard McGill and Mr. William Parker.
References 1. Smith ER, Redwood DR, McCarron WE, et al: 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 myocardttl ischemia. Circulatfon 4751-57, 1973
2. Hlrshfeld JW, Borer JS, Goldeteln RE, et al: Reduction in severity and extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion. Circulatiin 49:291-297,1974 3. Borer JS, Kent KM, Goldafeln RE, et al: Nitroglycerin-induced
April 1974
The American Journal of CARBKXGGY
Vehane 33
919
AL.
4.
5. 6.
7.
6.
9. 10.
11.
12.
13.
14.
520
enhancement of ventricular electrlll stability and reduction in the lnckfsnce of spontaneous ventricular flbrfllation during coronary occfusbn in dogs (abstr). Circulation 48:suppl IV:IV-126, 1973 Kent KM, Sdth ER. Redwood DR, et al: Beneficial electro physic effects of nitroglycerin during acute myocardiil infarct&n. Am J Cardiol33:513-516.1974 Porter W’R On the results of ligation of the coronary arteries. J Fhysfoll5:121-136, 1694 Hefnbecker P, Barton WA: An effective method for the development of collateral circulation to the myocardium. Ann Surg 114:166-190, 1941 APert JB, Leadl JR: Effect of the level of ligature on mot-talky follow@ ligation of the circumflex coronary artery in the dog. Am Heart J 39273-276, 1950 Memhg GW, McEechem CG, Hall GE: Reflex coronary spasm fo6owfng sudden occlusion of other coronary branches. Arch Intern Med 64~661-674.1939 sndth FM The ligation of coronary arteries with electrocardiographic study. Arch Intern Med 22:8-27, 1918 Khan MI, Hadton Jl, Manning GW: protective effect of beta abenerglc blockade in experimental coronary occlusion in conscious dogs. Am J Cardbl30:832-837, 1972 Paeyk S, Boor CM, Khourl EM, et al: Systemic and coronary effects of coronary artery occlusion in the unanesthetized dog. Am J Fhyslol220:646-654, 1971 SkeKon RB, Gergeiy N, Yanntng GW, et al: Mortalii studies in experlmental coronary occlusion. J Thorac Cardiovasc Surg 44390-96.1962 Herds AS: Factors which determine prognosis in experimental coronary occlusion. In, Sudden Cardiac Death (Surawicz B, Pellegrin ED, ed). New York, Grune 8 Stratton, 1964, p 1 IO-121 BtePhen~~ SE, Cole RK, Parrish TF, et al: Ventricular fibrillation during and after coronary artery occlusion: incidence and protection afforded by various drugs. Am J Cardiol 577-87, 1960
rrprH 1974
The Amerkan
Journal of CARDIOLOGY
15. Gchewr 0, Grea L, Btum L: Hemodynamlc studies in experimental coronary ocdusbn: IV. Stellate ganglbnectomy experiments. Am Heart J 14669-676.1937 16. Fe5 HI, Klltr LN, Moore RA, et al: The electrocardiographic changes in myocardlal lschemla: I. The effects of ligation of the feft anterior descending coronary artery with and without occlusion of the inferior vena cava. Am Heart J 6522-535, 1931 17. Johnrt~n FD, HI6 IGW, wlbon FN: The form of the electrocardiogram in experimental myocardial infarction. II. The early effects produced by ligation of the anterior descending branch of the left coronary artery. Am Heart J 10:889-902,1935 18. Harris RR, Hwsey R: The electrocardiographic changes following coronary artery llgation in dogs. Am Heart J 12:724-735, 1936 19. DonaM D, t&x HE: The canine septal coronary artery: an anatomic and electrophysbbgic study. Am J Physiol 176: 143154.1954 20. wibon FN, Httl KIW, John&on TD: The form of the electrocardii ogram in experimental myocardiil infarction: I. Septal infarcts and the origin of the preliminary deflections of the canine levocardiogram. Am Heart J 9596-615, 1934 21. Hfll fGW, Johnson FD, Wtteon FM The form of the electrocardiogram in experimental myocardiil infarction: V. The later effects produced by ligation of the right coronary artery. Am Heart J 16:309-320.1936 22. 6oherte9 RJ, Lazrara R, Abellelra JL, et al: Mechanisms of early and late arrhythmias due to myocardiil ischemia and infarction (abstr). Circulation 46:suppl IMI-59, 1972 23. Lown B, Rubemvan W: The concept of pm-coronary care. Mod Cone Cardtovasc Dls 39:97-102. 1970 24. Pentrldge JF, Geddee JS: A mobile intensive-care unit in the management of myocardtl infarction. Lancet 2:271-273, 1967 25. odd HK, Lelnbech RC, Sandem CA: Use of sublingual nitroglycerin in congestive heart failure following acute myocardial infarction. Ciiculatbn 46:639-845, 1972
Volume 33