Effect of a ‘vagomimetic’ atropine dose on canine cardiac vagal tone and susceptibility to sudden cardiac death

Abstract

We manipulated the level of cardiac vagal tone in dogs with healed myocardial infarctions during exercise plus acute ischemia, to explore vagal involvement in the pathophysiology of sudden cardiac death. We occluded the circumflex coronary artery during the last minute of treadmill exercise in 32 dogs with healed anterior myocardial infarctions. Twenty-one dogs experienced ventricular fibrillation (susceptible) and 11 did not (resistant). On a subsequent day, we gave intravenous low-dose atropine to susceptible dogs to increase their levels of cardiac vagal tone, as estimated by moving polynomial time-series analysis of R-R interval variability (0.24-1.04 Hz). We also measured vagal responses to coronary occlusion at rest, before and after low-dose atropine. In susceptible dogs, atropine increased the average vagal tone index at rest (atropine: 7.3 +/- 0.4 versus control: 6.6 +/- 0.5 ln ms2, P < 0.01) and during maximum exercise (atropine: 2.5 +/- 0.4 versus control: 1.6 +/- 0.3 ln ms2, P < 0.01), but failed to prevent ventricular fibrillation actually decreased from 63 +/- 3 to 42 +/- 2s (P < 0.01), and R-R interval shortening elicited by coronary occlusion increased (atropine: delta -144 +/- 64 versus control: delta -55 +/- 32 ms, P < 0.01). In resting susceptible dogs, atropine significantly increased preocclusion indexes of vagal tone (atropine: 7.8 +/- 0.3 versus control: 6.9 +/- 0.4 ln ms2, P < 0.01), but did not prevent large reductions of vagal tone during ischemia (atropine: delta -4.4 +/- 0.6 versus control: delta -3.8 +/- 0.4 ln ms2, P > 0.05). We conclude that increases of resting vagal tone after low-dose atropine in dogs with healed anterior myocardial infarctions do not protect against sudden cardiac death. Quite the contrary, vagal tone is withdrawn more completely during ischemia, and the time to ventricular fibrillation during exercise plus ischemia is shortened.

Animal models of lethal arrhythmias

“…Nonuniformities in refractory period could set the stage for the formation of irregular reentrant pathways and ventricular arrhythmias. In a similar manner, the ATP-sensitive potassium-channel antagonist glibenclamide was shown to attenuate ischemically induced reductions in the refractory period [Tweedie et al, 1993;Billman et al, 1998]. In contrast, activation of the ATP-sensitive potassium current with pinacidil elicited a marked dispersion of repolarization and refractory period between the epicardium and endocardium, leading to the development of extrasystoles [DiDiego and Antzelevitch, 1993].…”

“…This drug can attenuate the ischemically induced changes in the ST-segment in intact anesthetized or unanesthetized animals [Kondo et al, 1996;Billman et al, 1998]. Glibenclamide also prevented arrhythmias induced by ischemia in isolated hearts [Pogatsa et al, 1988;Wolleben et al, 1989;Kantor et al, 1990;Gwilt et al, 1992;Tosaki et al, 1995].…”

“…Billman et al [1993,1998] further demonstrated that glibenclamide prevented ventricular fibrillation induced by the combination of acute ischemia during submaximal exercise in animals previously shown to be susceptible to sudden death. It should be noted, however, that in these animals glibenclamide significantly reduced both the exercise-and reactive-hyperemia-induced increases in coronary blood flow as well as depressed ventricular function (large reductions in left ventricular dP/dt maximum) [Billman et al, 1993[Billman et al, , 1998]. In the isolated working rabbit heart, glibenclamide provoked an immediate decrease in coronary blood flow, reducing forward flow to zero [Wolk et al, 1999].…”

“…Similar results were also obtained in conscious dogs. Billman et al [1998] demonstrated that either glibenclamide or the cardioselective ATP-sensitive potassium-channel antagonist HMR 1098 attenuated ischemically induced S-T segment changes. These drugs also prevented ischemically induced increases in the descending portion of the T wave (an index of the transmural dispersion of repolarization [Yan and Antzelevitch, 1998].…”

Cardiac cholinergic NO-cGMP signaling following acute myocardial infarction and nNOS gene transfer

“…Furthermore, we also hypothesized that gene transfer of nNOS into the right atria would restore parasympathetic control of cardiac excitability since enhanced cardiac vagal activity is antiarrhythmic (17,21,52).…”