Dissociation of the Inotropic Effect of Digitalis From Its Effect on Atrioventricular Conduction
YOUNG I. KIM, MD* R. JOE NOBLE, MD, FACC DOUGLAS P. Z!PES, MD, FACC Indianapolis, Indiana
From the Krannert Institute of Cardiology, the Department of Medicine, Indiana University School of Medicine, and the Veterans Administration Hospital, Indianapolis, Ind: This study was supported in part bY the Herman C. Krannert Fund, Indianapolis, Ind.; Grants HL-060308, HL05363 and HL-05749 from the National Heart and Lung Institute, Nationa! Institutes of Health, Bethesda, Md; and the Indiana Heart Association, Indianapolis, Ind. Manuscript accepted December 27 , 1974. * Present address: Department of Medicine, D.ivis!on of Cardiology, University Of Galveston Medical Branch, Galveston, Texas 77550. This studY was carried out during Dr. Kim's tenure as a U. S. Public Health Service Trainee in Cardiology. Address for reprints: R. Joe Noble, MD, FACC, Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, Ind. 46202.
The relation between sequential changes in left ventricular contractility and atrioventricular (A-V) nodal conduction and refractoriness was as, sessed in open chest dogs during intravenous administration of acetylstrophanthidin (5 #g/kg) at 5 minute intervals until toxic arrhythmias developed. At each time interval, high fidelity left ventricular pressure, its electronic derivative (dP/dt) and a His bundle electrogram were simultaneously recorded and the A-V nodal refractory period was measured by graded trains of stimuli. Animals were studied with an intact autonomic state (Group I), with pharmacologic blockade of both the beta adrenergic and parasympathetic system (Group II) and with parasympathetic blockade (Group III). Whereas contractility increased in response to small doses of digitalis, displaying a linear dose-response relation independent of autonomic tone, A-V nodal transmission indexes responded minimally to less than 50 percent of the toxic dose of digitalis, and the response was dependent upon autonomic tone. These results indicate a dissociation between the effects of digitalis on contractility and A-V transmission in that the major drug action on the ventricular contractile mechanism is a direct, linear one in contrast to the nonlinear response of A-V nodal transmission, which is predominantly mediated through the autonomic system. Clinically, these observations imply that the optimal dose and serum level of digitalis required to treat congestive heart failure may differ significantly from those required to treat supraventricular tachycardias, the therapeutic response of the latter being largely determined by the underlying autonomic tone.
In clinical practice, digitalis is used for two important pharmacologic actions: (1) to augment inotropic state, especially in depressed myocardium; and (2) to slow atrioventricular (A-V) conduction and prolong A-V refractory period in order to treat supraventricular tachyarrhythmias. Although the effects of digitalis on myocardial contractility 1-5 and A-V nodal conduction and refractoriness T M have been extensively studied in the past, little is known of the comparative changes in these two variables as a function of the dose.related response .12 The objective of this study was to quantitate simultaneously sequential changes in left ventricular contractility and A-V nodal con. duction and refractoriness. Since the actions of digitalis may be either direct, or indirect, as a consequence of the interaction of digitalis with the autonomic system, 13 the experiments were conducted in the setting of variable, but defined autonomic tone. Methods Preparation
Eighteen mongrel dogs, weighing 14 to 24 kg, were anesthetized with pentobarbital alone or in combination with morphine sulfate (see later) and were
October 6, 1975
The American Journal of CARDIOLOGY
Volume 36
459
DIGITALIS
AND A-V CONDUCTION--KIM ET AL.
100 - -
PRESSURE ( m m Hg)
L.V.
dp/dt
50-
2000
FIGURE 1. Simultaneous tracings
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