The purpose of this study was to assess the cardiovascular effects of an ultra-short-acting β-blocker, ONO-1101, by using halothane-anesthetized beagle dogs in comparison with esmolol. ONO-1101 (n = 6) or esmolol (n = 6) was administered at four infusion rates of 0.3, 3, 30, and 300 μg/kg/min. Each infusion was performed over a 30-min period, and the parameters were measured at 20-30 min after the start of each infusion. ONO-1101 significantly decreased the heart rate, rate-pressure product, left ventricular contraction, cardiac output, and relative refractory period of the right ventricle, suppressed the AV nodal conduction, and increased the effective refractory period of the right ventricle, whereas no significant change was observed in the preload and afterload of the left ventricle, intrinsic sinus nodal automaticity, His-Purkinje-ventricular conduction, and the monophasic action-potential duration of the right ventricle. The cardiovascular effects of esmolol were comparable to those of ONO-1101, except that the preload of the left ventricle was significantly increased, and the ventricular repolarization phase was shortened by 300 μg/kg/min of esmolol infusion. Meanwhile, ONO-1101 as well as esmolol significantly reduced the isoproterenol-induced increase in heart rate and ventricular contraction, but the inhibitory action of ONO-1101 was 6-8 times greater than that of esmolol. These results suggest that the suppressive effects of ONO-1101 on cardiovascular performance are significantly less potent than those of esmolol at equipotent β-blocking doses.

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The present study was designed to investigate what kinds of adaptation occurred in the canine chronic AV block model, which has been used to study torsade de pointes (TdP). Dogs at 7-10 days (acute phase) and 28-56 days (chronic phase) after AV block were assessed. Ventricular effective refractory period and monophasic action potential duration were prolonged in chronic animals compared with acute animals; moreover the electrically vulnerable period was prolonged in chronic animals. Non-specific IKr channel blocker cisapride (1 and 10 mg/kg, p.o.) was administered without anesthesia to estimate the feasibility of QT prolongation. In chronic animals, QT prolongation followed by TdP was induced in one dog by the low dose and in all by the high dose, which was not observed in acute animals. MR images indicated increases of diameter and wall thickness of both ventricles in chronic animals. The degree of hypertrophy was prominent in the right ventricular wall and septal wall. Heart weight of the chronic animals was 1.7 times greater than that of normal control subjects. Photo- and electron-micrograph analyses showed myocardial cell hypertrophy with parallel increases of collagen fiber and extracellular space in chronic animals. These electrophysiological, anatomical and histological adaptations may predispose the chronic AV block heart to drug-induced QT prolongation with enhanced risk of re-entry and early after depolarization, leading to the onset of TdP.

Chronotropic, inotropic and coronary vasodilator actions of the clinically available ampoule preparation of Salvia miltiorrhiza/Dalbergia odorifera mixture were examined using canine isolated, blood-perfused heart preparations. The mixture slightly decreased the sinoatrial rate and significantly increased coronary blood flow, but hardly affected the developed tension of the papillary muscle. The effect on coronary blood flow was induced by at least a 10-fold smaller dose than that which induced the chronotropic effect. These results were quite similar to those of a typical calcium channel blocker, verapamil, used in a previous study, suggesting that the Salvia miltiorrhiza/Dalbergia odorifera mixture may have potential as an anti-anginal drug. (Circ J 2002; 66: 182 - 184)