Effects of HNS-32, a Novel Antiarrhythmic Agent, on Guinea-Pig Myocardium

Abstract

The electrophysiological and mechanical effects of HNS-32, a novel azulene-1-carboxamidine derivative with antiarrhythmic activity, were studied in isolated guinea-pig myocardial preparations. HNS-32 (10^–6–10^–4 mol/l) concentration-dependently decreased the maximum rate of rise (V_max) of action potential in isolated papillary muscle; the potency was the same or slightly higher than that of disopyramide. At 10^–4 mol/l, HNS-32 also shortened the action potential duration (APD) and depolarized the resting membrane potential; these effects were similar to those of 10^–5 mol/l verapamil. HNS-32 (10^–7–10^–4 mol/l), as well as verapamil (10^–8–10^–5 mol/l) and disopyramide (10^–6–10^–3 mol/l), had concentration-dependent negative chronotropic and negative inotropic effects on isolated right atrial and right ventricular papillary muscle preparations, respectively. The concentration-response relationship for the positive chronotropic effect of isoproterenol was not affected by HNS-32 (10^–5 mol/l). In isolated ventricular myocytes, HNS-32 (10^–6–10^–4 mol/l) concentration-dependently inhibited the peak amplitude of the L-type Ca²⁺ current. These results suggest that NHS-32 has V_max reducing activity on myocardial tissue, which may be responsible for antiarrhythmic effect. The drug may also have additional effect on the Ca²⁺ channel at higher concentrations.

A Review of HNS‐32: A Novel Azulene‐l‐Carboxamidine Derivative with Multiple Cardiovascular Protective Actions

“…Direct in vitro effects of HNS-32 on cardiac tissues were further investigated in isolated guinea pig tissue (20). HNS-32 ( tions of the isolated and electrically-driven (at 1 Hz) right ventricular papillary muscle (negative inotropic effects, EC 50 = 9 ìM).…”

“…To obtain additional direct evidence that HNS-32 has ion channel blocking actions, the effects of this compound on electrophysiological parameters were investigated in isolated guinea pig ventricular papillary muscle (20). Figure 7A shows the changes in action potential configuration before and after the administration of HNS-32 ( ( Fig.…”

“…Direct in vitro effects of HNS-32 on cardiac tissues were further investigated in isolated guinea pig tissue (20). HNS-32 (10 -6 to 10 -4 M) decreased the rate of contractions of guinea pig right atria (negative chronotropic effects, EC 50 = 19 ìM) and inhibited contrac-Cardiovascular Drug Reviews, Vol.…”

Cardiovascular Effects of Orally Administered HNS-32, an Originally Synthesized Azulene-1-carboxamidine Derivative, Assessed in the In Vivo Rat Model

“…It has been shown to inhibit sodium and calcium channels of guinea pig myocardial cells (2,3), to suppress the sinus nodal automaticity and ventricular contractile force of the isolated guinea pig and canine hearts (1,3), and to inhibit the atrioventricular nodal and intraventricular conduction of isolated canine hearts (1). This drug has been shown to inhibit both L-type calcium channel-dependent and -independent vascular contraction of pig coronary artery and rabbit aorta (4,5), to increase the coronary blood flow of the isolated canine heart (1), and to exert antiarrhythmic effects against canine and rat ventricular arrhythmia models (1,2).…”