Effects of HNS-32, a novel antiarrhythmic agent, on guinea-pig myocardium.
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 Ca(2+) 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 Ca(2+) channel at higher concentrations.
Noguchi
Kazuo
K
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan. kazuo.noguchi@po.rd.taisho.co.jp
Kase
Junya
J
Saitoh
Mariko
M
Masumiya
Haruko
H
Saitoh
Masaki
M
Nakazawa
Tomoo
T
Tanaka
Yoshio
Y
Tanaka
Hikaru
H
Hashimoto
Keitaro
K
Shigenobu
Koki
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D011725:Pyridines; C108264:HNS 32; D014700:Verapamil; D004206:Disopyramide