A novel benzothiazine Ca2+ channel antagonist, semotiadil, inhibits cardiac L-type Ca2+ currents.
The influence of semotiadil fumarate, a novel vasoselective Ca2+ channel antagonist with a benzothiazine skeleton, was measured on the high-threshold Ca2+ current ICa,L in guinea-pig ventricular myocytes prepared by coronary perfusion with collagenase solution. Patch- and voltage-clamp methods were used to measure ICa,L. Diltiazem, nifedipine and amlodipine were studied for comparison. Samotiadil could be shown to inhibit ICa,L in a dose-dependent manner in concentrations similar to those of diltiazem but was less effective than amlodipine and nifedipine. The IC50 for nifedipine and amlodipine was in the range between 0.1 and 1 microM and that of semotiadil and diltiazem was between 10 and 100 microM. Recovery from inactivation of ICa,L in the control and under the influence of nifedipine 0.01 microM) and amlodipine (0.1 microM) was complete alter I. Semotiadil (0.1 microM) and diltiazem (1 microM) prolonged the time to full recovery to 20 s. This significant delay in the recovery of ICa,L produced by semotiadil indicates a mode of action similar to that of the verapamil type of Ca2+ channel antagonists and masses a clear distinction between it and the dihydropyridines, which have no effect on the recovery process. The rate dependence of the effect in combination with a distinct influence of the holding potential underlines the use dependence of the mechanism underlying the effect of semotiadil. The well-known high vasoselectivity of semotiadil in combination with a relatively low Ca2+ channel antagonistic influence on the heart makes semotiadil an interesting candidate for the treatment of coronary heart diseases.
Koidl
B
B
Institut für Medizinische Physik und Biophysik, Universität Graz, Austria. bernd.koidl@kfunigraz.ac.at
Miyawaki
N
N
Tritthart
H A
HA
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D020746:Calcium Channels, L-Type; D004110:Diltiazem / Q000494:pharmacology; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D013844:Thiazoles; C064356:sesamodil; D004110:Diltiazem