Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

Abstract

To evaluate the negative inotropic effect of various Ca2(+)-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca2(+)-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II-III) and in terminally failing (heart transplantation, NYHA IV) human hearts. The IC50 values were lower in auricular trabeculae than in papillary muscle strips. The difference was significant for nifedipine, nitrendipine, and verapamil. The restorative effects of external Ca2+ after pretreatment with Ca2(+)-antagonists were significantly less strong after pretreatment with 1,4-dihydropyridine than with non-dihydropyridines in papillary muscle strips. It is concluded that 1,4-dihydropyridines and verapamil and diltiazem did differently influence Ca2(+)-mediated increase in force of contraction. Moreover, a relation between the therapeutically active free plasma concentration in vivo and the negative inotropic potency in vitro can be found. This relation follows a rank order of potency for negative inotropism (isradipine less than or equal to nitrendipine less than diltiazem less than nifedipine less than verapamil) and might have clinical relevance in the treatment of patients with compromised cardiac function.

Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine

“…The difference in sensitivity to nifedipine and verapamil was thus comparable or greater than that of human arteries (Schwinger et al . ; Sarsero et al . ).…”

Frequency‐ and Potential‐Dependency of the Negative Inotropic Action of Various Dihydropyridine and Non‐Dihydropyridine Calcium Antagonists

“…For instance, it can be seen that the EC5, of nifedipine is practically independent of the K + concentration (as in Robertson & Lumley 1989) between 2.7 and 5.4 mM K + a t 1 Hz ( fig. 1987;Briand et al 1988;Schwinger et al 1990). On the other hand, it is steeply dependent on the Kf concentration (as in Lumley&Robertson 1987, orcurtis& Walker 1988 between 5.4 and 10.8 mM K + at higher stimulus frequencies ( fig.…”

Cardiovascular Characterization of [1,4]Thiazino[3,4-c][1,2,4]oxadiazol-1-one Derivatives: Selective Myocardial Calcium Channel Modulators

“…9, 10 We obtained the new 8-hydroxy-8-phenyl-8H- [1,4]thiazino [3,4-c] [1,2,4]oxadiazol-3-one (6) in a similar manner from 5-nitroso-6-phenylimidazo[2,1-b] [1,3]thiazole and dilute hydrochloric acid (Scheme 1).…”