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Different negative inotropic activity of Ca2(+)-antagonists in human myocardial tissue
R H Schwinger1, M Böhm, E Erdmann
1Medizinische Klinik I der Universität München.
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.
Insights
Calcium channel blockers like verapamil and diltiazem, and 1,4-dihydropyridines, show varying negative inotropic effects on human heart muscle. Their potency relates to therapeutic plasma concentrations, impacting heart failure treatment.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Calcium channel blockers (CCBs) are crucial in cardiovascular therapy.
- Understanding their inotropic effects on human myocardium is vital for clinical application.
- Previous studies often lack direct comparison across different CCB classes in human tissues.
Purpose of the Study:
- To assess the negative inotropic effects of various CCBs on isolated human cardiac muscle.
- To compare the potency of different CCB classes (1,4-dihydropyridines, phenylalkylamines, benzothiazepines).
- To investigate the influence of heart failure severity and tissue type on CCB effects.
Main Methods:
- Isometric force of contraction was measured in human papillary muscle strips and auricular trabeculae.
- Concentration-dependent effects of isradipine, nitrendipine, nifedipine, verapamil, and diltiazem were evaluated.
- Restorative effects of external calcium (Ca2+) were assessed after CCB pretreatment.
Main Results:
- All tested CCBs exhibited concentration-dependent negative inotropic effects.
- CCB potency was consistent across different stages of heart failure (NYHA II-III vs. NYHA IV).
- Auricular trabeculae showed higher sensitivity (lower IC50 values) to CCBs than papillary muscles, notably for nifedipine, nitrendipine, and verapamil.
Conclusions:
- 1,4-dihydropyridines, verapamil, and diltiazem differentially affect Ca2+-mediated force generation.
- A correlation exists between in vitro negative inotropic potency and in vivo therapeutic plasma concentrations.
- The rank order of potency (isradipine ≤ nitrendipine < diltiazem < nifedipine < verapamil) has potential clinical relevance for managing cardiac dysfunction.