Potent vasodilatory with minor cardiodepressant actions of mibefradil in human cardiac tissue.
1. The present study compared the cardiovascular effects of mibefradil (MIB), a novel Ca2+-channel antagonist with high selectivity for T-type Ca2+-channels to the effect of the L-type Ca2+-channel-antagonists nifedipine (NIF) and diltiazem (DIL) in left ventricular myocardium and coronary arteries of hearts obtained from patients suffering from dilated cardiomyopathy (NYHA IV). Right atrial myocardium from patients undergoing aortocoronary bypass surgery without signs of cardiac failure was studied as well. 2. NIF and DIL (100 micromol l(-1)) completely depressed force of contraction (FOC) in electrically driven left ventricular myocardium (NIF 6.5+/-1.4% and DIL 7.1+/-1.2% of control), whereas a similar concentration of MIB only reduced force of contraction to 55.1+/-4.0% of the basal FOC. The negative inotropic potency as measured by the concentration needed to reduce basal FOC for 25% was NIF (0.0095 micromol l(-1))>DIL (0.041 micromol l(-1))>MIB (9.47 micromol l(-1)). 3. All three Ca2+-channel antagonists were more potent in human atrial compared to human left ventricular myocardium to reduce FOC. 4. The rank order of Ca+-antagonistic moiety as measured by the decrease of the intracellular Ca2+-transient (fura-2 ratio method) was NIF>DIL>MIB. 5. All Ca2+-channel antagonists completely relaxed human coronary arteries (% of papaverine effect: MIB 81.7+/-5.5%, DIL 91.3+/-0.9%, NIF 96.4+/-3.7%) precontracted with PGF2alpha (0.3 micromol l(-1)). The rank order of vasodilatory potency was NIF (EC50; 0.02 micromol l(-1))>DIL (0.13 micromol l(-1))>MIB (2.05 micromol l(-1)). 6. The vasoselectivity measured by the ratio of the concentration needed to achieve a 25% decrease in force and the concentration needed for 25% vasodilatation was 316 for MIB, 1.5 for NIF and 1.0 for DIL. 7. The present study provides evidence that blockade of T-type Ca2+-channels (e.g. mibefradil) results in potent vasodilatory properties with only minor cardiodepressant effects.
Brixius
K
K
Laboratory of Muscle Research and Molecular Cardiology, Clinic III of Internal Medicine, University of Cologne, Germany.
Mohr
V
V
Müller-Ehmsen
J
J
Hoischen
S
S
Münch
G
G
Schwinger
R H
RH
D000328:Adult; D000368:Aged; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D006321:Heart / Q000187:drug effects*; D006801:Humans; D020748:Mibefradil; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D005456:Fluorescent Dyes; D013764:Tetrahydronaphthalenes; D014665:Vasodilator Agents; D020748:Mibefradil; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium; D016257:Fura-2