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Potent vasodilatory with minor cardiodepressant actions of mibefradil in human cardiac tissue
Author(s) -
Brixius Klara,
Mohr Valeska,
MüllerEhmsen Jochen,
Hoischen Susanne,
Münch Götz,
Schwinger Robert H G
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702034
Subject(s) - mibefradil , nifedipine , medicine , vasodilation , contraction (grammar) , inotrope , diltiazem , verapamil , cardiology , contractility , chemistry , calcium channel , calcium
1 The present study compared the cardiovascular effects of mibefradil (MIB), a novel Ca 2+ ‐channel antagonist with high selectivity for T ‐type Ca 2+ ‐channels to the effect of the L ‐type Ca 2+ ‐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 μmol 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 μmol l −1 )>DIL (0.041 μmol l −1 )>MIB (9.47 μmol l −1 ). 3 All three Ca 2+ ‐channel antagonists were more potent in human atrial compared to human left ventricular myocardium to reduce FOC. 4 The rank order of Ca 2+ ‐antagonistic moiety as measured by the decrease of the intracellular Ca 2+ ‐transient (fura‐2 ratio method) was NIF>DIL>MIB. 5 All Ca 2+ ‐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 PGF 2α (0.3 μmol l −1 ). The rank order of vasodilatory potency was NIF (EC 50 ; 0.02 μmol l −1 )>DIL (0.13 μmol l −1 )>MIB (2.05 μmol 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 Ca 2+ ‐channels (e.g. mibefradil) results in potent vasodilatory properties with only minor cardiodepressant effects.British Journal of Pharmacology (1998) 125 , 41–48; doi: 10.1038/sj.bjp.0702034