HUMAN VASCULAR TO CARDIAC TISSUE SELECTIVITY OF L-TYPE AND T-TYPE CALCIUM-CHANNEL ANTAGONISTS

1 Voltage-operated calcium channel (VOCC) antagonists are effective an tihypertensive and antianginal agents but they also depress myocardial contractility. 2 We compared four L-type calcium channel antagonists, felodipine, nifedipine, amlodipine and verapamil and a relatively T-t ype selective calcium channel antagonist, mibefradil, on human and rat isolated tissue assays to determine their functional vascular to card iac tissue selectivity (V/C) ratio. 3 The V/C ratio was calculated as the ratio of the IC50 value of the antagonist that reduced (by 50%) su bmaximally contracted (K+ 62 mM) human small arteries from the aortic vasa vasorum (vascular, V) mounted in a myograph and the IC50 value of the antagonist that reduced (-)-isoprenaline (6 nM) submaximally stim ulated human right atrial trabeculae muscle (cardiac, C) mounted in or gan chambers. 4 The average pIC(50) Values (-log IC50 M) for the human vascular preparations were felodipine 8.30, nifedipine 7.78, amlodipi ne 6.64, verapamil 6.26 and mibefradil 6.22. The average pIC(50) value s for the cardiac muscle were felodipine 7.21, nifedipine 6.95, verapa mil 6.91, amlodipine 5.94, and mibefradil 4.61. 5 The V/C ratio calcul ated as antilog [pIC(50)V-pIC(50)C] is thus mibefradil 41, felodipine 12, nifedipine 7, amlodipine 5 and verapamil 0.2. 6 In rat small mesen teric arteries the pIC(50) values for the five drugs were similar to t he values for human vasa vasorum arteries contracted by K+ 62 mM. Howe ver for methoxamine (10 mu M) contraction in the rat arteries the pIC( 50) values were lower for felodipine 7.24 and nifedipine 6.23, but sim ilar for verapamil 6.13, amlodipine 6.28 and mibefradil 5.91. 7 In con clusion in the human tissue assays, the putative T-channel antagonist mibefradil shows the highest vascular to cardiac selectivity ratio; so me 3 fold higher than the dihydropyridine, felodipine, and some 200 fo ld more vascular selective than the phenylalkylamine, verapamil. This favourable vascular to cardiac selectivity for mibefradil, from a new chemical class of VOCC antagonist, may be explained by its putative T- channel selectivity.