Human vascular to cardiac tissue selectivity of L- and T-type calcium channel antagonists

Abstract

1. Voltage-operated calcium channel (VOCC) antagonists are effective antihypertensive 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-type selective calcium channel antagonist, mibefradil, on human and rat isolated tissue assays to determine their functional vascular to cardiac 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%) submaximally 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 stimulated human right atrial trabeculae muscle (cardiac, C) mounted in organ chambers.

4. The average pIC₅₀ values (−log IC₅₀ M) for the human vascular preparations were felodipine 8.30, nifedipine 7.78, amlodipine 6.64, verapamil 6.26 and mibefradil 6.22. The average pIC₅₀ values for the cardiac muscle were felodipine 7.21, nifedipine 6.95, verapamil 6.91, amlodipine 5.94, and mibefradil 4.61.

5. The V/C ratio calculated as antilog [pIC₅₀V-pIC₅₀C] is thus mibefradil 41, felodipine 12, nifedipine 7, amlodipine 5 and verapamil 0.2.

6. In rat small mesenteric arteries the pIC₅₀ values for the five drugs were similar to the values for human vasa vasorum arteries contracted by K⁺ 62 mM. However for methoxamine (10 μM) contraction in the rat arteries the pIC₅₀ values were lower for felodipine 7.24 and nifedipine 6.23, but similar for verapamil 6.13, amlodipine 6.28 and mibefradil 5.91.

7. In conclusion, in the human tissue assays, the putative T-channel antagonist mibefradil shows the highest vascular to cardiac selectivity ratio; some 3 fold higher than the dihydropyridine, felodipine, and some 200 fold 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.

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