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

Abstract

1 Voltage-operated calcium channel (VOCC) antagonists are e ective 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 IC 50 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 IC 50 value of the antagonist that reduced (7)-isoprenaline (6 nM) submaximally stimulated human right atrial trabeculae muscle (cardiac, C) mounted in organ chambers. 4 The average pIC 50 values (7log IC 50 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 pIC 50 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 [pIC 50 V-pIC 50 C] is thus mibefradil 41, felodipine 12, nifedipine 7, amlodipine 5 and verapamil 0.2. 5 In rat small mesenteric arteries the pIC 50 values for the ®ve drugs were similar to the values for human vasa vasorum arteries contracted by K + 62 mM. However for methoxamine (10 mM) contraction in the rat arteries the pIC 50 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.

Evidence against an action of mibefradil at N-type voltage-operated calcium channels

“…Therefore, mibefradil may also have effects postjunctionally. For example, although these functional assays are sensitive to TTX (0.1 nM; neuronal Na + channel inhibitor), adrenoceptor antagonists and GVIA (N-type VOCC selective; Pruneau and Angus 1990), mibefradil at 30 µM also inhibited postjunctional calcium channels opened by exogenous isoprenaline in human isolated atria muscle (Sarsero et al 1998).…”

“…This 15-fold or so selectivity is exhibited by its potency (IC 50 ) to inhibit the T-type calcium currents in cloned (α1G, 0.27 µM and α1H, 0.14 µM with 2.0 mM Ca 2+ as charge carrier; Martin et al 2000) and native T-type Ca 2+ currents (rat vascular smooth muscle 0.2 µM; Mishra and Hermsmeyer 1994) at lower concentrations than required to inhibit L-type calcium currents (α1C from 1.7 µM to 21 µM, rat vascular smooth muscle 2.6 µM; Mehrke et al 1994;Mishra and Hermsmeyer 1994;Bezprozvanny and Tsien 1995;Seisenberger et al 1995;Welling et al 1995;Martin et al 2000). Some effects of mibefradil that may be due to T-type VOCC inhibition include: the selectivity for vascular relaxation over negative cardiac inotropism (Osterrieder and Holck 1989;Brixius et al 1998;Sarsero et al 1998), reduction in heart rate (Ertel et al 1997), reduction in subendothelial cell proliferation (Schmitt et al 1995(Schmitt et al , 1996, and protective benefits in hypertension and animals with heart failure (Bernink et al 1996;Davies et al 1997;Li and Schiffrin 1997;Massie et al 1997;Oparil et al 1997;Hermsmeyer 1998;Clozel et al 1999;Sandmann et al 2001). Although mibefradil has been withdrawn from therapy by the manufacturer because of interactions with other drugs (Griffin 1998;Krahenbuhl et al 1998;Mullins et al 1998;Spoendlin et al 1998), the therapeutic benefits of mibefradil were considered to be mainly due to the blockade of T-type VOCCs.…”

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

“…Mibefradil increased CF with an EC 50 of 54 nM and reduced contractility of myocardium and aorta with EC 50 values of 14 µM and 275 nM, respectively [337]. In human small arteries, the potassium contractures and isoprenaline-stimulated right atrial contractions were inhibited with IC 50 values of 603 nM and 24.5 µM, respectively, indicating a high (41) vascular selectivity of mibefradil [8]. 300 and 600 nM mibefradil showed a marked vascular selectivity in Langendorff-perfused rat hearts [334].…”

Efonidipine Hydrochloride: A Dual Blocker of L‐ and T‐Type Ca2+ Channels

“…The inotropic potency of verapamil was 1/3 of its vasodilator potency; this ratio was 1/17 for nifedipine, and less than 1/800 for efonidipine. In isolated human or rat tissues the vascular (as compared to cardiac) selectivity was higher for mibefradil than for other Ca 2+ channel blockers that acted mainly on L-type Ca 2+ channels (47). The extremely low negative inotropic potency of efonidipine may also involve additional mechanisms such as enhancement of Ca 2+ sensitivity of myocardial contractile proteins (27).…”