Combined L-/T-type calcium channel blockers: ready for prime time.

Opening of the voltage-dependent Ca 2 channels permits influx of Ca across the plasma membrane, triggering diverse physiological processes. These channels are widely distributed in the cardiovascular system, constituting the main route for Ca entry essential for excitation and contraction. Ten unique 1 subunits, grouped in 3 families (CaV1, CaV2, and CaV3), that encode the low-voltage– activated T-type and the high-voltage–activated L-, N-, P/Qand R-type Ca channels, have been identified.1,2 L-type Ca channels are predominantly expressed in the hearts and peripheral vasculature and serve as the preferred molecular target of the initial Ca channel antagonists in the treatment of hypertension.3 Recently, a growing body of evidence has accumulated depicting important roles of T-type Ca channels in the regulation of cardiovascular function, such as generation of pacemaker potential and regulation of arterial resistance.3,4 T-type Ca channels are found in various cell types, including neurons, cardiomyocytes, vascular smooth muscle cells, and endocrine cells, where they participate in a variety of physiological processes, such as low-threshold Ca spike generation, action potential firing, pacemaking, impulse conduction, maintenance of myogenic tone, cell proliferation, and hormone secretion.1 In addition to their predominant role in the regulation of vascular function, T-type Ca channels are also involved in cardiomyocyte growth and survival.3 T-type Ca channel blockers are capable of interrupting certain pathological hypertrophic signaling pathways, including calcineurin-mediated nuclear factor of activated T cells–3 activation.1 The importance of voltage-dependent Ca channels is demonstrated by the clinical efficacy of Ca channels blockers in certain disease conditions, as well as the widespread distribution and function of these channels.1 Three classes of chemically distinct L-type Ca channel blockers have been widely used clinically depending on their biophysical and conformation-dependent interactions with the L-type Ca channel. These 3 classes include the dihydropyridine, the phenylalkylamine (verapamil), and the benzothiazepine (diltiazem). Dihydropyridines are characterized by greater potency as vasodilators with less cardiodepressant properties than the other 2 types of Ca channel blockers. Although the clinical benefits of L-type Ca channel blockers have been well defined, the clinical value of T-type Ca channel blockade remains somewhat elusive. The newly developed dihydropyridine Ca channel blockers, including manidipine, nilvadipine, benidipine, and efonidipine, as well as the benzimidazole mibefradil, appear to possess vasodilatory properties other than blockade of L-type Ca channels.1,4 These Ca channel blockers may antagonize both Land T-type Ca channels, which possibly underlie their excellent clinical profiles, such as minimum reflex tachycardia and renal protection. Nonetheless, controversy still exists with regard to the precise role of T-type Ca channels in the regulation of vascular tone. Mice deficient in CaV3.2 T-type Ca channels display normal contractile responses and reduced acetylcholine-induced relaxation.2 Moreover, mibefradil exerts little effect on blood pressure or peripheral resistance in mice with conditional knockout of L-type Ca channels.2 R(–)-enantiomer of efonidipine, with a greater selectivity for T-type Ca channels over efonidipine, fails to alter blood pressure in hypertensive rats. The presence of Tbut not L-type Ca channel mRNA, was confirmed in microvessels with a diameter 40 m.5 T-type Ca channels are highly expressed in the microvasculature, including mesenteric and cremaster arterioles. Inhibition of these channels by mibefradil dampens vasoconstriction of these arterioles, although such effect seems to be attributed to L-type Ca channel blockade.2 In this issue of Hypertension, Ball et al6 compared the inhibition of vascular contractile responses by L-type Ca channel blockers (verapamil and nifedipine) and combined L-/T-type Ca channel blockers (mibefradil and efonidipine) in large conduit (rat aorta) and small (rat mesenteric and human subcutaneous) vessels. Although all 4 of the Ca channel blockers inhibited contractile responses to a similar extent in large vessels, the combined L-/T-type Ca channel blockers produced a significantly greater inhibition of contraction than L-type Ca channel blockers alone in small vessels. Such a differential T-channel effect in microvessels was supported by a greater expression of T-type as opposed to L-type Ca channels in microvessels but not large vessels. Given that microvessels play a pivotal role in the regulation of blood pressure, renal perfusion, and coronary blood flow, their findings implicate that T-type Ca channels may contribute to the additional benefits of the combined L-/Ttype Ca blockers in treating renal and cardiovascular The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Geriatrics (W.G., J.R.), Xijing Hospital, Fourth Military Medical University, Xi’an, China; and Center for Cardiovascular Research and Alternative Medicine (J.R.), University of Wyoming College of Health Sciences, Laramie, Wy. Correspondence to Jun Ren, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071. E-mail [email protected] (Hypertension. 2009;53:00-00.) © 2009 American Heart Association, Inc.