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(Circulation Research. 2007;100:342.)
© 2007 American Heart Association, Inc.

Reviews

Ca²⁺ Channel Subtypes and Pharmacology in the Kidney

Koichi Hayashi, Shu Wakino, Naoki Sugano, Yuri Ozawa, Koichiro Homma, Takao Saruta

From the Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

Correspondence to Koichi Hayashi, MD, PhD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail khayashi{at}sc.itc.keio.ac.jp

A large body of evidence has accrued indicating that voltage-gated Ca²⁺ channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca²⁺ channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca²⁺ channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca²⁺ channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca²⁺ channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca²⁺ channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca²⁺ channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type Ca²⁺ channels mediate aldosterone release as well as its effect on renal efferent arteriolar tone. Furthermore, T-type CCBs are reported to exert inhibitory action on inflammatory process and renin secretion. Similarly, N-type Ca²⁺ channels are present in nerve terminals, and the inhibition of neurotransmitter release by N-type CCBs (eg, cilnidipine) elicits dilation of afferent and efferent arterioles and reduces glomerular pressure. Collectively, the kidney is endowed with a variety of Ca²⁺ channel subtypes, and the inhibition of these channels by their specific CCBs leads to variable impact on renal microcirculation. Furthermore, multifaceted activity of CCBs on T- and N-type Ca²⁺ channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.

Key Words: afferent arteriole • efferent arteriole • Ca²⁺ channel blockers • renal microcirculation • voltage-dependent Ca²⁺ channels • renal disease • efonidipine • mibefradil

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