Hayashi Koichi, Wakino Shu, Sugano Naoki, Ozawa Yuri, Homma Koichiro, Saruta Takao
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Circ Res. 2007 Feb 16;100(3):342-53. doi: 10.1161/01.RES.0000256155.31133.49.
A large body of evidence has accrued indicating that voltage-gated Ca(2+) channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca(2+) channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca(2+) channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca(2+) channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca(2+) channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca(2+) channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.
大量证据表明，包括L型、T型、N型和P/Q型在内的电压门控Ca(2+)通道亚型存在于肾血管和肾小管组织中，阻断这些Ca(2+)通道会对肾微循环产生多种作用。由于硝苯地平仅作用于L型Ca(2+)通道，硝苯地平主要扩张入球小动脉这一观察结果表明肾内L型Ca(2+)通道分布存在异质性，并提示其可能导致肾小球高血压。相比之下，最近开发的Ca(2+)通道阻滞剂（CCB），包括米贝拉地尔和依福地平，对L型和T型Ca(2+)通道具有阻断作用，并引起入球和出球小动脉的血管舒张，这表明两种小动脉中均存在T型Ca(2+)通道，且对肾小球内压有明显影响。最近，醛固酮已被确认为肾脏疾病的加重因素，T型Ca(2+)通道介导醛固酮释放及其对肾出球小动脉张力的影响。此外，据报道T型CCB对炎症过程和肾素分泌具有抑制作用。同样，N型Ca(2+)通道存在于神经末梢，N型CCB（如西尼地平）抑制神经递质释放会引起入球和出球小动脉扩张并降低肾小球压力。总的来说，肾脏具有多种Ca(2+)通道亚型，其特异性CCB对这些通道的抑制会对肾微循环产生不同影响。此外，CCB对T型和N型Ca(2+)通道的多方面作用可能通过非血流动力学机制在慢性肾脏病进展中提供额外益处。
