||The organ-protective effect of N-type Ca(2+) channel blockade.
Kuwahara, KoichiroKimura, Takeshi
Pharmacology & therapeutics
7 , 2015-07 , Elsevier Inc.
The six subtypes of voltage-dependent Ca(2+) channels (VDCCs) mediate a wide range of physiological responses. N-type VDCCs (NCCs) were originally identified as a high voltage-activated Ca(2+) channel selectively blocked by omega-conotoxin (ω-CTX)-GVIA. Predominantly localized in the nervous system, NCCs are key regulators of neurotransmitter release. Both pharmacological blockade with ω-CTX-GVIA and, more recently, mice lacking CNCNA1B, encoding the α1B subunit of NCC, have been used to assess the physiological and pathophysiological functions of NCCs, revealing in part their significant roles in sympathetic nerve activation and nociceptive transmission. The evidence now available indicates that NCCs are a potentially useful therapeutic target for the treatment of several pathological conditions. Efforts are therefore being made to develop effective NCC blockers, including both synthetic ω-CTX-GVIA derivatives and small-molecule inhibitors. Cilnidipine, for example, is a dihydropyridine L-type VDCC blocking agent that also possesses significant NCC blocking ability. As over-activation of the sympathetic nervous system appears to contribute to the pathological processes underlying cardiovascular, renal and metabolic diseases, NCC blockade could be a useful approach to treating these ailments. In this review article, we provide an overview of what is currently known about the physiological and pathophysiological activities of NCCs and the potentially beneficial effects of NCC blockade in several disease conditions, in particular cardiovascular diseases.