Elucidation of roles and development of selective blockers for novel voltage-gated Ca2+ channels in peripheral resistant arterioles

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We have recently found that in peripheral resistant arterioles which mainly contribute to regulating the blood pressure and circulation, nifedipine-insensitive (NI-CC) voltage-dependent Ca2+ channels (VDCCs) having entirely distinct biophysical and pharmacological properties from those of hitherto-known VDCCs predominantly exist. The density of NICCs in peripheral circulation appears to increase dramatically towards the periphery, reaching almost 100 %. In this study, we have clarified the following points about these NI-CCs :(1)NI-CCs showing almost identical properties to those in guinea-pig mesenteric terminal artery have been identified in the same regions of rat and rabbit,(2) NI-CCs undergo the effective regulation of a major sympathetic neurotransmitter ATP, which potentiates and inhibits NI-CC activities through channel protein phosphorylation by protein kinases A and C at low and higher ATP concentrations, respectively.(3) Arteriolar diameter or tone under pressurized conditions appears to be at least in part maintained by Ca2+ entry through NI-CC.(4) Amongst peptide (w-contoxin GVIA, MVIIC, w-agatoxin IVA, SNX482, sFTX3.3) and chemical blockers for VDCCs that are available at present, only mibefradil (Ro40-5967 ; F-Hoffman La Roche) and arylpiperadine derivatives (Snp200001,200002,200003 ; Suntory) completely suppressed NI-CC currents at micromolar concentrations. However, these effects are nonspecific to other types of VDCCs such as T- and R-type VDCCs, the IC50 values being not as three times low as those for the latter two VDCCs. New peptide bloekers selective for NI-CC have not yet been successfully obtained from the screening of natural toxins of snakes, the efforts will be extended to insect and marine toxins in future investigations.