ROLE OF CALCIUM-ACTIVATED K-OXIDE( CHANNELS IN VASODILATION INDUCED BY NITROGLYCERINE, ACETYLCHOLINE AND NITRIC)

A comparative analysis was carried out of the sensitivities of in vitr o vasorelaxations by nitroglycerine (NTG), acetylcholine (ACh) and nit ric oxide (NO) to blockade by glyburide, a blocker of ATP-sensitive K channels (K(ATP)), as well as to blockade by charybdotoxin (ChTX) and iberiotoxin (IbTX), potent blockers of calcium-activated K+ channels (K(Ca)). In the isolated rabbit mesenteric artery (RMA) precontracted with 5 muM norepinephrine (NE), ACh (0.01-1 muM), NTG (0.01-5 muM) and NO (0.075-2.7 muM) produced a dose-dependent vasodilation. Glyburide (0.5 muM) had no significant effect on relaxation dose-response curves (DRCs) to ACh, NTG or NO. In contrast, glyburide completely abolished the relaxation DRC by pinacidil, a known K(ATP) opener. ChTX (10 or 1 00 nM) caused an inhibition of relaxation DRCs to ACh, NTG and NO. In all cases, ChTX shifted the relaxation DRC to the right and depressed the maximal response. Another potent K(Ca) blocker, IbTX (20 nM) also significantly inhibited relaxation DRCs to NTG, ACh and NO and inhibit ed maximal relaxation response to SNP. The effects of ChTX and IBTX we re selective; they did not inhibit relaxations by pinacidil and forsko lin. Finally, it was observed that the use of 80 mM K+ as a contractil e stimulus inhibited NTG relaxations in a manner similar to the K(Ca) blockers. Collectively, these data provide strong support for the hypo thesis that the activation of K(Ca) plays an important role in mediati ng the vasorelaxation caused by NTG, SNP, ACh and NO. It is suggested that whereas the K(ATP) play an important role in modulating vascular relaxation during hypoxia and that induced by antihypertensive drugs s uch as minoxidil and pinacidil, the K(Ca) play a similarly significant role in the regulation of vascular tone by the endothelium as well as by the therapeutic nitrates.