Mechanisms responsible for MaxiK_<Ca> channel-mediated vascular relaxation

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The intracellular pathway(s) controlling vascular relaxation/induced by a prostaglandin I_2 (PGI_2b, IP) agonist beraprost was investigated. Beraprost-induced relaxation of guinea-pig aorta was almost abolished in high-KCl-contracted tissue, indicating a major role of K^+ conductances in the vascular reponse. Beraprost-induced relaxation was also practically abolished by a selective MaxiK_<Ca> channel blocker, Iberiotoxin (10^<-7> M). The relaxation induced by beraprost was not significantly affected by other K^+ channel blockers glibenclamide or Ba^<2+>, but was slightly attenuated by 4-aminopyridine. Beraprost increased intracellular cANP levels, suggesting a role for cAMP-dependent pathways. RO-20-1724, a selective inhibitor of cAMP-specific phosphodiesterase, significantly potentiated beraprost-induced vascular relaxation. Iberiotoxin completely counteracted this potentiation. Moreover, tension decrement due to forskolin or 8-bromo-cyclic AMP was thoroughly restored by the toxin, c … More onfirming a role for a cAMP-dependent mechanism. However, SQ 22,536, an adenylyl cyclase inhibitor, did not affect beraprost-induced vascular relaxation though it almost totally inhibited the elevation of cAMP contents induced by beraprost, which suggests the existence of cyclic AMP-independent mechanism. Moreover, cholera toxin, an activator of the stimulatory G protein of adenylyl cyclase (Gs), significantly inhibited PGF_<2α>-induced contraction both in the absence and presence of SQ 22,536. Iberiotoxin was also capable of restoring the relaxation induced by cholera toxin. These findings suggest that MaxiK_<Ca> channel plays a central role in mediating smooth muscle relaxation following stimulation of IP receptor with beraprost in guinea-pig aorta. Both cyclic AMP-dependent and -independent pathways contribute to the MaxiK_<Ca> channel-mediated relaxation following IP receptor stimulation in this vascular tissue. Direct regulation of MaxiK_<Ca> channels by Gs partly accounts for the cyclic AMP-independent relaxant mechanism. Less