Role of Ca(2+)-dependent K+ channels in cerebral vasodilatation induced by increases in cyclic GMP and cyclic AMP in the rat.

BACKGROUND AND
PURPOSE: The mechanisms by which cAMP and cGMP produce vasorelaxation are not entirely clear. In this study we examined the hypothesis that relaxation of cerebral arterioles in response to receptor-mediated activation of adenylate cyclase (increase in cAMP) is mediated through Ca(2+)-dependent K+ channels.
METHODS: We measured the diameter of cerebral arterioles (basal diameter, 47 +/- 1 microns) using an open cranial window in anesthetized rats. Agonists and antagonists were applied locally in the cranial window.
RESULTS: Topical application of adenosine (0.1 and 1 mmol/L), a receptor-mediated activator of adenylate cyclase, and dibutyryl cAMP (60 and 200 mumol/L), a cell-permeable analogue of cAMP, dilated cerebral arterioles. Iberiotoxin (50 nmol/L), a selective inhibitor of Ca(2+)-dependent K+ channels, reduced vasodilatation in response to 0.1 and 1 mmol/L adenosine by 66% and 28%, respectively. Tetraethylammonium (TEA) (1 mmol/L), another inhibitor of Ca(2+)-dependent K+ channels, reduced vasodilatation to 0.1 and 1 mmol/L adenosine by 58% and 42%, respectively, and reduced vasodilatation in response to 60 and 200 mumol/L dibutyryl cAMP by 75% and 66%, respectively. Topical application of sodium nitroprusside (0.1 and 1 mumol/L), a direct activator of guanylate cyclase, and 8-bromo cGMP (200 and 600 mumol/L), a cell-permeable analogue, produced dilatation of cerebral arterioles that was inhibited by iberiotoxin (50 nmol/L) and TEA (1 and 3 mmol/L). In contrast, dilatation of cerebral arterioles in response to papaverine (which produces vasodilatation in large part by inhibition of Ca2+ channels) and aprikalim (which produces vasodilation by activation of ATP-sensitive K+ channels) was not inhibited by iberiotoxin or TEA.
CONCLUSIONS: These findings suggest that dilatation of cerebral arterioles by receptor-mediated activation of adenylate cyclase and by direct activation of guanylate cyclase in the rat is mediated in large part by activation of Ca(2+)-dependent K+ channels.