ARGININE ANALOGS INHIBIT RESPONSES MEDIATED BY ATP-SENSITIVE K+ CHANNELS

Because arginine analogues have been reported to block the vasodilator response to hypercapnia, we investigated the effect of nitro-L-argini ne (L-NNA) on the dilation of pial arterioles to arterial hypercapnia induced by inhalation of 3, 5, and 7% CO2 in anesthetized cats equippe d with cranial windows. L-NNA at 250 mu M, but not at lower concentrat ions, significantly reduced hypercapnia-induced dilation. This effect could be reversed by L-arginine. However, hypercapnic hyperemia is not the result of increased guanosine 3',5'-cyclic monophosphate via the usual NO-mediated activation of guanylate cyclase, because application of LY-83583, which blocks guanylate cyclase, did not alter the vessel response to CO2. L-NNA at 250 mu M also abolished the pial arteriolar dilation in response to cromakalim, minoxidil, and pinacidil, three k nown openers of ATP-sensitive K+ channels, and this effect could be re versed by L-arginine. Application of glyburide, which blocks ATP-sensi tive K+ channels, also reduced the response to CO2. Subsequent applica tion of L-NNA in these experiments had no additional effect. Vasodilat ion induced by sodium nitroprusside and 3-morpholinosydnonimine, two k nown NO donors, was unaffected by glyburide. N-G-monomethyl-L-arginine had effects similar to those of L-NNA in the cat and rat at concentra tions as low as 20 mu M. Our findings suggest that arginine analogues inhibit hypercapnic vasodilation by blocking ATP-sensitive K+ channels , independently of activation of guanylate cyclase via increased produ ction of NO. Furthermore, the data suggest that ATP-sensitive K+ chann els may have an arginine site that influences their function.