Arginine analogues 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-arginine (L-NNA) on the dilation of pial arterioles to arterial hypercapnia induced by inhalation of 3, 5, and 7% CO2 in anesthetized cats equipped with cranial windows. L-NNA at 250 microM, but not at lower concentrations, 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 microM also abolished the pial arteriolar dilation in response to cromakalim, minoxidil, and pinacidil, three known openers of ATP-sensitive K+ channels, and this effect could be reversed by L-arginine. Application of glyburide, which blocks ATP-sensitive K+ channels, also reduced the response to CO2. Subsequent application of L-NNA in these experiments had no additional effect. Vasodilation induced by sodium nitroprusside and 3-morpholinosydnonimine, two known NO donors, was unaffected by glyburide. NG-monomethyl-L-arginine had effects similar to those of L-NNA in the cat and rat at concentrations as low as 20 microM. Our findings suggest that arginine analogues inhibit hypercapnic vasodilation by blocking ATP-sensitive K+ channels, independently of activation of guanylate cyclase via increased production of NO. Furthermore, the data suggest that ATP-sensitive K+ channels may have an arginine site that influences their function.
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Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond 29298, USA.
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D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives*; D001160:Arterioles / Q000187:drug effects; D002415:Cats; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006935:Hypercapnia / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D006162:Guanylate Cyclase