Characteristics of heterogeneity in the expression of vasoconstriction in response to N(G)-monomethyl-L-arginine in isolated canine arteries.
We characterized the contractile effect of a nitric oxide (NO) synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), in isolated canine arteries. L-NMMA induced a heterogenous response: potent vasoconstriction in the cerebral arteries, and weak or no vasoconstrictor responses in different peripheral arteries. The vasoconstriction of the cerebral artery was inhibited by L-arginine but not D-arginine. L-NMMA (1(-4) M) caused a 53% decrease in guanosine 3'5'-cyclic monophosphate (cGMP) levels in the cerebral artery, but it was not significant compared with that in peripheral arteries. The L-NMMA-induced vasoconstriction was inhibited by diltiazem and nicardipine, and the heterogeneity was mimicked by treatment with charybdotoxin, a Ca2+-activated K+ (BK(Ca)) channel blocker, channels which are regulated by NO/cGMP. Both L-NMMA and charybdotoxin caused a potent vasoconstriction in the mesenteric artery precontracted with 20 mM KCl. 1 H-[1,2,4]oxadiazolo[4,3-alpha] quinoxalin-1-one (ODQ) (10(-5) M), a selective guanylate cyclase inhibitor, caused vasoconstriction in the presence of nitroprusside in the endothelium-denuded basilar artery, but not in the endothelium-denuded mesenteric artery. In conclusion, LNMMA-induced heterogenous vasoconstriction was due to the different sensitivities of vascular smooth muscles to NO/cGMP. The heterogeneity may result from a difference in the basal state of ion channels such as the voltage-dependent Ca2+ channel and the BK(Ca) channel in vascular smooth muscles.
Kikkawa
K
K
Discovery Research Laboratory, Tanabe Seiyaku, Toda-shi, Saitama, Japan. kohei-k@tanabe.co.jp
Hoshino
T
T
Yamauchi-Kohno
R
R
Murata
S
S
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism; D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009529:Nicardipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D018999:Charybdotoxin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009529:Nicardipine; D004110:Diltiazem; D006152:Cyclic GMP