Mechanism underlying substance P-induced relaxation in dog isolated superficial temporal arteries.
1. In helical strips of dog superficial temporal arteries with intact endothelium, substance P elicited a concentration-related relaxation with an EC50 of 2.8 (2.4-3.2) x 10(-10) M. 2. The relaxant response to the peptide in low concentrations (1-4 x 10(-10) M) sufficient to produce approximately half maximal relaxation was not inhibited by indomethacin, but was markedly suppressed by NG-nitro-L-arginine (L-NOARG), a nitric oxide (NO) synthase inhibitor, and by endothelium denudation. 3. High concentration (10(-7) M) of substance P produced marked relaxations in endothelium-intact strips. Removal of the endothelium attenuated the relaxation, and indomethacin or tranylcypromine suppressed the endothelium-independent relaxation. In indomethacin-treated strips with intact endothelium, L-NOARG attenuated but did not abolish the relaxation. The residual, L-NOARG-resistant relaxation was not significantly inhibited by ouabain, glibenclamide or tetraethylammonium. 4. Substance P (10(-7) M) increased the levels of cyclic GMP and cyclic AMP. The increase in cyclic GMP was abolished by endothelium denudation and treatment with L-NOARG, whereas the cyclic AMP increment was abolished by indomethacin. 5. Three different mechanisms may be involved in the substance P-induced relaxation: (1) an endothelium-dependent relaxation mediated by the release of NO from the endothelium, resulting in an increase of cyclic GMP (low and high concentrations of the peptide); (2) an endothelium-independent relaxation in association with cyclic AMP increment caused by prostaglandin I2 released from subendothelial tissues (high concentration), and (3) another endothelium-dependent relaxation possibly mediated by unidentified mediator(s) released from the endothelium (high concentration).
Enokibori
M
M
Department of Pharmacology, Shiga University of Medical Sciences, Ohtsu, Japan.
Okamura
T
T
Toda
N
N
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019335:Nitroarginine; D013373:Substance P / Q000494:pharmacology*; D013699:Temporal Arteries / Q000187:drug effects* / Q000502:physiology
D019335:Nitroarginine; D013373:Substance P; D001120:Arginine; D000242:Cyclic AMP; D006152:Cyclic GMP; D007213:Indomethacin