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 EC(50) 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 E-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 endo thelium-independent relaxation in association with cyclic AMP increment caused by prostaglandin I-2 released from subendothelial tissues (high concentration), and (3) another endothelium-dependent relaxation possibly mediated by unidentified mediator(s) released from the endothelium (high concentration).