Pharmacologic characteristics of non-prostanoid, non-nitric oxide mediatedand endothelium-dependent relaxation of guinea-pig aorta in response to substance P

The pharmacologic characteristics of the non-prostanoid (prostacyclin, PGI( 2)), non-nitric oxide (NO) mediated endothelium-dependent relaxation in res ponse to substance P were examined in the guinea-pig aorta. Substance P, in a concentration-dependent manner, relaxed the ring preparations of guinea- pig thoracic aorta preconstricted with norepinephrine (NE) in an endotheliu m-dependent manner. Substance P-induced endothelium-dependent relaxation wa s not affected by indomethacin (3 x 10(-6) M) as in the case of acetylcholi ne (ACh)-induced endothelium-dependent relaxation. Although N-G-nitro-L-arg inine (L-NNA, 3 x 10(-5) M), an inhibitor of nitric oxide (NO) synthase, si gnificantly inhibited substance P-induced endothelium-dependent relaxation in the presence of indomethacin, about 50% of the vasorelaxant response to substance P remained in the combined presence of L-NNA and indomethacin. By comparison, indomethacin-resistant component of endothelium-dependent rela xation to ACh was mostly suppressed by the treatment with L-NNA plus indome thacin. Substance P-induced non-PGI(2), non-NO mediated vascular relaxation was attenuated markedly in high (40 mM) KCI solution or by tetraethylammon ium (TEA, 5 x 10(-3) M). Furthermore, substance P-induced non- PGI(2), non-NO mediated vascular rela xation was not appreciably affected by glibenclamide (10(-6) M), apamin (10 (-7) M), iberiotoxin (10(-7) M), but was greatly attenuated by the combined treatment with charybdotoxin (10(-7) M) plus apamin (10(-7) M), which sugg esting that endothelium-derived hyperpolarizing factor(s) (EDHF(s)) mediate s the response. Interestingly, after applied repetitively, the substance P- induced vasorelaxant component remaining in the combined presence of indome thacin and L-NNA was decreased more profoundly than the response to substan ce P in the presence of indomethacin alone. Possible contribution of non-PG I(2), non-NO vasorelaxant(s) (EDHF(s)) from the endothelium to the total re laxation response to substance P was greater in thoracic aorta isolated fro m adult guinea-pigs than that from neonatal ones. These findings suggest th at 1) endothelium-dependent vascular relaxation of guinea-pig thoracic aort a in response to substance P is attributable to the release of both NO and EDHF(s); 2) possible release of EDHF(s) from the endothelium of guinea-pig thoracic aorta decreases after repetitive stimulation with substance P; and 3) contribution of EDHF(s) to substance P-induced functional relaxation of the thoracic aorta is greater in adult guinea-pigs than neonatal ones.