ENDOTHELIUM-DEPENDENT CONTRACTION IN INTRAPULMONARY ARTERIES - MEDIATION BY ENDOTHELIAL NK1 RECEPTORS AND TXA(2)

1 We have examined whether three natural tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) induce an endothelium-dependent contraction (EDC) in the rabbit isolated intrapulmonary artery. 2 Removal of the endothelium almost abolished the contraction induced by SP (10(-8) M) while it did not attenuate the contraction induced by SP (10(-7) M), NKA (10(-9)-10(-7) M) or NKB (10(-8) and 10(-7) M). 3 The EDC induced by SP (10(-8) M) was abolished by M(1 antagonists (FK-888, CP-96345, CP-99994 and SR-140333) but not by an NK2 antagonist (SR-48968). 4 The EDC induced by SP was attenuated by cyclo-oxygenase inhibitors (aspirin and indomethacin), thromboxane A(2) (TXA(2)) synthetase inhibitors (OKY-046, KY-234 and KY-063) and a TXA(2) antagonist (S-1452). 5 The rank order of potency causing endothelium-independent contraction (EIC) was NKA > NKB > SP. The EIC induced by SP (10(-7) M) was attenuated by an NK2 antagonist but not by NK1 antagonists, cyclo-oxygenase inhibitors, TXA(2) synthetase inhibitors or a TXA(2) antagonist. 6 In conclusion, SP at 10(-8) M induces EDC via endothelial NK1 receptors and TXA(2) production, and SP at 10(-7) M induces EIC via NK2 receptors in the rabbit intrapulmonary artery.