Endothelium-dependent contraction induced by substance P in canine cerebral arteries: involvement of NK1 receptors and thromboxane A2.

We characterized the endothelial responses to substance P (SP) in the isolated canine cerebral artery. SP caused concentration-dependent contraction at 10(-10) - 10(-7) M and relaxation at 10(-10) and 10(-9) M, which were abolished by removal of the endothelium. The SP-induced endothelium-dependent relaxation (EDR) was suppressed, while the endothelium-dependent contraction (EDC) was increased by repeated application. The EDC induced by SP (10(-7) M) was attenuated by SR-140333 (10(-9) - 10(-7) M) and CP-99994 (10(-7) M), both NK1 antagonists, but not by SR-48968 (10(-7) M), an NK2 antagonist, or four antagonistic SP analogues (10(-6) M). The EDC induced by SP (10(-7) M) was attenuated by aspirin (10(-5) M), a cyclooxygenase inhibitor, OKY-046 (10(-5) M), a TXA2 synthetase inhibitor and ONO-3708 (10(-8) M), a TXA2 antagonist. Neurokinin A (10(-7) M) but not neurokinin B (10(-7) M) caused EDC similar to that induced by SP. In conclusion, SP induces EDC via endothelial NK1 receptors and TXA2 production in canine cerebral arteries.