Endothelium-dependent contraction induced by substance P in canine cerebral arteries: Involvement of NK1 receptors and thromboxane A(2)

We characterized the endothelial responses to substance P (SP) in the isola ted canine cerebral artery. SP caused concentration-dependent contraction a t 10(-10) - 10(-7) M and relaxation at 10(-10) and 10(-9) M, which were abo lished by removal of the endothelium. The SP-induced endothelium-dependent relaxation (EDR) was suppressed, while the endothelium-dependent contractio n (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 TXA(2) synthetase inhibitor and ONO-3708 (10(-8) M), a TX A(2) antagonist. Neurokinin A(10(-7) M) but not neurokinin B (10(-7) M) cau sed EDC similar to that induced by SP. In conclusion, SP induces EDC via en dothelial NK1 receptors and TXA(2) production in canine cerebral arteries.