Pharmacological characterization of tachykinin receptor mediating endothelium-dependent contraction and relaxation in rabbit intrapulmonary arteries

We have reported that substance P (SP) causes endothelium-dependent contraction (EDC) via TXA_2 , and relaxation (EDR) via NO in isolated rabbit intrapulmonary arteries. In the present study, we pharmacologically characterized the tachykinin receptor subtypes mediating these responses. The potencies of SP analogues for causing of EDC under EDR-blockade and EDR under EDC-blockade were compared in the presence of SR-48968 (10^-7 M), an NK_2 antagonist. The rank order of potency was not different between EDC and EDR：SP > SP methyl ester (SPME) > Neurokinin A (NKA) > neurokinin B (NKB) >> [Ala^5 , β-Ala^8 ]- α -neurokinin fragment 4-10 (AANF) > senktide. The sensitivity to SP, SPME, NKA and NKB for causing EDR was higher than that for EDC. CP-99994 (10^-9 - 10^-7 M) and SR-140333 (10^-12 - 10^-10 M), both selective NK_1 antagonists concentration-dependently inhibited the SPME-induced EDC and EDR to similar extent. NK_1 receptors are postulated to lead to activate phospholipase C (PLC) followed by increase in intracellular Ca^2+ concentration. In fact, U-73122 (10^-5 M), a PLC inhibitor inhibited both EDR and EDC induced by SPME. A-23187, which is a Ca^2+ ionophore caused EDR more effectively than EDC. In conclusion, tachykinins activate the same NK_1 , receptor, which leads to an increase in intracellular Ca^2+ concentration. Thus, Ca^2+ may activate the EDR pathway more effectively than EDC pathway.