Endothelium‐dependent relaxation followed by contraction mediated by NK 1 receptors in precontracted rabbit intrapulmonary arteries

In the present study, we examined whether substance P (SP) and SP methyl ester (SPME), a selective NK 1 agonist, cause biphasic responses consisting of endothelium‐dependent relaxation (EDR) and contraction (EDC) in precontracted rabbit intrapulmonary arteries. In arteries contracted with PGF 2α (2×10 −6   M ), SP as well as SPME caused only EDR at low concentration (10 −9   M ) and EDR followed by EDC at higher concentrations, indicating the involvement of NK 1 receptors. The SP (10 −8   M )‐induced EDR was abolished in arteries moderately contracted by PGF 2α (5×10 −7   M ) and the EDC in arteries maximally contracted by PGF 2α (10 −5   M ), indicating that EDR and EDC are inversely dependent on preexisting tone. Indomethacin (10 −8 –10 −6   M ), a cyclo‐oxygenase inhibitor, and ozagrel (10 −8 –10 −6   M ), a TXA 2 synthetase inhibitor attenuated the EDC in the SPME (10 −7   M )‐induced biphasic response and markedly potentiated the EDR. AA‐861 (10 −8 –10 −6   M ), a 5‐lipoxygenase inhibitor, did not affect the EDR or EDC. L ‐N G ‐nitro‐arginine methyl ester (10 −5 –10 −4   M ), a nitric oxide synthase inhibitor, attenuated the EDR and slightly potentiated the EDC. CP‐99994 (10 −10 –10 −8   M ), an NK 1 antagonist, attenuated the EDC and potentiated the EDR in the SPME (10 −7   M )‐induced biphasic response, while the NK 2 antagonist SR‐48968 (10 −9 –10 −7   M ) had no effect. CP‐99994 attenuated the SPME (10 −7   M )‐induced EDC under EDR‐blockade to a greater extent than the EDR under EDC‐blockade, indicating that CP‐99994 enhanced the EDR component by preferential inhibition of the EDC component. In conclusion, NK 1 agonists caused a biphasic endothelium‐dependent response (EDR and EDC) in submaximally precontracted intrapulmonary arteries. The EDC and EDR mediated by NK 1 receptors may play physiological and/or pathophysiological roles in modulation of vascular tone.British Journal of Pharmacology (2000) 129 , 937–942; doi: 10.1038/sj.bjp.0703140