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(2alpha) (2x10(-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(2alpha) (5x10(-7) M) and the EDC in arteries maximally contracted by PGF(2alpha) (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.
Shirahase
H
H
Pharmacology Division, Radioisotope Research Center, Kyoto University, Kyoto 606-8501, Japan.
Kanda
M
M
Kurahashi
K
K
Nakamura
S
S
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
D001549:Benzamides; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; C073839:SR 48968; C033611:substance P, methyl ester-; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester