Role of intracellular alkalinization in inhibition of acetylcholine-induced relaxation by FMLP in rat aorta.
N-formylmethionyl-leucyl-phenylalanine (FMLP), a chemotactic tripeptide, is known to cause intracellular alkalinization. Moreover, there is a specific receptor for FMLP in vascular endothelial cells but not in vascular smooth muscle cells. Because we have already reported that intracellular alkalinization inhibits acetylcholine (ACh)-induced relaxation, we examined whether FMLP alters the vasodilation of endothelial cells through intracellular alkalinization. FMLP reduced ACh-induced relaxation in aortic rings from Sprague-Dawley rats but did not affect nitroglycerin-induced relaxation. N-t-butoxycarbonyl-phenylalanyl -D-leucyl-phenylalanyl-D-leucyl-phenylalanine, a specific formyl receptor antagonist, reversed the impairment of ACh-induced relaxation, as did the protein kinase C inhibitors sphingosine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). The sodium/proton antiport inhibitor amiloride and the proton ionophore nigericin normalized the attenuated ACh-induced relaxation. FMLP-induced impairment was normalized by the phospholipase A2 inhibitor quinacrine, the cyclooxygenase inhibitor indomethacin, and the antagonists of the prostaglandin H2 and/or thromboxane A2 receptor, ONO-3708 and S-1452, respectively. Superoxide dismutase inhibited the effect of FMLP. In conclusion, FMLP attenuated ACh-induced relaxation, possibly through intracellular alkalinization. Increased production of vasoconstrictor prostaglandin(s) and superoxide may contribute to the inhibitory effect of FMLP-induced alkalinization on ACh-induced relaxation.
Ando
K
K
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Fujita
T
T
D000109:Acetylcholine / Q000494:pharmacology*; D000468:Alkalies / Q000378:metabolism*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009550:Nigericin / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D000468:Alkalies; D009842:Oligopeptides; D011453:Prostaglandins; D009240:N-Formylmethionine Leucyl-Phenylalanine; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D000584:Amiloride; D000109:Acetylcholine; D009550:Nigericin