Mechanisms of desensitization of vasodilatation induced by platelet-activating factor in hypertensive rats.
We found that vasodilator effects of platelet-activating factor (PAF) on the mesenteric arterial bed of the rat were significantly attenuated in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Perfusion of the mesentery with acetylcholine and PAF caused endothelium-dependent vasodilatation accompanied by an increase in cyclic GMP levels in the mesentery from normotensive Wistar Kyoto rats (WKY). Acetylcholine caused a significant increase in cyclic GMP levels in the effluent in both SHR and RHR, whereas PAF could not increase cyclic GMP levels in SHR and slightly increased cyclic GMP in RHR. Incubating the mesentery with PAF markedly inhibited the vasodilatation induced by PAF, but not acetylcholine or sodium nitroprusside. The cyclic GMP accumulation in the effluent was impaired in the mesenteric arterial bed pretreated with PAF and in that obtained from rats given islet-activating protein (IAP). The PAF-induced vasodilatation was completely reversed by the PAF receptor antagonist, CV-6209 (2-[N-acetyl-N-(2-methyl-3-octadecylcarbamoyl-oxypropoxycarbony l) aminomethyl]-1-ethylpyridinium chloride). These results suggest that (1) attenuated vasodilator effects of PAF and decreased cyclic GMP levels in the mesentery from SHR and RHR are due to desensitization but not to impairment of the endothelium; (2) GTP-binding protein, which is IAP-sensitive, may be involved in PAF-induced vasodilatation and cyclic GMP accumulation; (3) desensitization of the mesentery to PAF in SHR and RHR may be due to PAF receptor and GTP-binding protein uncoupling.
Kamata
K
K
Department of Physiology and Morphology, Hoshi University, Shinagawa-ku, Tokyo, Japan. off
Numazawa
T
T
Kasuya
Y
Y
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006978:Hypertension, Renovascular / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D037342:Pertussis Toxin; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014664:Vasodilation / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D010566:Virulence Factors, Bordetella; C039351:platelet activating factor receptor; C053321:CV 6209; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D006152:Cyclic GMP; D000109:Acetylcholine