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 attenuate d in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Perfusion of the mesentery with acetylcholine and PAF caused e ndothelium-dependent vasodilatation accompanied by an increase in cycl ic GMP levels in the mesentery from normotensive Wistar Kyoto rats (WK Y). Acetylcholine caused a significant increase in cyclic GMP levels i n the effluent in both SHR and RHR, whereas PAF could not increase cyc lic GMP levels in SHR and slightly increased cyclic GMP in RHR. Incuba ting the mesentery with PAF markedly inhibited the vasodilatation indu ced by PAF, but not acetylcholine or sodium nitroprusside. The cyclic GMP accumulation in the effluent was impaired in the mesenteric arteri al bed pretreated with PAF and in that obtained from rats given islet- activating protein (IAP). The PAF-induced vasodilatation was completel y reversed by the PAF receptor antagonist, CV-6209 -oxypropoxycarbonyl )aminomethyl]-1-ethylpyridinium chloride). These results suggest that (1) attenuated vasodilator effects of PAF and decreased cyclic GMP lev els in the mesentery from SHR and RHR are due to desensitization but n ot to impairment of the endothelium; (2) GTP-binding protein, which is IAP-sensitive, may be involved in PAF-induced vasodilatation and cycl ic GMP accumulation; (3) desensitization of the mesentery to PAF in SH R and RHR may be due to PAF receptor and GTP-binding protein uncouplin g.