ALPHA-2-ADRENOCEPTOR SUBTYPE CAUSING NITRIC OXIDE-MEDIATED VASCULAR RELAXATION IN RATS

The alpha-2 adrenoceptor subtype and its signal transduction pathway m ediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries. Removal of endothelium or incubation with N-G-nitro-L-arginine completely blocked relaxant responses to UK 14,304, suggesting endothelium-derived nitric oxide mediates relaxatio n. The order of potency for full (F) or partial (P) agonists causing r elaxation was guanabenz (P) > UK14,304 (F) > clonidine (P) > epinephri ne (F) > norepinephrine (F). Affinities (K-B) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side- by-side experiments comparing rat mesenteric arteries with pig coronar y arteries. Relaxation of pig coronary arteries is known to be mediate d by the alpha-2A adrenoceptor subtype. K-B values in nM for rauwolsci ne (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and praz osin (1531) for blocking relaxation in rat arteries were consistent wi th their affinities for binding at the alpha-2D adrenoceptor subtype. K-B values for rauwolscine and WE-4101, drugs distinguishing the alpha -2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, sug gesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxati on in rat arteries. We used forskolin to oppose alpha-2 adrenoceptor-m ediated inhibition of cAMP formation by directly stimulating cAMP form ation in endothelium. Forskolin did not affect the relaxant response t o UK14,304, suggesting that cAMP is not involved in the coupling of al pha-2 adrenoceptors to nitric oxide-induced vascular relaxation.