RELATION BETWEEN ALPHA-1-ADRENOCEPTOR SUBTYPES AND NORADRENALINE-INDUCED CONTRACTION IN RAT PORTAL-VEIN SMOOTH-MUSCLE

1 In vascular smooth muscle, alpha1-adrenoceptors have been classified recently into two or three subtypes. We examined which alpha1-adrenoc eptor subtypes are involved in the noradrenaline-induced contraction o f rat portal vein smooth muscle. 2 Binding studies with [H-3]-prazosin in membranes from equine portal vein smooth muscle revealed the prese nce of two distinct affinity binding sites. The high-affinity site for [H-3]-prazosin was also identified in intact strips of rat portal vei n. Prazosin, HV723 lpha-(3-((2-(2-methoxyphenoxy)ethyl)-amino)-propyl benzene-acetonitrile fumarate), WB4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane), 5-methylurapidil, phentolamine and yohi mbine antagonized [H-3]-prazosin binding at both types of sites. Pretr eatment with 50 mum chloroethylclonidine (CEC) eliminated the high-aff inity sites for prazosin but had no effect on the low-affinity sites. 3 Noradrenaline produced a concentration-dependent contraction in the rat portal vein. Pretreatment with 50 mum CEC induced a slight rightwa rd displacement of the concentration-response curve but the maximal co ntraction was not significantly affected suggesting that the CEC-sensi tive alpha1-adrenoceptors played a minor role in the noradrenaline-ind uced contraction. Prazosin, WB4101 and HV723 produced a concentration- dependent inhibition of noradrenaline-induced contractions. The inhibi tion curves were little affected by CEC-pretreatment and yielded a rel ative order of potency of WB4101 > prazosin > HV723. 4 In the presence of 0.1 mum isradipine to block voltage-dependent Ca2+ channels, the n oradrenaline-induced contraction is due to release of Ca2+ ions from a gonist-sensitive intracellular Ca2+ stores. Under these conditions, th e noradrenaline-induced contraction was not significantly affected by pretreatment with 50 mum CEC but was inhibited by the antagonists ment ioned above with affinities different from those in the absence of isr adipine. The rank order of potency became HV723 greater-than-or-equal- to WB4101 > prazosin. 5 The present results indicate the existence of two distinct al-adrenoceptor subtypes in rat portal vein smooth muscle , which show high- and low-affinities respectively for each of prazosi n, WB4101 and HV723 and correspond to alpha1H- and alpha1L-adrenocepto r subtypes. According to recent alpha1-adrenoceptor subclassifications , the alpha1H-adrenoceptor subtype which is sensitive to inactivation by CEC may correspond to the alpha1B-adrenoceptor subtype. The contrac tion induced by noradrenaline seems to be predominantly mediated throu gh the alpha1L-adrenoceptor subtypes which may include the alpha1N-adr enoceptor subtype, as recently proposed.