Heterogeneity of Postjunctional α₁-Adrenoceptors in Mammalian Aortae: Subclassification Based on Chlorethylclonidine, WB 4101 and Nifedipine

Abstract

The effects of chlorethylclonidine, WB 4101 and nifedipine on norepinephrine-induced contractions of rat, guinea-pig, rabbit and dog aortae were investigated in order to characterize the α₁-adrenoceptor subtype(s) present in the aortae of these different species. The putative α_1A-adrenoceptor antagonist, WB 4101, was significantly more potent in the rat aorta compared to the rabbit, guinea-pig and dog aortae which were not significantly different from each other. The calcium channel antagonist, nifedipine (1 µM), had little or no effect on norepinephrine-induced contractions in aortic segments from the rabbit, guinea pig and dog; whereas in the rat aorta, nifedipine significantly inhibited the response to norepinephrine. Based on the studies with WB 4101 and nifedipine, α₁-adrenoceptors in rat aorta would be tentatively classified as α_1A-adrenoceptors, whereas those in the guinea-pig, rabbit and dog aortae would be of the α_1B-adrenoceptor subtype. The putative irreversible α_1B-adrenoceptor antagonist, chlorethylclonidine, inhibited the response to norepinephrine in aortae from all species, but to dramatically different degrees. The response to norepinephrine was inhibited by 500-fold and 450-fold by chlorethylclonidine in the rat and dog aortae, respectively, whereas in the guinea-pig and rabbit aortae, the potency of norepinephrine was reduced by only 3- and 20-fold, respectively. Thus, based on studies with chlorethylclonidine, α₁-adreno-ceptors in the rat and dog aortae would be classified as α_1B-adrenoceptors (i.e., chlorethyl-clonidine-sensitive), whereas α_1A-adrenoceptors (chlorethylclonidine-insensitive) would predominate in the guinea-pig aorta, and possibly both α_1A- and α_1B-adrenoceptors would coexist in the rabbit aorta. It is apparent that the subclassification of α₁-adrenoceptors based on chlorethylclonidine does not agree with the subclassification based on WB 4101 and nifedipine in these tissues. Specifically, studies with WB 4101 and nifedipine indicate that the rat aorta contains primarily α_1A-adrenoceptors, whereas the high sensitivity to chlorethylclonidine in the rat aorta would indicate the existence of α_1B-adrenoceptors. Similar discrepancies exist in the aortae from the other species. The results indicate clearly that significant heterogeneity exists in α₁-adrenoceptors in mammalian aortae. Furthermore, our findings suggest that chlorethylclonidine and WB 4101 are not sufficiently reliable tools to use in subclassifying α₁-adrenoceptors in vascular smooth muscle, and the results obtained in the present study do not allow α₁-adrenoceptors in mammalian aortae to be subclassified reliably as either α_1A-or α_1B-adrenoceptors.

Investigation of the actions of chloroethylclonidine in rat aorta

“…CEC has been used as a diagnostic tool in the identification of al-adrenoceptor subtypes. CEC binds to all subtypes of aladrenoceptor (Michel et al, 1993) (Oriowo & Bevan, 1990;Oriowo & Ruffolo, 1992 Dolphin, 1987), so that the interaction between CEC and NA may be at this conformation of the receptor.…”

(−)‐Discretamine, a selective α1D‐adrenoceptor antagonist, isolated from Fissistigma glaucescens

“…Among them, the olc-adrenoceptor is not present in any rat tissue . The subtype of al-adrenoceptor present in the rat aorta has been variously classified as MIB (Han et al, 1990), both alp and XIB (Tian et al, 1990;Piascik et al, 1991) or atypical (Muramatsu et al, 1991;Aboud & Docherty, 1992;Oriowo & Ruffolo, 1992 (Perez et al, 1991). The al-adrenoceptor subtypes possess different susceptibilities to 5-methyl-urapidil (5-MU), and CEC.…”

“…(Muramatsu et al, 1991;Aboud & Docherty, 1992;Oriowo & Ruffolo, 1992). In the last three studies, CEC failed to reduce the maximum response to NA, but caused a parallel shift in the concentration-response curve.…”

Characterization of an α1D‐adrenoceptor mediating the contractile response of rat aorta to noradrenaline

“…In an attempt to characterize the ocl-adrenoceptor mediating the contractile response of the rat aorta, several studies have concluded that the receptor cannot be classified as either a1A or a1B (Oriowo & Ruffolo, 1992;Aboud et al, 1994) although others have suggested that a number of different subtypes contribute to the contractile response van der Graaf et al, 1993). Rat aorta expresses OClD-adrenoceptors at the mRNA level (Perez et al, 1991) and Aboud et al (1994) suggested that since the pharmacological profile of the response could not be reconciled with either an a1A or OCIB subtype, this tissue may possess a functional alD-adrenoceptor.…”