RT Journal Article SR Electronic T1 α1-Adrenoceptor Subtypes Mediating Inotropic Responses in Rat Heart JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 829 OP 836 VO 291 IS 2 A1 You-Yi Zhang A1 Kai-Ming Xu A1 Chide Han YR 1999 UL http://jpet.aspetjournals.org/content/291/2/829.abstract AB We studied the distribution of α1-adrenoceptor subtypes by radioligand binding assays using 125I-labeled 2-β(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE2254) and RNase protection assays, and determined the role of each subtype in mediating the inotropic response in rat heart. Chlorethylclonidine preincubation causes a ∼72% decrease in the maximal binding capacity (Bmax). On the other hand, protection from phenoxybenzamine alkylation by 5-methyl-urapidil or BMY7378 decreasedBmax by 59 and 70%. By competitive inhibition, we have identified 19 to 28% and 30% high-affinity binding sites for the α1A- and α1D-selective antagonists in rat ventricles, with the α1B-adrenoceptor estimated as 45%. Consistent with the receptor-binding result, a similar distribution of mRNAs encoding α1A, α1B, and α1D (22, 39, and 39%), based on RNase protection assays, was observed. In addition, we demonstrated that the noradrenaline response through α1-adrenoceptor was antagonisted by 5-methyl-urapidil, RS-17053, BMY7378, and WB4101 in contraction functional experiments. KI values for the above compounds were defined for all three α1-adrenoceptor subtypes expressed in the human embryonic kidney 293 cell stably, and were further compared with the corresponding pA2 values. Interestingly, the correlation was significantly higher for α1A(r2 = 0.73) and α1B(r2 = 0.66) than α1D(r2 = 0.35) in these experiments. Because the potential of α1D measured to be 21% based on protection from phenoxybenzamine-caused inhibition by BMY7378, the combined potential of α1A and α1B can be estimated as ∼80%. Taken together, these results suggest that the three α1-adrenoceptor subtypes coexist in rat heart, with α1A and α1B playing a more prominent role in the positive inotropic response to noradrenaline. The American Society for Pharmacology and Experimental Therapeutics