Receptor Protection Studies with Phenoxybenzamine Indicate that a Single α1-Adrenoceptor May Be Coupled to Two Signal Transduction Processes in Vascular Smooth Muscle

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Abstract
Full α1-adrenoceptor agonists, such as (–)-norepinephrine, produce vasoconstriction in the rat aorta primarily through the mobilization of intracellular stores of calcium, whereas partial α1-adrenoceptor agonists, such as (–)-dobutamine, produce vasoconstriction primarily through the translocation of extracellular calcium. The different pools of calcium utilized by full and partial α1-adrenoceptor agonists have been proposed to result from the activation of different α1-adrenoceptor subtypes. The irreversible α1-adrenoceptor antagonist, phenoxybenzamine, selectively eliminates only that component of an α1-adrenoceptor-mediated response in the rat aorta that is dependent upon the mobilization of intracellular stores of calcium. In order to determine whether in the rat aorta there exist two distinct at -adrenoceptor subtypes linked separately to the mobilization of intracellular and extracellular calcium, we utilized the full and partial α1-adrenoceptor agonists, (–)-norepinephrine and (–)-dobutamine, respectively, and the irreversible antagonist, phenoxybenzamine, as pharmacologic tools in a classical receptor-protection study to probe these α1-adrenoceptor mediated vasoconstrictor processes). Our logic was that if the intracellular and extracellular pools of calcium were coupled to different α1-adrenoceptor subtypes, then only (–)-norepinephrine, and not (–)-dobutamine, would protect against α1-adrenoceptor alkylation by phenoxybenzamine, since phenoxybenzamine only eliminates the process that depends on intracellular calcium. Alternatively, if both (–)-norepinephrine and (–)-dobutamine produce a similar degree of α1-adrenoceptor protection against phenoxybenzamine, our results would suggest that a single α1-adrenoceptor subtype exists which activates both the translocation of extracellular calcium and the mobilization of intracellular calcium. Phenoxybenzamine (30 nM) abolished contractions of the rat aorta produced by (–)-norepinephrine, as expected. Pretreatment of the tissues with either (–)-norepineph-rine or (–)-dobutamine, at concentrations that produced equivalent degrees of α1-adrenoceptor occupancy, resulted in equal protection against alkylation of α1-adrenocep-tors by phenoxybenzamine, arguing against the existence of two distinct α1-adrenoceptor subtypes in the rat aorta. These results are consistent with our previous hypothesis that two different signal-transduction processes may be activated in the rat aorta by a single α1-adrenoceptor population, with the intrinsic efficacy of the agonist determining which signal-transduction process is activated.

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