Pharmacologically distinct phenotypes of α1B-adrenoceptors: variation in binding and functional affinities for antagonists

Background and PurposeThe pharmacological properties of particular receptors have recently been suggested to vary under different conditions. We compared the pharmacological properties of the (1B)-adrenoceptor subtype in various tissue preparations and under various conditions. Experimental Approach[H-3]-prazosin binding to (1B)-adrenoceptors in rat liver (segments, dispersed hepatocytes and homogenates) was assessed and the pharmacological profiles were compared with the functional and binding profiles in rat carotid artery and recombinant (1B)-adrenoceptors. Key ResultsIn association and saturation-binding experiments with rat liver, binding affinity for [H-3]-prazosin varied significantly between preparations (K-D value approximately ten times higher in segments than in homogenates). The binding profile for various drugs in liver segments also deviated from the representative (1B)-adrenoceptor profile observed in liver homogenates and recombinant receptors. L-765,314 and ALS-77, selective antagonists of (1B)-adrenoceptors, showed high binding and antagonist affinities in liver homogenates and recombinant (1B)-adrenoceptors. However, binding affinities for both ligands in the segments of rat liver and carotid artery were 10 times lower, and the antagonist potencies in (1B)-adrenoceptor-mediated contractions of carotid artery were more than 100 times lower than the representative (1B)-adrenoceptor profile. Conclusions and ImplicationsIn contrast to the consistent profile of recombinant (1B)-adrenoceptors, the pharmacological profile of native (1B)-adrenoceptors of rat liver and carotid artery varied markedly under various receptor environments, showing significantly different binding properties between intact tissues and homogenates, and dissociation between functional and binding affinities. In addition to conventional subtype' characterization, phenotype' pharmacology must be considered in native receptor evaluations in vivo and in future pharmacotherapy.