Determination of α1‐adrenoceptor subtype selectivity by [3H]‐prazosin displacement studies in guinea‐pig cerebral cortex and rat spleen membranes

Abstract

[3H]‐prazosin homogeneously labels α1‐adrenoceptors in guinea‐pig cerebral cortex and rat spleen membranes with dissociation constants of 1.28 and 1.49 × 10−10 m respectively. Phentolamine and WB 4101 displacement studies show that guinea‐pig cerebral cortex contains 30% α1A‐ and 70% α1B‐adrenoceptor subtypes, whereas rat spleen contains a virtually homogeneous α1B‐adrenoceptor subtype population. The α1‐adrenoceptor population of rat thoracic aorta is predominantly of the α1A‐adrenoceptor subtype, and in guinea‐pig thoracic aorta it is mainly of the α1B‐adrenoceptor subtype. Half of the compounds displacing [3H]‐prazosin bound to guinea‐pig cerebral cortex membranes display α1A‐adrenoceptor selectivity. Among these compounds, WB 4101 and methoxamine are most selective, displaying selectivity ratios of ∼38 and ∼26 respectively. The affinity constants of the non‐selective compounds for the α1‐adrenoceptors in guinea‐pig cerebral cortex membranes correlate well with the affinity constants obtained for α1B‐adrenoceptors in rat spleen membranes. The affinities of selective compounds for the α1B‐adrenoceptor subtype in guinea‐pig cerebral cortex correlate very well with their affinity for α1B‐adrenoceptor in the rat spleen homogenate. Both regression lines coincide with the line of identity. The affinity constants of selective compounds for the α1A‐adrenoceptors in guinea‐pig cerebral cortex only apparently correlate with the affinity for either the α1B‐adrenoceptors in guinea‐pig cerebral cortex or in the rat spleen. Regression analyses indicate a straight line relationship (r2 > 0.9) between pKα1A and pKα1B but the regression lines deviate from the line of identity. 1992 British Pharmacological Society