Mechanisms underlying the differential sensitivity to a1‐adrenoceptor activation in the bisected rat vas deferens

1 The factors underlying the different responsiveness of the prostatic and epididymal portions of rat vas deferens to α1‐adrenoceptor stimulation were investigated. 2 The α1‐adrenoceptors in membranes of both halves of rat vas deferens were labelled with [3H]‐prazosin and the affinities of agonists and antagonists for these receptors were determined. In saturation studies, the Bmax and KD values for [3H]‐prazosin in membranes of both portions were the same. 3 In competition studies, the inhibition curves for phentolamine were biphasic and consistent with the presence of both α1a‐ and α1b‐adrenoceptor subtypes. The proportions of binding sites with high and low affinity for phentolamine in both halves of rat vas deferens were similar and in good agreement with the percentages of binding sites for WB‐4101 and phentolamine previously reported in the whole rat vas deferens. 4 The phenylethylamines displaced [3H]‐prazosin with a shallow inhibition curve. The data are compatible with the assumption of two affinity states for the binding sites. For the imidazoline compounds no such distinct affinity states could be demonstrated. 5 The affinity for, and the relative intrinsic efficacy on postsynaptic α1‐adrenoceptors of both portions of rat vas deferens were studied for noradrenaline, phenylephrine and methoxamine by irreversible inactivation of the α1‐adrenoceptors by phenoxybenzamine. The parameters for partial agonists were determined by comparing the responses to the partial agonist to those of a full agonist in the same tissue. Homogeneous estimates of the equilibrium dissociation constants (Ka) were obtained, indicating that these agonists bind to the receptors of both tissues in an identical manner. Further, estimation of the intrinsic efficacy of agonists relative to noradrenaline, indicated no differences between the two halves of rat vas deferens. 6 Ka values for agonist activation of the functional α1‐adrenoceptors were compared with KI values for agonist inhibition of specific [3H]‐prazosin binding. The Ka values were well correlated with the low affinity KI values for phenylethylamines in both portions of rat vas deferens, suggesting that the initial event in signal transduction by α1‐adrenoceptors is the binding to the low affinity state of the receptor. 7 There was a non‐linear relationship between response and receptor occupancy in both halves of rat vas deferens but the occupancy‐response coupling was more efficient in the epididymal than in the prostatic portion. This fact may account for the differences observed in the functional responses.