ANALYSIS OF THE EFFECTS OF ALPHA(1)-ADRENOCEPTOR ANTAGONISTS ON NORADRENALINE-MEDIATED CONTRACTION OF RAT SMALL MESENTERIC-ARTERY

1 In this study, we examined the interaction between noradrenaline (NA ) and phenylephrine (PE) with seven antagonists (prazosin, tamsulosin, phentolamine, WB-4101, 5-methylurapidil, spiperone and HV 723) in an attempt to characterize the alpha(1)-adrenoceptor population of the ra t isolated small mesenteric artery (SMA) preparation. 2 Six of the sev en antagonists investigated produced concentration-dependent, parallel , rightward shift of the NA concentration-effect (E/[A]) curves. The e xception was tamsulosin, which produced significant decrease of the up per asymptote. In the case of 5-methylurapidil and HV723, the Schild p lot slope parameters were not significantly different from unity over the range of concentrations used. However, the Schild plot slopes obta ined for the other antagonists were all significantly greater than uni ty, inconsistent with expectations for simple competitive antagonism. 3 HV723, prazosin and tamsulosin were also tested using PE as an agoni st. All three antagonists produced concentration-dependent, parallel, rightward shifts of the PE curves and Schild analysis yielded slope pa rameters not significantly different from unity. The pK(B) estimates o btained for tamsulosin and prazosin were not significantly different f rom the pA(2) values obtained when NA was used as agonist. In the case of HV723, the 95% confidence intervals for the pK(B) values yielded w ith NA and PE did not overlap (pK(B) = 8.80 - 9.13 and 8.15 - 8.77 for NA and PE, respectively). 4 In the absence of evidence to indicate th at the steep Schild plots were due to failure to satisfy the basic cri teria for quantitative analysis in a one-receptor system, we considere d the possibility that the complexity was caused by an action of NA at inhibitory D-1 receptors. The selective D-1 receptor antagonists, SCH -23390 (10 nM), had no significant effect on the NA E/[A] control curv e, but the apparent potency of 100 nM prazosin was reduced by similar to 3.5 fold. 5 This study indicates that the steep Schild plots obtain ed from the interaction between NA. and alpha(1)-adrenoceptor antagoni sts were due to the simultaneous activation of inhibitory D-1 receptor s by NA. Notwithstanding this complexity, our explanatory model of the system (see Appendix) suggests that the antagonist affinity values es timated in the absence of D-1 receptor block were not significantly af fected by this other action of NA. The low affinity estimate obtained for prazosin suggests that the pharmacologically-defined alpha(IL)-sub type operates in the SMA.