Abstract
1. In this study, the effect of seven alpha 1-adrenoceptor antagonists (tamsulosin, phentolamine, prazosin, WB-4101, 5-methylurapidil, spiperone and HV723) have been examined on the contractile response to noradrenaline (NA) and phenylephrine (PE) in rat isolated aorta. 2. NA and PE, when administered using a cumulative dosing schedule, both produced concentration-dependent contraction of aortic rings. It was possible to fit the individual concentration-effect (E/[A]) curve data to the Hill equation to provide estimates of the curve midpoint location (p[A]50 = 7.74 +/- 0.10 and 7.14 +/- 0.18), midpoint slope (nH = 0.82 +/- 0.03 and 0.99 +/- 0.10) and upper asymptote (alpha = 3.2 +/- 0.3 and 3.1 +/- 0.2 g) parameters for NA and PE, respectively. However, the Hill equation provided a better fit to the E/[A] curve data obtained with another contractile agent, 5-hydroxytryptamine (5-HT) (p[A50] = 6.09 +/- 0.08, nH = 1.49 +/- 0.09, alpha = 2.6 +/- 0.3 g), as judged by calculation of the mean sum of squares of the differences between the observed and predicted values. 3. All of the antagonists investigated produced concentration-dependent inhibition of the contractile responses of the aorta to NA and PE. Although no significant effects on the upper asymptotes of the E/[A] curves of any of the antagonists tested were detected, only tamsulosin and 5-methylurapidil did not have a significant effect on the slope (nH) of the NA and PE E/[A] curves. The other antagonists produced significant steepening of the curves obtained with NA and/or PE. 4. Notwithstanding the fact that one of the basic criteria for simple competitive antagonism at a single receptor class was not always satisfied, the individual log [A]50 values estimated in the absence and presence of antagonist within each experiment were fitted to the competitive model. The Schild plot slope parameters for the antagonism of NA and PE by phentolamine and HV723 were found to be significantly less than unity. The Schild plot slope parameters for the other antagonists were not significantly different from unity. 5. In the absence of evidence to suggest that the deviations from simple competitive antagonism were due to failure to satisfy basic experimental conditions for quantitative analysis, an attempt was made to see whether the data could be accounted for by an existing two-receptor model (Furchgott, 1981). The goodness-of-fit obtained with the two-receptor model was significantly better than that obtained with the one-receptor model. Furthermore, with the exception of the data obtained with phentolamine, the pKB estimates for the two receptors were independent of whether NA or PE was used as agonist. 6. To determine which alpha 1-adrenoceptor subtypes may be associated with those defined by the two receptor model, the mean pKB estimates obtained from the two-receptor model fit were compared with affinities measured by Laz et al. (1994) for rat cloned alpha 1-adrenoceptor subtypes expressed in COS-7 cells. The sum of squared differences of the data points from the line of identity was smallest for both pKB1 and pKB2 in the case of the alpha 1a/d-adrenoceptor (now referred to as alpha 1d-adrenoceptor; Hieble et al., 1995). Therefore, the complexity exposed in this study may be due to the expression of closely-related forms of the alpha 1d-adrenoceptor. However, relatively good matches were also found between pKB1 and alpha 1c and between pKB2 and alpha 1b. Therefore, on the basis of these data, it is not possible to rule out the involvement of all three alpha 1-adrenoceptors. The conflicting reports concerning the characteristics of the alpha 1-adrenoceptor population mediating contraction of the rat aorta may, at least in part, be due to the lack of highly selective ligands and to between-assay variation in the expression of multiple alpha 1-adrenoceptors.
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