Existence of Spare α1-Adrenoceptors, but Not α2-Adrenoceptors, for Respective Vasopressor Effects of Cirazoline and B-HT 933 in the Pithed Rat

Abstract

The existence of a receptor reserve (spare receptors) was investigated for postsynaptic vascular alpha1- and alpha2-adrenoceptors in the pithed rat by evaluating the effects of progressive inactivation of alpha1- and alpha2-adrenoceptor pools by the irreversible antagonist phenoxybenzamine on the pressor responses of cirazoline and B-HT 933. Dose-response curves for the alpha1-adrenoceptor-mediated vasoconstrictor effects of cirazoline were shifted in a rightward direction with no depression of the maximum response by lower does of phenoxybenzamine (0.1-0.2 mg/kg, i.v.). Progressively higher doses of phenoxybenzamine (greater than 1 mg/kg, i.v.) produced further rightward shifts in the dose-response curves of cirazoline, but also depressed the maximum response. In contrast, all doses of phenoxybenzamine that inhibited the alpha2-adrenoceptor-mediated pressor effects of B-HT 933 produced a reduction in the maximum response. These results are highly suggestive of the existence of a receptor reserve in the pithed rat for the postsynaptic vascular alpha1-adrenoceptor-mediated effects of cirazoline, but not for the postsynaptic vascular alpha2-adrenoceptor-mediated effects of B-HT 933. Confirmation of the existence of a receptor reserve for only the postsynaptic vascular alpha1-adrenoceptor-mediated effects of cirazoline came from further analysis of the antagonism, by phenoxybenzamine, of cirazoline and B-HT 933 dose-response curves. The maximum pressor response that could be elicited by the alpha1-adrenoceptor agonist cirazoline was a hyperbolic function on the size of the alpha1-adrenoceptor pool, the latter being progressively decreased by phenoxybenzamine treatment. Such a hyperbolic relationship is indicative of a receptor reserve. In marked contrast, the maximum pressor response that could be evoked by the alpha2-adrenoceptor agonist B-HT 933 was a linear function of the size of the intact alpha2-adrenoceptor pool, characteristic of a lack of spare receptors. Further analysis showed that the occupancy-response relationship is fivefold more favorable for the alpha1-adrenoceptor-mediated pressor effects of cirazoline than for the alpha2-adrenoceptor-mediated pressor effects of B-HT 933, indicating that any given maximum pressor response in the pithed rat may be obtained with one-fifth as many alpha1-adrenoceptors being activated by cirazoline than alpha2-adrenoceptors being stimulated by B-HT 933. (ABSTRACT TRUNCATED AT 250 WORDS)