EXISTENCE OF SPARE ALPHA-1-ADRENOCEPTORS, BUT NOT ALPHA-2-ADRENOCEPTORS, FOR RESPECTIVE VASOPRESSOR EFFECTS OF CIRAZOLINE AND B-HT 933 IN THE PITHED RAT

  • 1 January 1984
    • journal article
    • research article
    • Vol. 6  (6) , 1011-1019
Abstract
The existence of a receptor reserve (spare receptors) was investigated for postsynaptic vascular .alpha.1- and .alpha.2-adrenoceptors in the pithed rat by evaluating the effects of progressive inactivation of .alpha.1- and .alpha.2-adrenoceptor pools by the irreversible antagonist phenoxybenzamine on the pressor responses of cirazoline and B-HT 933. Dose-response curves for the .alpha.1-adrenoceptor-mediated vasoconstrictor effects of cirazoline were shifted in a rightward direction with no depression of the maximum response by lower doses of phenoxybenzamine (0.1-0.2 mg/kg, i.v.). Progressively higher doses of phenoxybenzamine (> 1 mg/kg, i.v.) produced further rightward shifts in the dose-response curves of cirazoline, but also depressed the maximum response. All doses of phenoxybenzmine that inhibited the .alpha.2-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 .alpha.2-adrenoceptor-mediated effects of cirazoline, but not for the postsynaptic vascular .alpha.2-adrenoceptor-mediated effects of B-HT 933. Confirmation of the existence of a receptor reserve for only the postsynaptic vascular .alpha.1-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 .alpha.1-adrenoceptor agonist cirazoline was a hyperbolic function of the size of the .alpha.1-adrenoceptor pool, the latter being progressively decreased by phenoxylbenzamine treatment. Such a hyperbolic relationship is indicative of a receptor reserve. The maximum pressor response that could be evoked by the .alpha.2-adrenoceptor agonist B-HT 933 was a linear function of the size of the intact .alpha.2-adrenoceptor pool, characteristic of a lack of spare receptors. The occupancy-response relationship is 5-fold more favorable for the .alpha.1-adrenoceptor-mediated pressor effects of cirazoline than for the .alpha.2-adrenoceptor-mediated pressor effects of B-HT 933, indicating that any given maximum pressor response in the pithed rat may be obtained with 1/5 as many .alpha.1-adrenoceptors being activated by cirazoline than .alpha.2-adrenoceptors being stimulated by B-HT 933. The large receptor reserve for the postsynaptic vascular .alpha.1-adrenoceptor-mediated pressor effects of cirazoline, but not for the postsynaptic vascular .alpha.2-adrenoceptor-mediated pressor effects of B-HT 933, must be considered when assessing possible differential effects of noncompetitive antagonists on .alpha.1- or .alpha.2-adrenoceptor-mediated pressor effects in the pithed rat.

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