POSSIBLE RELATIONSHIP BETWEEN RECEPTOR RESERVE AND THE DIFFERENTIAL ANTAGONISM OF ALPHA-1 AND ALPHA-2 ADRENOCEPTOR-MEDIATED PRESSOR-RESPONSES BY CALCIUM-CHANNEL ANTAGONISTS IN THE PITHED RAT

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 230  (3) , 587-594
Abstract
The effect of the Ca channel antagonist diltiazem was investigated on the .alpha.-1 and .alpha.-2 adrenoceptor-mediated pressor responses elicited by cirazoline and B-HT 933, respectively, in pithed rat. Diltiazem (3 mg/kg i.v.) selectively inhibited the .alpha.-2 adrenoceptor-mediated pressor effect of B-HT 933 but did not affect the .alpha.-1 adrenoceptor-mediated pressor effect of cirazoline. However, after removal of spare postsynaptic vascular .alpha.-1 adrenoceptors by treatment with the irreversible .alpha. adrenoceptor antagonist phenoxybenzamine, the .alpha.-1 adrenoceptor-mediated pressor response of cirazoline became highly sensitive to antagonism by diltiazem and resembled in this regard .alpha.-2 adrenoceptor-mediated vasoconstriction for which no receptor reserve exists. In addition, as the .alpha.-1 adrenoceptor reserve was progressively reduced by treatment with increasing doses of phenoxybenzamine, the .alpha.-1 adrenoceptor-mediated pressor response of cirazoline became progressively more sensitive to inhibition by diltiazem, such that there was a high inverse correlation between the magnitude of the .alpha.-1 adrenoceptor reserve and the degree to which this response was antagonized by diltiazem. There was also a high inverse correlation between the intrinsic activity of .alpha.-1 adrenoceptor selective agonists and the degree to which their pressor responses were inhibited by diltiazem. Thus, pressor responses of agonists with high intrinsic activities (large receptor reserve) were resistant to antagonism by diltiazem. The .alpha.-1 adrenoceptor-mediated pressor responses of partial agonists with low intrinsic activities (no receptor reserve) were highly sensitive to antagonism by diltiazem. The apparent resistance of the .alpha.-1 adrenoceptor-mediated pressor response to antagonism by the Ca channel blocking agents may result, at least in part, from a large .alpha.-1 adrenoceptor reserve that serves to buffer .alpha.-1 adrenoceptor-mediated pressor responses from inhibition by noncompetitive antagonists, such as the Ca channel antagonists.