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.

The effect of the calcium 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, whereas the alpha-1 adrenoceptor-mediated pressor responses of partial agonists with low intrinsic activities (no receptor reserve) were highly sensitive to antagonism by diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)