Phenoxybenzamide deriv

The effects of 2 unrelated vasodilators, nifedipine and nitroprusside, on the pressor response to the α₁-adrenoceptor full agonist cirazoline and the partial agonist Sgd 101/75 in pithed rats were examinedThe experiments were performed on vasoconstriction which was mediated by newly synthesized α₁-adrenoceptors after removal of existing α₁-adrenoceptors by phenoxybenzamide treatment (5 mg/kg, i.p.).The half-lives for recovery of the maximum response and ED₅₀ of cirazoline were 23.1 and 26.9, resp., while that for recovery of the maximum response of Sgd 101/75 was 59.2 h.The relationship between the pressor response and the fractional receptor occupancy for cirazoline showed a rectangular hyperbola.This occupancy-response curve markedly shifted to the right 1 day after phenoxybenzamine and subsequently returned to the control, indicative of a large receptor reserve.However, for Sgd 101/75 the occupancy-response curve exerted less of a hyperbola and shifted little after phenoxybenzamine.While the maximum response to cirazoline in the controls rats was resistant to inhibition by the Ca²⁺ entry blocker nifedipine, this resistance was reduced 1 and 3 days after phenoxybenzamine, just as the maximum response to Sgd 101/75 was sensitive to nifedipine in the control rats.When nitroprusside was used instead, the results were similar for the cirazoline and Sgd 101/75 effects.It seems unlikely that the resistance to Ca²⁺ entry blocker of the full agonist effect can be wholly ascribed either to the receptor reserves or to the differential Ca²⁺ utilization itself.Alternatively, the differential resistance to Ca²⁺ antagonists can result from the magnitude of the variables involved in the activation of α₁-adrenoceptor coupling processes depending on the full or partial agonist.