Abstract
Chloroethylclonidine (CEC) inhibition of norepinephrine-induced contractile response was studied in rat and rabbit aorta. CEC inhibition was irreversible, but displayed a competitive pattern characterized by rightward shifts of the norepinephrine EC50 with little or no decrease in maximum response. CEC appeared to shift response to a discrete but lower affinity state. The time course for irreversible inhibition by 10 microM CEC was faster for rat aorta (T1/2 = 18 min) than for rabbit aorta (T1/2 = 118 min) indicating a difference either in receptor occupation or in the rate of alkylation after occupation. Measurements of reversible CEC affinity in rabbit aorta yielded a pKB of 6.3 and the rate of alkylation was not significantly increased at 100 microM CEC so that lower occupation could not account for the difference. Pretreatment with phenoxybenzamine significantly increased the sensitivity of rabbit aorta to CEC indicating a role for receptor reserve in determining the extent of CEC inhibition. Membrane fluidity measured by diphenylhexatriene fluorescence was lower in rabbit than rat aorta; however, dimethylsulfoxide or ethanol failed to alter the rate of irreversible CEC inhibition in the rabbit. Protein kinase C activation with phorbol dibutyrate failed to alter CEC alkylation in rabbit aorta. WB 4101 [2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane] affinity was higher in rabbit aorta (pKB = 8.9) than rat aorta (pKB = 8.3) consistent with a contribution of alpha-1A and alpha-1B adrenergic receptor subtypes to differences in CEC sensitivity, although the difference was not as great as would be predicted.(ABSTRACT TRUNCATED AT 250 WORDS)
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