Interaction of imidazolines with alkylation-sensitive and -resistant alpha-1 adrenoceptor subtypes

The interaction of imidazolines with alpha-1 adrenoceptor subtypes sensitive and resistant to inactivation by SZL-49 and chlorethylclonidine (CEC) has been evaluated. Clonidine, oxymetazoline, phentolamine and naphazoline or the phenethylamine, phenylephrine, interacted with high- and low-affinity sites labeled by [³H]prazosin. SZL-49 (1-1000 nM) eliminated the high-affinity sites and caused a significant reduction of the low-affinity sites. CEC (1-100 μM) reduced the number of low-affinity sites, while the effect on high-affinity sites was dependent on the route of administration. In control aortic rings the dose-response curves for either clonidine or naphazoline were biphasic, consisting of high- and low-affinity components. Only the high-affinity component was blocked by prazosin. SZL-49 was more potent than CEC at inhibiting agonist-induced contraction of rat aortic rings. The agonist responses obtained after treatment with either SZL-49 or CEC were only weakly antagonized by prazosin. The combination of SZL-49 and CEC produced no greater inhibition of muscle contraction than did SZL-49 alone. These data show that 1) imidazolines interact with different affinity at sites labeled by [³H]prazosin and these sites correspond to the alpha-1a and alpha-1b adrenoceptor subtype designation; 2) imidazolines induced smooth muscle contraction by interacting at high- and low-affinity sites; 3) these low-affinity sites do not appear to have properties of an alpha-1 adrenoceptor; 4) there may be three sites of interaction for imidazolines on the aorta, the alpha-1a and alpha-1b adrenoceptors and a site that does not have alpha-1 adrenoceptor characteristics.