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 microM) 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 induce 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.
Department of Pharmacology, University of Kentucky College of Medicine, Lexington.
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Piascik
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Sparks
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D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010646:Phentolamine / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; C051307:SZL 49; D010656:Phenylephrine; C051731:chlorethylclonidine; D003000:Clonidine; D011224:Prazosin; D010646:Phentolamine