title: Relationship between alpha adrenoceptor occupancy and response for the alpha-1 adrenoceptor agonist, cirazoline, and the alpha-2 adrenoceptor agonist, B-HT 933, in canine saphenous vein.
abstract: The relationship between alpha adrenoceptor occupancy and response was investigated for the alpha-1 adrenoceptor agonist, cirazoline, and the alpha-2 adrenoceptor agonist, B-HT 933, in canine saphenous vein, a tissue known to contain both alpha adrenoceptor subtypes. Both cirazoline and B-HT 933 produced dose-dependent vasoconstrictor responses in canine saphenous vein, with the maximum vasoconstrictor response elicited by B-HT 933 being only 75% of that produced by cirazoline. Dissociation constants were obtained for cirazoline (0.61 microM) and B-HT 933 (4.99 microM) for interaction with postsynaptic vascular alpha-1 and alpha-2 adrenoceptors, respectively, by the method of fractional irreversible receptor inactivation using phenoxybenzamine. Based on this information, alpha-1 and alpha-2 adrenoceptor occupancy-response relationships were constructed. The alpha-1 adrenoceptor occupancy-response relationship obtained for cirazoline was approximately 4-fold more favorable than the alpha-2 adrenoceptor occupancy-response relationship for B-HT 933, although both agonists were associated with a significant receptor reserve. The alpha-1 adrenoceptor occupancy-response relationship of cirazoline and the alpha-2 adrenoceptor occupancy-response relationship of B-HT 933 were both rectangular hyperbolas, suggesting that both compounds have high intrinsic efficacy at their respective alpha adrenoceptor subtypes. The results indicate that a receptor reserve exists for the alpha-1 and alpha-2 adrenoceptor-mediated effects of cirazoline and B-HT 933, respectively, and that the alpha adrenoceptor reserve may be significantly larger for postsynaptic vascular alpha-1 adrenoceptors than for postsynaptic vascular alpha-2 adrenoceptors in canine saphenous vein.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
authors.forename: R L
authors.initials: RL
authors.lastname: Zeid
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014680:Veins / Q000032:analysis*
chemical_list: D000316:Adrenergic alpha-Agonists; D001381:Azepines; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D010643:Phenoxybenzamine; C015603:azepexole; C014282:cirazoline