title: Different desensitization mechanisms of two alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta.
abstract: Using alpha 1-adrenoceptor selective antagonists chlorethylclonidine (CEC) and WB4101, both functional and radioligand binding studies showed that rabbit aorta contains at least two pharmacologically distinct alpha 1-adrenoceptor subtypes of approximately 10% alpha 1a and 90% alpha 1b receptors, and that each receptor subtype has a distinct role in the alpha 1-adrenoceptor-mediated vasoconstrictive response through different biochemical mechanisms for increasing intracellular Ca2+; alpha 1a receptors cause tonic response predominantly dependent on the influx of extracellular Ca2+, while alpha 1b receptors stimulate phosphoinositides (PI) hydrolysis/intracellular Ca2+ mobilization and cause phasic response mainly independent of extracellular Ca2+. Incubation of rabbit aorta with 10 microM noradrenaline (NA) for 2 h resulted in a reduction in the phasic response and PI hydrolysis to NA with no change in the tonic response. Similar to the NA incubation, the protein kinase C stimulator PMA (1 microM) selectively attenuated alpha 1b-receptor mediated PI hydrolysis and phasic contraction but had little effect on alpha 1a-receptor-mediated tonic response. The protein kinase C inhibitor H-7 (10 microM) blocked these inhibitory effects of PMA. Treatment with H-7 (10 microM) prevented the NA-induced alpha 1b receptor desensitization in inositol monophosphate (IP) formation and phasic response. The results suggest that activation of C kinase may be involved in the development of selective desensitization of alpha 1b receptors by a short-time in vitro incubation of NA.
authors.affiliation: Department of Pharmacology, Yamanashi Medical College, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Suzuki
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010627:Phenethylamines / Q000378:metabolism; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D044024:Tetralones
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D010627:Phenethylamines; D011942:Receptors, Adrenergic, alpha; D044024:Tetralones; C051731:chlorethylclonidine; C010652:BE 2254; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D009638:Norepinephrine