Role of alpha 1A- and alpha 1B-adrenoceptors in phenylephrine-induced positive inotropic response in isolated rat left atrium.
We determined the distribution of alpha 1A- and alpha 1B-adrenoceptor subtypes and their functional roles in phenylephrine (PE)-induced positive inotropic responses in rat atrium. Radioligand binding assays in membrane preparations of rat atria showed that 62% of [125I]BE 2254 binding sites were irreversibly inactivated by pretreatment with 20 microM chloroethylclonidine (CEC). Inhibition curves for WB 4101 and 5-methyl-urapidil (5-MU) were better fit by a two-site model, comprising 29-35% high-affinity sites and 65-71% low-affinity sites, suggesting that rat atria contains both alpha 1A and alpha 1B subtypes in a ratio of approximately 1:2. In isolated perfused atria, pretreatment with CEC inhibited the maximum PE-induced positive inotropic response by 55%, and pA2 values for WB 4101 and 5-MU in inhibiting this response were 8.26 +/- 0.4 and 7.85 +/- 0.07, respectively, between the KD values for alpha 1A and alpha 1B subtypes. PE shifted the concentration-contractile response curve for Ca2+ to the left and upward. Pretreatment with CEC completely abolished whereas 1 nM WB 4101 did not alter, the effect of PE on Ca2+ sensitivity. These results demonstrate that both alpha 1A- and alpha 1B- adrenoceptor subtypes are involved in the PE-induced positive inotropic response. Only activation of the alpha 1B subtype potentiates the positive inotropic effect induced by increasing extracellular Ca2+, however, which suggests that the mechanisms involved in the action of the two subtypes may differ at least in part.
Yu
G S
GS
Institute of Vascular Medicine, Third Hospital, Beijing Medical University, China.
Han
C
C
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010627:Phenethylamines / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D044024:Tetralones
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007295:Inositol Phosphates; D010627:Phenethylamines; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D044024:Tetralones; C057446:5-methylurapidil; D010656:Phenylephrine; C051731:chlorethylclonidine; C010652:BE 2254; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D002118:Calcium