title: Alpha1-adrenergic stimulation of sarcolemmal Na+-H+ exchanger activity in rat ventricular myocytes: evidence for selective mediation by the alpha1A-adrenoceptor subtype.
abstract: Alpha1-adrenoceptor (alpha1-AR) stimulation increases sarcolemmal Na+-H+ exchanger (NHE) activity. The present study was designed to determine the role(s) of alpha1-AR subtype(s) in mediating this response. As an index of NHE activity, acid efflux rates (JHs) were determined in single rat ventricular myocytes loaded with the pH-sensitive fluoroprobe carboxy-seminaphthorhodafluor-1 after 2 consecutive intracellular acid pulses in bicarbonate-free medium. JH at pHi 6.90 did not change significantly during the second pulse relative to the first in control cells but increased in a dose-dependent manner when the second pulse occurred in the presence of phenylephrine (nonselective alpha1-AR agonist) or A61603 (alpha1A-AR-selective agonist), with EC50 values of 1.24 micromol/L and 3.6 nmol/L, respectively (both agonists given together with 1 micromol/L atenolol). Stimulation of NHE activity by 10 micromol/L phenylephrine was inhibited in a dose-dependent manner by the competitive antagonists prazosin, WB4101, and 5-methylurapidil, with IC50 values of 12, 32, and 149 nmol/L, respectively. Analyses of the relative EC50 and IC50 values obtained (and Ki values estimated from the antagonist IC50s) in relation to the relative potencies of these agents at native rat alpha1-AR subtypes and their relative affinities for recombinant rat alpha1-ARs suggest that alpha1-adrenergic stimulation of sarcolemmal NHE activity is likely to be mediated selectively by the alpha1A-AR.
authors.affiliation: Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Yokoyama
authors.forename: M
authors.initials: M
authors.lastname: Yasutake
authors.forename: M
authors.initials: M
authors.lastname: Avkiran
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: C094643:A 61603; C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D017923:Sodium-Hydrogen Exchangers; D013764:Tetrahydronaphthalenes; C057446:5-methylurapidil; D010656:Phenylephrine; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D011224:Prazosin