title: Alpha 1-adrenoceptor mediated activation of Na/K/2Cl cotransport and K+ channels in the rat heart involves different receptor subtypes.
abstract: Involvement of receptor subtypes in the alpha 1-adrenoceptor mediated activation of Na/K/2Cl-cotransport and K+ channels was studied in isolated perfused spontaneously beating rat hearts stimulated by phenylephrine (30 mumol/l) in the presence of a beta-adrenoceptor antagonist (1 mumol/l timolol). The effects of alpha 1-adrenoceptor stimulation on K+ translocation mechanisms were studied by measuring the efflux of 86Rb+ (a potassium analogue). The effects of 50 mumol/l bumetanide (Na/K/2Cl-cotransport inhibitor) and 0.1-0.3 mmol/l 4-aminopyridine (inhibitor of K+ channels) were studied in the presence of alpha 1-adrenoceptor subtype selective antagonists. Bumetanide reduced the alpha 1-adrenoceptor mediated increase in 86Rb+ efflux by 53 +/- 16.4% (n = 14, P < 0.001) in hearts pretreated with the preferentially alpha 1B-adrenoceptor antagonist chloroethylclonidine (CEC, 10 mumol/l), and by 35 +/- 7.3% (n = 15, P < 0.001) in the presence of the preferentially alpha 1D-adrenoceptor antagonist BMY 7378 (1 mumol/l). In the presence of the preferentially alpha 1A-adrenoceptor antagonist 5-methylurapidil (10 mumol/l), however, bumetanide had no effect on the response to phenylephrine. 4-Aminopyridine reduced the phenylephrine stimulated 86Rb+ efflux in the presence of 5-methylurapidil, but the effect of the K(+)-channel blocker was eliminated in CEC treated hearts. Thus the effects of the two translocation inhibitors were influenced differently by the two subtype selective antagonists, showing that alpha 1-adrenoceptor stimulation activates a bumetanide sensitive Na/K/2Cl-cotransport mechanism in the rat heart mainly through the alpha 1A-receptor subtype while the 4-aminopyridine sensitive K+ channels, are mainly activated by the alpha 1B-adrenoceptor subtype.
authors.affiliation: Department of Pharmacology, University of Oslo, Blindern, Norway.
authors.forename: G O
authors.initials: GO
authors.lastname: Andersen
authors.forename: M
authors.initials: M
authors.lastname: Enger
authors.forename: T
authors.initials: T
authors.lastname: Skomedal
authors.forename: J B
authors.initials: JB
authors.lastname: Osnes
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters
chemical_list: D000317:Adrenergic alpha-Antagonists; D002352:Carrier Proteins; D002712:Chlorides; D010879:Piperazines; D015221:Potassium Channels; D018340:Receptors, Adrenergic, alpha-1; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; C057446:5-methylurapidil; D010656:Phenylephrine; C051731:chlorethylclonidine; D012964:Sodium; D015761:4-Aminopyridine; C053428:BMY 7378; D003000:Clonidine; D011188:Potassium