title: Receptor-effector coupling pathway for alpha 1-adrenergic modulation of abnormal automaticity in 'ischemic' canine Purkinje fibers.
abstract: We studied the receptor-effector coupling mechanism responsible for alpha 1-adrenergic receptor-induced increases in abnormal automaticity (AA) occurring at low membrane potentials in "ischemic" Purkinje fibers, superfused with Tyrode's solution containing [K+]o 10 mmol/L, pH 6.8, PO2 < 25 mm Hg. To exclude beta-adrenergic actions, propranolol was added to all solutions. We derived membrane slope resistance (Rsl) from the current-voltage relation obtained with two microelectrodes for intracellular current injection and transmembrane voltage recording. We also measured the membrane time constant, Tm, to assess changes in membrane resistance (Rm). Phenylephrine effects on Rsl in simulated ischemia were studied in the absence or presence of the alpha 1-subtype blockers WB 4101 (WB) or chloroethylclonidine (CEC), both 0.1 mumol/L, and in Purkinje fibers from dogs injected with pertussis toxin (PTX) (30 micrograms/kg i.v., 60 to 72 hours before study). There were no significant differences in mean values of Rsl before phenylephrine superfusion among all groups of Purkinje fibers. Tm increased by 23% during phenylephrine 0.1 mumol/L superfusion, and Rsl increased by 11%. These two results suggest a 23% increase in Rm with no concordant change in longitudinal resistance. In the presence of CEC, phenylephrine increased Rsl by 12%. In contrast, WB blocked phenylephrine effects on Rsl (0.3%). In PTX-treated Purkinje fibers, the levels of PTX-sensitive G protein as well as phenylephrine effects on Rsl (3%) were significantly reduced. In the absence of WB and of CEC, the phenylephrine effects both on Rsl and on the incidence of AA were directly related to the level of PTX-sensitive substrate.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
authors.forename: E P
authors.initials: EP
authors.lastname: Anyukhovsky
authors.forename: S F
authors.initials: SF
authors.lastname: Steinberg
authors.forename: I S
authors.initials: IS
authors.lastname: Cohen
authors.forename: M R
authors.initials: MR
authors.lastname: Rosen
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000494:pharmacology; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D008564:Membrane Potentials / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D037342:Pertussis Toxin; D010656:Phenylephrine / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; D010566:Virulence Factors, Bordetella; D010656:Phenylephrine; D001464:Barium; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D037342:Pertussis Toxin; D003000:Clonidine