title: Interleukin-1 enhances beta-responsiveness of cardiac L-type calcium current suppressed by acidosis.
abstract: Modulation of the beta-adrenergic control of the cardiac L-type Ca2+ current (ICa) by human recombinant interleukin-1 beta (IL-1) was examined in guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was evoked in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. In the presence of an acidic external solution (pH 5.8), the response of ICa to isoproterenol (Iso; 0.01 and 1 microM) was markedly decreased compared with control myocytes studied at pH 7.4. However, when cells were pretreated with 1 ng/ml IL-1 and then exposed to acid media, beta-responsiveness was significantly increased compared with untreated cells. Despite this effect of IL-1, maximum ICa density with 0.01 and 1 microM Iso was still 51 and 58%, respectively, less than that measured at pH 7.4. The enhanced beta-responsiveness produced by IL-1 was eliminated by adding amiloride to block Na+/H+ exchange or protein kinase C inhibitors staurosporine (10 nM) and calphostin C (50 nM). However, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, did not mimic the effects of the cytokine. These data demonstrate that IL-1 partially restores the beta-adrenergic control of cardiac Ca2+ channels suppressed under acidic conditions. Moreover, they suggest that IL-1 acts by enhancing Na+/H+ exchange through a second messenger pathway that may involve protein kinase C. These cellular mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes that are initiated by myocardial ischemia.
authors.affiliation: Department of Physiology, University of Nebraska College of Medicine, Omaha 68189-4575.
authors.forename: G J
authors.initials: GJ
authors.lastname: Rozanski
authors.forename: R C
authors.initials: RC
authors.lastname: Witt
mesh_terms: D000138:Acidosis; D000470:Alkaloids / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D009281:Naphthalenes; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000470:Alkaloids; D015220:Calcium Channels; D007375:Interleukin-1; D009281:Naphthalenes; D011083:Polycyclic Compounds; D011994:Recombinant Proteins; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D012964:Sodium; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate