© 1995 American Heart Association, Inc.
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Forskolin Stimulates Swelling-Induced Chloride Current, Not Cardiac Cystic Fibrosis Transmembrane-Conductance Regulator Current, in Human Cardiac Myocytes
From the Departments of Surgery (M.C.O.) and Pharmacology (S.S.), Columbia University, New York, NY.
Correspondence to Dr Steve Sorota, Department of Pharmacology, Columbia University, 630 W 168th St, New York, NY 10032.
Abstract Whole-cell patch clamp was used to look for cystic fibrosis transmembrane-conductance regulator (CFTR)–like chloride currents in calcium-tolerant human cardiac myocytes. Potassium-containing solutions were used initially. Steady state currents were measured with hyperpolarizing ramps (-16.25 mV/s). Peak net inward currents during voltage steps from -50 to +5 mV were used as an index of L-type calcium current. Isoproterenol (1 µmol/L) or forskolin (10 µmol/L) were used in attempts to evoke CFTR-like chloride current. No forskolin- or isoproterenol-induced steady state current was found in any of 17 atrial cells from seven patients in the absence of cell swelling. Every cell exhibited a large increase in net inward current in response to forskolin, suggesting that cAMP-dependent stimulation of L-type calcium current was present. Swelling with osmotic stress induced an outwardly rectifying steady state current with a reversal potential close to the chloride equilibrium potential. Once this current was activated, exposure to forskolin caused a further increase that subsided on washout (four of four cells, two patients). The atrial swelling-induced current was studied in more detail by using cesium-containing solutions. The current was determined to be a chloride current because the reversal potential was sensitive to changes in intracellular chloride and outward currents were blocked by 150 µmol/L DIDS. Ventricular cells were isolated from five failing human hearts. No CFTR-like current was found in any of 17 cells. In eight of eight ventricular cells, a swelling-induced current was found. The amplitude of the swelling-induced current was enhanced by forskolin. In human ventricular cells, outward swelling-induced currents were inhibited by DIDS. The present results are in apparent conflict with mRNA measurements made by others. Our results suggest that significant amounts of functional channels do not accumulate despite the reported presence of cardiac CFTR mRNA in human heart. However, human myocardium does express a swelling-induced chloride current that can be stimulated by forskolin.
Key Words: chloride current • protein kinase A • swelling • cystic fibrosis transmembrane-conductance regulator
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