This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 54/2/286    most recent HYPERTENSIONAHA.109.130138v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Liang, W. Articles by Ward, M. E. PubMed PubMed Citation Articles by Liang, W. Articles by Ward, M. E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Electrophysiology Remodeling Cardiovascular Pharmacology Ion channels/membrane transport Pulmonary biology and circulation Smooth muscle proliferation and differentiation Pulmonary circulation and disease

(Hypertension. 2009;54:286.)
© 2009 American Heart Association, Inc.

Original Articles

Regulation of Proliferation and Membrane Potential by Chloride Currents in Rat Pulmonary Artery Smooth Muscle Cells

Wenbin Liang; Julie Basu Ray; Jeff Z. He; Peter H. Backx; Michael E. Ward

From the Departments of Physiology and Medicine (W.L., P.H.B.), Division of Respirology, Department of Medicine (J.B.R., J.Z.H., M.E.W.), Division of Cardiology, University Health Network (W.L., P.H.B.), University of Toronto; and Li Ka Shing Knowledge Institute (J.B.R., J.Z.H., M.E.W.), St Michael’s Hospital, Toronto, Ontario, Canada.

Correspondence to Peter H. Backx, Heart and Stroke/Richard Lewar Centre, 150 College St, Toronto, Ontario, Canada M5S 3E2. E-mail p.backx{at}utoronto.ca

Pulmonary artery smooth muscle cell (PASMC) proliferation contributes to increased pulmonary vascular resistance and pulmonary hypertension. Because proliferation depends on membrane potential (V_m) and because V_m is, in part, determined by Cl^– currents (I_Cl), we examined the effects of I_Cl inhibition with 4,4`-diisothiocyanatostilbene-2,2`-disulfonic acid (DIDS) on cultured rat PASMCs. DIDS (30 µmol/L) reduced cell numbers, decreased 5-bromodeoxyuridine incorporation and delayed cell cycle progression. I_Cl inhibition with 5-Nitro-2-(3-phenylpropylamino) benzoic acid (100 µmol/L) also reduced cell numbers of cultured rat PASMCs. To test the possible involvement of I_Cl in the regulation of PASMC proliferation, we measured V_m and I_Cl in both cultured (proliferating) and acutely dissociated (nonproliferating) rat PASMCs. V_m (–39.3±1.4 mV) was close to the equilibrium potential of Cl^– (–39 mV) in proliferating PASMCs but differed from equilibrium potential of Cl^– in acutely dissociated cells (–45.3±0.9 mV). DIDS and substitution of extracellular Cl^– with I^– induced V_m hyperpolarization in proliferating but not nonproliferating PASMCs. Consistent with V_m recordings, DIDS-sensitive baseline and swelling-activated (Ca²⁺-independent) I_Cls, recorded with low Ca²⁺ (<1 nmol/L) pipette solutions, were 5-fold greater in proliferating than in nonproliferating PASMCs. By contrast, Ca²⁺-activated I_Cl did not differ between proliferating and nonproliferating PASMCs. Ca²⁺-independent I_Cls were also increased in proliferating PASMCs acutely dissociated from rats exposed to hypoxia (10% O₂; 7 days). These findings are consistent with the conclusion that I_Cls regulate proliferation of PASMCs and suggest that selective I_Cl inhibition may be useful in treating pulmonary hypertension.

Key Words: Ca²⁺-independent chloride currents • pulmonary hypertension • hypoxia • cell cycle • phenotypic transition