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This Article Full Text Full Text (PDF) All Versions of this Article: 579/1/127    most recent jphysiol.2006.123638v1 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Alvarez, B. V. Articles by Casey, J. R. Search for Related Content PubMed PubMed Citation Articles by Alvarez, B. V. Articles by Casey, J. R. Related Collections Cardiovascular

¹ Department of Physiology
² Department of Physiology, Membrane Protein Research Group
³ Department of Pharmacology University of Alberta, Edmonton, Canada T6G2H7
⁴ Department of Physiology and Pharmacology, University of Western Ontario, London, Canada N6A5C1

Hypertrophic cardiomyocyte growth contributes substantially to the progression of heart failure. Activation of the plasma membrane Na⁺–H⁺ exchanger (NHE1) and Cl^––HCO₃^– exchanger (AE3) has emerged as a central point in the hypertrophic cascade. Both NHE1 and AE3 bind carbonic anhydrase (CA), which activates their transport flux, by providing H⁺ and HCO₃^–, their respective transport substrates. We examined the contribution of CA activity to the hypertrophic response of cultured neonatal and adult rodent cardiomyocytes. Phenylephrine (PE) increased cell size by 37 ± 2% and increased expression of the hypertrophic marker, atrial natriuretic factor mRNA, twofold in cultured neonatal rat cardiomyocytes. Cell size was also increased in adult cardiomyocytes subjected to angiotensin II or PE treatment. These effects were associated with increased expression of cytosolic CAII protein and the membrane-anchored isoform, CAIV. The membrane-permeant CA inhibitor, 6-ethoxyzolamide (ETZ), both prevented and reversed PE-induced hypertrophy in a concentration-dependent manner in neonate cardiomyocytes (IC₅₀ = 18 µM). ETZ and the related CA inhibitor methazolamide prevented hypertrophy in adult cardiomyocytes. In addition, ETZ inhibited transport activity of NHE1 and the AE isoform, AE3, with respective EC₅₀ values of 1.2 ± 0.3 µM and 2.7 ± 0.3 µM. PE significantly increased neonatal cardiomyocyte Ca²⁺ transient frequency from 0.33 ± 0.4 Hz to 0.77 ± 0.04 Hz following 24 h treatment; these Ca²⁺-handling abnormalities were completely prevented by ETZ (0.28 ± 0.07 Hz). Our study demonstrates a novel role for CA in mediating the hypertrophic response of cardiac myocytes to PE and suggests that CA inhibition represents an effective therapeutic approach towards mitigation of the hypertrophic phenotype.

(Received 25 October 2006; accepted after revision 23 November 2006; first published online 23 November 2006)
Corresponding author J. R. Casey: Department of Physiology, Membrane Protein Research Group, University of Alberta, Edmonton, Canada T6G2H7. Email: joe.casey{at}ualberta.ca