HYDROGEN HANDLING IN CARDIAC HYPERTROPHY - WHEN BIGGER IS NOT BETTER
Lea M.D. Delbridge, Petcharat Trongtorsak, Andrea A. Domenighetti, Department of Physiology, University of Melbourne, Parkville, Vic.
Cardiomyocyte pH regulation relies on the combined activities of the sarcolemmal Na-H exchanger (NHE1), the Na-HCO3 co-transporter and the anion exchanger (AE). Modulation of cardiomyocyte pH can produce both acute alterations in contractile performance and chronic regulation of cellular growth. For instance, the circulating and locally produced mediators angiotensin-II (AngII) and endothelin-1 exert a positive inotropic effect by causing an intracellular alkalinization which increases myofilament sensitivity to Ca. In vitro studies have shown that the sustained elevation in cardiomyocyte pH occurring on exposure to these peptides is NHE1-mediated and associated with the induction of a hypertrophic growth programme. Other studies using a variety of animal models have shown that increased activity of the NHE1 is a common hypertrophic phenotype. In the Spontaneously Hypertensive Rat (SHR), NHE1 hyperactivity is partially offset by the AE, minimising the cardiomyocyte pH shift but leaving a residual Na load1. In vivo treatment with enalapril normalises the NHE1 activity in the SHR, indicating that endogenous AngII levels have a role in regulating cardiomyocyte pH2. This is confirmed by experiments investigating the effects of chronic AngII infusion by osmotic minipump on cardiomyocyte function. Hypertrophic myocytes from these animals exhibit enhanced NHE1-dependent contractile recovery from acidosis3. Similarly, in transgenic mice where cardiac specific over-production of AngII has been induced, myocardial NHE1 expression is increased in association with a prolongation of the cardiomyocyte contractile cycle4. Thus, whilst NHE1-mediated growth stimulation coincident with enhanced hydrogen handling is an adaptive response to altered trophic or loading conditions, other functional consequences of NHE1 hyperactivity which include cardiomyocyte Na loading and delayed relaxation are ultimately detrimental to performance.
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(2) Ennis IL, Alvarez BV, Camilion de Hurtado MC, Cingolani HE. Hypertension. 1998;31:961-967.
(3) Trongtorsak P, Eitle E, Hart DP, Delbridge LMD. Heart, Lung & Circulation. 2002;11:A16.
(4) Domenighetti AA, Wang Q, Pedrazzini T, Delbridge LMD. Proc AHMRC Melbourne 2002.
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