Atrial natriuretic peptide has different effects on contractility and intracellular pH in normal and hypertrophied myocytes from pressure-overloaded hearts

Background-Atrial natriuretic peptide (ANP) depresses contractility in left ventricular myocytes. Its expression is upregulated in pressure-overloaded hypertrophied hearts; however, the effects of ANP on contractility in hype rtrophied myocytes are not known. Our aims were (1) to examine the cellular mechanisms of this depression in contractility in normal myocytes and (2)t o test the hypothesis that the effects of ANP on contractility differ in hy pertrophied myocytes from rats with ascending aortic stenosis, Methods and Results-We measured the myocyte shortening as ari index of cont ractility, [Ca2+](i) with flue 3, and pH(i) with seminaphthorhodafluor-1 (S NARF-1). In normal control myocytes (n=26), ANP caused a concentration-depe ndent depression of contractility and reduction in pHi, In the presence of 10(-6) mol/L ANP, fractional cell shortening was 78+/-5% of baseline (P<0.0 5) and pH(i) was reduced by 0.16+/-0.04 U from baseline (P<0.01) without ch anges in [Ca2+](i). The magnitude of the depression of contraction caused b y ANP was similar to that caused by intracellular acidification induced by an NH4Cl pulse. The effects of ANP on contractility and pH(i) were-prevente d in the presence of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA), which inhibi ts the Na+/H+ exchanger. In hypertrophied myocytes (n=23), ANP did not depr ess either myocyte contractility or pHi at concentrations of either 10(-8), 10(-7), or 10(-6) mol/L, ANP caused no change in pH, or the [Ca2+](i) tran sient in hypertrophied myocytes. The cGMP level was increased and Na+/H+ ex changer mRNA levels were normal in left ventricles from aortic stenosis rat s compared with controls. Conclusions-ANP directly depresses contractility in normal myocytes via int racellular acidification, which decreases myofilament [Ca2+](i) sensitivity , In contrast, ANP causes no effects on contractility and pH(i) in hypertro phied myocytes, suggesting a suppression in the coupling of the ANP-cGMP in tracellular signaling pathway to the Na+/H+ exchanger.