ANG II type 2 receptor (AT2) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca2+ concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT2 was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT 2 in the ventricular myocytes and partial colocalization of AT 2 with AT1. Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca2+ concentration, 25°C) and study of contractile reserve at faster pacing rates (1-5 Hz) revealed Ca2+-dependent contractile dysfunction in myocytes from AT2 transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT2 expression. Second, activity of the Na+/H+ exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to β-adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to β-adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca2+ in wild-type myocytes but caused a negative inotropic effect in myocytes from AT2 transgenic mice. In contrast with β-adrenergic response, the depressed response to ANG II was related to level of AT2 overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT2 has the potential to cause Ca2+- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Issue number||1 57-1|
|Publication status||Published - 2005 Jan 1|
- Calcium ion transients
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)