Alteration of intracellular Ca2(+)-handling and receptor regulation in hypertensive cardiac hypertrophy: insights from Ren2-transgenic rats.

Abnormal intracellular Ca2(+)-handling appears to be a major cause of systolic and diastolic dysfunction in animals and humans with cardiac hypertrophy due to pressure overload and heart failure. However, the precise mechanisms which cause alteration of Ca2(+)-handling remain unclear. Several lines of evidence suggest that activation of neurohormonal systems may play a central role. In particular, widespread awareness of the importance of the renin-angiotensin system (RAS) has occurred since experimental and clinical studies have detailed the efficacy of angiotensin-converting enzyme inhibitors in reducing morbidity and mortality in patients with left ventricular dysfunction. To evaluate in vivo the role of activated RAS in the regulation of (a) cardiac receptor expression and signal transduction mechanisms and (b) Ca2+ homeostasis, transgenic TG(mREN2)27 rats harbouring the murine renin Ren2d gene were chosen. These animals develop fulminant hypertension and cardiac hypertrophy at an early age despite low levels of renin in the plasma. High expression of the transgene in the vasculature and the heart is associated with increased local formation of angiotensin II. In the Ren2-transgenic model alterations of beta-adrenergic neuroeffector mechanisms, Ca2(+)-handling and alpha-adrenergic signal transduction are observed which are very similar to those observed in the myocardium of patients with end-stage heart failure. Moreover, treatment with specific inhibitors of the RAS, such as angiotensin-converting enzyme inhibitors or angiotensin II-receptor antagonists, largely reversed these defects. Studies on TG(mREN2)27 rats may provide new insights into the pathogenesis of hypertensive heart disease and mechanisms which promote disease progression to end-stage heart failure and also may have important implications with regard to therapeutics of heart failure in man.