REGULATION OF INTRARENAL AND CIRCULATING RENIN-ANGIOTENSIN SYSTEMS IN SEVERE HEART-FAILURE IN THE RAT

Objective: Activation of the intrarenal renin-angiotensin system may contribute to the pathophysiology of heart failure by accelerating the generation of angiotensin II at local sites within the kidneys. Activation of the local intrarenal renin-angiotensin system occurs in rats and with mild heart failure. The aim of the present study was to examine components of the circulating as well as the intrarenal renin-angiotensin system in rats with severe heart failure. Methods: Six weeks after experimental myocardial infarction (heart failure, HF; n=8) or sham operation (control, C; n=6), haemodynamics and the circulating and intrarenal components of the renin-angiotensin system were studied. Results: HF rats were characterised by large infarctions (scar tissue >40% of the left ventricular circumference). In comparison to sham operated controls, large myocardial infarctions resulted in severe heart failure with decreased systolic [108(SEM 3) mm Hg v 132(3) in C; p<0.001] and diastolic arterial blood pressure [83(3) mm Hg v 95(2) in C; p<0.05], decreased left ventricular systolic pressure [109(3) mm Hg v 132(3) in C; p<0.0051 and increased left ventricular end diastolic pressure [27(2) mm Hg v 5(1) in C; p<0.0001]. In rats with severe heart failure, the circulating renin-angiotensin system was activated, with an increase in plasma renin activity (3.5-fold, p<0.05) and plasma angiotensin II concentration (threefold, p<0.01). In parallel, the intrarenal renin-angiotensin system was activated in severe heart failure. Increases occurred in renal renin mRNA level (1.7-fold, p<0.01), renal angiotensinogen mRNA level (1.8-fold, p<0.05), and renal angiotensin II concentration (twofold, p<0.05) compared to C. Intrarenal angiotensin II concentrations exceeded plasma levels by a factor of 50 and were positively correlated with renal angiotensinogen mRNA levels (r=0.874, p<0.001), suggesting that local synthesis is the major source of angiotensin II found in the kidney. Conclusions: The intrarenal renin-angiotensin system may be selectively activated in mild heart failure, while both circulating and intrarenal renin-angiotensin systems are induced as the extent of left ventricular function worsens.