TISSUE-SPECIFIC ACTIVATION OF CARDIAC ANGIOTENSIN CONVERTING ENZYME IN EXPERIMENTAL HEART-FAILURE

In addition to the circulating renin-angiotensin system, recent data demonstrate the existence of tissue renin-angiotensin systems that may be important in cardiovascular homeostasis. However, the relative activities of the circulating and tissue renin-angiotensin systems have not been examined previously in pathophysiological states, such as congestive heart failure. The present study was performed to examine the status of plasma and tissue angiotensin converting enzyme (ACE) activities in compensated experimental heart failure induced by coronary artery ligation in the rat. Three groups of male Sprague-Dawley rats were examined: 1) nonoperated rats (NO, n = 5), 2) sham-operated rats (SO, n = 5), and 3) heart failure rats (HF, n = 11). Rats were studied an average of 85 days postoperatively. In HF animals, plasma renin concentration and serum ACE activities were not different compared with NO and SO control animals. Cardiac ACE activity was 50% greater in the right ventricle than the interventricular septum in NO and SO rats. Both right ventricular and interventricular septal ACE activity increased approximately twofold in HF animals as compared with NO and SO groups (p < 0.05). In contrast, pulmonary, aortic, and renal ACE activities were not altered in HF rats compared with control animals. A positive correlation existed between the histopathological size of myocardial infarction and the level of right ventricular ACE activity (r = 0.75, p less-than-or-equal-to 0.05). Such a relation between infarct size and either serum or noncardiac tissue ACE activities was not observed. To confirm that increased cardiac ACE activity was due to local synthesis, right ventricular myocardium from additional SO (n = 4) and HF (n = 6) rats was examined to determine the relative expression of ACE mRNA in this disease state. Harvested RNA was amplified by polymerase chain reaction (25 cycles); subsequent quantitation demonstrated a twofold increase in ACE mRNA level that also correlated with infarct size (r = 0.67, p < 0.05). These data demonstrate that compensated experimental heart failure is associated with tissue-specific activation of cardiac ACE activity, but not plasma or other tissue ACE activities. Additionally, the local activation of this component of the cardiac renin-angiotensin system appears to be directly associated with the magnitude of left ventricular dysfunction as suggested by the infarct size. Increased cardiac ACE mRNA level, ACE activity, and local synthesis of angiotensin II in experimental heart failure may be physiologically important and pertinent to the beneficial effects of ACE inhibition.