Angiotensin Receptor Regulates Cardiac Hypertrophy and Transforming Growth Factor-/^ Expression

The role of angiotensin II via the angiotensin type 1 or type 2 receptor in the development of cardiac hypertrophy was determined in adult male Sprague-Dawley rats subjected to coarctation of the abdominal aorta. Five groups of animals were studied: coarctation, coarctation plus DuP 753, coarctation plus PD 123319, sham plus DuP 753, or sham operation. Type 1 receptor blockade was accomplished with DuP 753 given in the drinking water and type 2 blockade with PD 123319 delivered by osmotic minipumps beginning with the day of surgery until 72 hours after aortic coarctation. Mean carotid blood pressures and the carotid-femoral artery blood pressure gradients were not different among coarctation, coarctation plus DuP 753, and coarctation plus PD 123319 animals. However, ratios of heart weight to body weight were higher in coarctation (4.95 ±0.8) or coarctation plus PD 123319 (4.52±0.5) than in sham animals (3.6±0.4; P<.005 and .05, respectively). In coarctation plus DuP 753-treated animals Cardiac hypertrophy is an important risk factor for sudden cardiac death in patients with cardiovascular disease.' Therefore, the determination of the mechanisms leading to cardiac hypertrophy is of extreme importance. Cardiac hypertrophy is a physiological adaptation to an increase in workload. This extra mechanical load is often accompanied by increases in circulating catecholamines, angiotensin II (Ang II), and endothelin,' which may play additional roles in mediating the hypertrophic process. Previous studies have implicated a potential role for Ang II by using converting enzyme inhibitors to prevent cardiac hypertrophy in rats after chronic abdominal coarctation. In humans, converting enzyme inhibitors have been used to successfully reduce left ventricular mass as a result of hypertension and increase survival after myocardial infarction.' Although these studies suggest a role of the reninangiotensin system, the potential participation of the kinin system could not be dismissed. Cardiocytes are known to bind Ang II with high affinity. Cardiac Ang II receptors have been divided into subtypes by their affinity for nonpeptide inhibitors into angiotensin type 1 (AT,; sensitive to DuP 753) and type 2 (AT2; sensitive to PD 123319). Recently, the AT, receptor was cloned from rat vascular smooth muscle, Received June 9, 1993; accepted in revised form February 12, 1994. From the University of Virginia Health Sciences Center, Department of Pediatrics, Charlottesville. Correspondence to Allen D. Everett, MD, University of Virginia, MR-4 Building, Box 14, Charlottesville, VA 22908. heart weight-body weight ratios were not different from sham or sham plus DuP 753 animals (3.9±0.4 versus 3.6±0.4 or 3.3±0.08, respectively). Type 1 receptor mRNA levels were significantly increased in the coarctation group, with the highest levels in the coarctation plus DuP 753 and sham plus DuP 753 groups. To determine whether growth factors were involved in the hypertrophic process, we measured transforming growth factor-^, mRNA levels. Northern analysis demonstrated a twofold increase in coarctation animals compared with sham or coarctation plus DuP 753-treated animals. Therefore, cardiac hypertrophy induced by abdominal coarctation of the aorta is mediated by the angiotensin type 1 receptor and results in upregulation of the cardiac angiotensin type 1 and transforming growth factor-/?, genes. (Hypertension. 1994^3:587-592.)