We examined long-term influence of the angiotensin II type 1-receptor blocker irbesartan and the beta1-adrenergic receptor blocker atenolol on some neurohormonal systems implicated in the pathophysiology of cardiac hypertrophy. Thus, 115 hypertensive patients with left ventricular hypertrophy were randomized to receive double-blind irbesartan or atenolol, with additional therapy if needed. Neurohormone measurements and echocardiography were performed at weeks 0, 12, 24, and 48. Left ventricular mass was reduced more by irbesartan than by atenolol (-26 g/m2 versus -14 g/m2, P = 0.024), despite similar reductions in blood pressure. Plasma renin activity and angiotensin II increased (P < 0.001) by irbesartan (0.9 +/- 0.7 to 3.4 +/- 4.2 ng/mL x h, and 3.0 +/- 1.6 to 13.0 +/- 17.7 pmol/L), but decreased (P < 0.01) by atenolol (1.0 +/- 0.6 to 0.7 +/- 0.6 ng/mL x h, and 3.4 +/- 1.6 to 3.2 +/- 2.2 pmol/L). Serum aldosterone decreased (P < 0.05) by both irbesartan (346 +/- 140 to 325 +/- 87 pmol/L) and atenolol (315 +/- 115 to 283 +/- 77 pmol/L). Changes in left ventricular mass by irbesartan related inversely to changes in plasma renin activity, angiotensin II, and aldosterone (all P < 0.05). Plasma levels and 24-hour urinary excretions of catecholamines, plasma leptin, proinsulin, insulin and insulin sensitivity remained largely unchanged in both groups. Thus, the renin-angiotensin aldosterone system appears to be an important non-hemodynamic factor in the regulation of left ventricular mass.