The renin-angiotensin system (RAS) has been implicated in the cardiovascular complications of diabetes. We showed that a high-fructose diet increases blood pressure and plasma angiotensin and impairs glucose tolerance. We investigated the role of angiotensin AT(1a) receptors in the development of fructose-induced cardiovascular and metabolic dysfunction. Male angiotensin AT(1a) knockout (AT1aKO) and wild-type (AT1aWT) mice with arterial telemetric catheters were fed a standard dietor one containing 60% fructose. Fructose increased mean arterial pressure (MAP) in AT1aWT but only during the dark phase (8% increase). In AT1aKO mice, fructose unexpectedly decreased MAP, during both light and dark periods (24 and 13% decrease, respectively). Analytical methods were used to measure systolic arterial pressure (SAP) and pulse interval (PI) variability in time and frequency domains. In fructose-fed AT1aWT mice, there was an increase in SAP variance and its low-frequency (LF) domain (11 +/- 3 vs. 23 +/- 4 mmHg(2), variance, and 7 +/- 2 vs. 17 +/- 3 mmHg(2), LF, control vs. fructose, P < 0.004). There were no changes in SAP variance in AT1aKO mice. Depressor responses to alpha(1)-adrenergic blockade were augmented in fructose-fed AT1a WT compared with AT1aKO mice. Fructose inhibited glucose tolerance with a greater effect in AT1aWT mice. Fructose increased plasma cholesterol in both groups (P < 0.01) and reduced ANG II in AT1aKO mice. Results document prominent interactions between genetics and diet with data showing that in the absence of angiotensin AT(1a) receptors, a fructose diet decreased blood pressure.