Left ventricular hypertrophy (LVH) is associated with elevated plasma angiotensin II (Ang II) levels and endothelial dysfunction. The relationship between Ang II and endothelial dysfunction remains unknown, however, but it may involve an alteration in endothelial cell redox state. We therefore investigated the effect of Ang II on NADH/NADPH oxidase-mediated superoxide anion (O(2)(-)) production by cultured guinea pig coronary microvascular endothelial cells (CMVEs) and CMVEs freshly isolated from a guinea pig, pressure-overload model of LVH. Lucigenin chemiluminescence was used to measure O(2)(-) production in the particulate fraction of CMVE lysates. In cultured cells, incubation with Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) resulted in significant (P<0.01) increases in both NADH- and NADPH-dependent O(2)(-) production, with a peak effect at 1 nmol/L. The latter was significantly (P<0.01) inhibited by the AT(1) receptor antagonist losartan (1 micromol/L for 18 hours). In contrast, the O(2)(-) response to Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) was largely unaffected by concomitant exposure to the AT(2) antagonist PD 123319 (1 micromol/L). In freshly isolated CMVEs from nonoperated animals, NADH- and NADPH-dependent O(2)(-) production was not different from that in sham-operated animals but was significantly (P<0.05) elevated in the aortic-banded animals. Plasma Ang II levels were significantly (P<0.001) elevated in the aortic-banded (1.25+/-0.12 microg/L, n=12) compared with sham-operated animals (0.63+/-0.06 microg/L, n=12). These data suggest that the endothelial dysfunction associated with LVH may be due, at least in part, to the Ang II-induced upregulation of NADH/NADPH oxidase-dependent O(2)(-) production.

Left ventricular hypertrophy (LVH) is a cardiovascular risk factor. A possible role for endothelial dysfunction in this condition was investigated in a Dunkin-Hartley guinea pig aortic-banded pressure overload-induced model of LVH. Aortic banding produced significant elevation of fore- and hindlimb blood pressure (BP), heart-to-body weight ratios, plasma angiotensin II (ANG II), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha) levels, and coronary microvascular endothelial cell (CMEC) NAD(P)H-dependent superoxide (O) production, and a significant decrease in basal and stimulated CMEC cGMP levels. Treatment of aortic-banded animals with the angiotensin-converting enzyme inhibitor quinapril and the antioxidant vitamin C, either alone or in combination, did not affect BP but caused a significant inhibition of the increases in the heart-to-body weight ratio, ANG II, ET-1, and TNF-alpha levels, and O production and restored cGMP responses to levels comparable with sham-operated animals. These data suggest that quinapril and vitamin C are capable of inhibiting LVH development due to pressure overload via mechanisms that involve the inhibition of oxidative stress, an improvement in coronary endothelial function, and increased nitric oxide bioavailability.