Abstract 427: Long-Term Treatment with an Angiotensin II Type 1 Receptor Blocker Ameliorates Metabolic Syndrome in Mice Lacking All Nitric Oxide Synthases
Background: We have recently developed mice lacking all three nitric oxide (NO) synthases (triply n/i/eNOS−/− [KO] mice) (PNAS 2005). Our preliminary study has revealed that those mice manifest metabolic syndrome. In this study, we examined whether or not an angiotensin II type 1 receptor blocker (ARB) ameliorates those metabolic phenotypes.
Methods: The following 6 groups were studied; 12-week-old wild-type (WT) and triply-KO mice treated with or without olmesartan (ARB, 5 mg/kg/day, PO) or hydralazine (anti-hypertensive drug, 0.05 mg/ml, PO) for 6 weeks.
Results: Hypertension (HT) (150± vs. 112± mmHg), increased plasma levels of triglyceride (TG) (153±2 vs. 109± mg/dl), impaired glucose tolerance (IGT) (plasma glucose after intravenous glucose, 475±3 vs. 241±0 mg/dl), insulin resistance (insulin-induced muscular [3H]-glucose uptake, 109± vs. 209±6%), and visceral obesity (epididymal fat, 0.28±.02 vs. 0.19±.01 g), were noted in untreated triply-KO mice as compared with untreated WT mice (all P<.05, n= −12). Enhanced angiotensin-converting enzyme activity in the aorta was also noted in the triply-KO mice compared with the WT mice (15± vs. 7±.7 unit/g protein, P<.05, n=−8). The treatment with olmesartan significantly ameliorated all the metabolic phenotypes in the triply-KO mice; HT (122±), TG (118±2), IGT (349±1), insulin resistance (122±5), and visceral obesity (0.18±0.01) (all P<0.05, n=8). Although the treatment with hydralazine significantly improved HT in the triply-KO mice to the same extent as with olmesartan, it did not significantly affect other metabolic parameters (n=8), suggesting that the beneficial effects of olmesartan were not mediated by its blood pressure-lowering effect. Importantly, plasma level of adiponectin, a key metabolic regulator, was markedly reduced in the untreated triply-KO mice compared with the untreated WT mice (8.7±1.6 vs.21±2.5 μg/ml, P<0.05), which level was significantly restored by the olmesartan treatment (13.7±0.7, P<0.05, n=8).
Conclusions: These results indicate that long-term treatment with an ARB ameliorates metabolic syndrome in the presence of defective NO system, along with restoration of adiponectin, suggesting a new therapeutic strategy for the disorder.