Abstract 460: Aldosterone Antagonism Restores Vascular Reactivity by Increasing Glucose-6-Phosphate Dehydrogenase Activity
Elevated levels of aldosterone (ALDO) are associated with impaired vascular reactivity, owing, in part, to a decrease in vascular glucose-6-phosphate dehydrogenase (G6PD) expression. G6PD is the first enzyme in the pentose phosphate pathway and, as the principal source of NADPH, regulates vascular function by limiting oxidant stress (OS) and maintaining endothelial nitric oxide synthase (eNOS) activity. We hypothesized that ALDO antagonism with spironolactone (SP) would restore G6PD activity to decrease OS, increase eNOS activity, and improve vascular reactivity. To examine this hypothesis, C3H wild-type mice were infused with ALDO (50 μg/kg/day) via Alzet pump for 14 days; after infusion day 7, mice were treated with SP (20 mg/kg/d) (ALDO-SP) or vehicle (ALDO-V) for the remaining week. Plasma levels of ALDO were increased similarly in ALDO-SP as compared to ALDO-V (4,221 ± 77 vs. 4,193 ± 55 pmol/L, p=NS); however, at day 14, systolic blood pressure was decreased in ALDO-SP compared to ALDO-V (102 ± 4 vs. 119 ± 8 mmHg, p<0.01). In aortas from ALDO-SP compared to ALDO-V, G6PD expression and activity were increased by 59% and 67%, respectively, resulting in a 51% increase in NADPH levels. Aorta superoxide formation was decreased in ALDO-SP as compared to ALDO-V (3.2 ± 0.2 vs.1.4 ± 0.3 nmol/L ·O2−/10 min/mg protein, p<0.01) while cGMP levels were increased (0.7 ± 0.1 vs. 0.3 ± 0.1 pmol/mg protein, p<0.01).Vascular reactivity, examined by in vivo intravital videomicroscopy of mesenteric arterioles, revealed that vasodilation to acetylcholine (ACh) (10−9-10−5 mol/L) was improved in ALDO-SP compared to ALDO-V (at 10−5 mol/L; 85 ± 5 vs.50 ± 7 % relaxation, p<0.01), similar to levels observed in untreated WT mice (91 ± 5%). In ALDO-SP, vascular reactivity to sodium nitroprusside (at 10−5 mol/L; 92 ± 6 vs. 70 ± 8 % change in vessel diameter, p<0.05) was also improved compared to ALDO-WT. These studies demonstrate that SP restores decreased G6PD expression and activity associated with hyperaldosteronism to improve endothelium-dependent and -independent vascular reactivity. SP-mediated increased G6PD expression may represent one mechanism by which ALDO antagonism decreases vascular OS, increases levels of bioavailable nitric oxide, and improves vascular dysfunction.