Abstract 351: Mineralocorticoid Receptor Antagonism During the Development of Hypertension Improves Cerebral Artery Endothelium Dependent Dilation Even After Treatment Withdrawal
Hypertension causes cerebral artery remodeling and increases the risk of stroke. Renin angiotensin system blockade during the development of hypertension has therapeutic effects even after treatment withdrawal. Mineralocorticoid receptor (MR) activation has been implicated in artery remodeling and impaired endothelial function. The possibility that there is a critical therapeutic window for MR antagonism has not been investigated. We hypothesized that temporary MR antagonism while hypertension develops would improve endothelium dependent dilation even after treatment withdrawal. Six-week-old male stroke prone spontaneously hypertensive rats (SHRSP) were treated with spironolactone (Spir; 25mg/kg/day, n=8) from 6-12 weeks then aged to 18 weeks. Age-matched untreated SHRSP were controls (n=8). The middle cerebral artery (MCA) was removed and mounted on a pressure myograph, endothelium dependent dilation was assessed by intralumenal perfusion of 2-methylthioadenosine 5′-triphosphate (2-MeS-ATP), or uridine 5′-triphosphate (UTP). Spir had no effect on blood pressure. The MCA diameter after the development of tone was not different between the groups (197.7 ± 8.7 vs. 199.1 ± 4.1 μm, Spir vs. control). Spir treatment increased nitric oxide (NO) mediated MCA dilation in response to 2-MeS-ATP (% change from baseline; 50.9 ± 5.0 vs. 28.0 ± 4.3, Spir vs. control, p<0.05 ANOVA). Spir treatment also increased UTP mediated dilation (% change from baseline; 48.4 ± 6.0 vs. 37.4 ± 6.7, Spir vs. control, p<0.05 ANOVA), and increased the MCAs sensitivity to UTP as evidenced by a reduction in the Log EC50 for UTP (-9.2 ±0.1 vs. -8.7±0.2 Spir vs. control, p<0.05 t-test). There was no difference in the response to sodium nitroprusside between the two groups (% change from baseline; 42.5 ± 7.2 vs. 47.0 ± 7.6, Spir vs. control). These results suggest that MR antagonism improves both NO and endothelium derived relaxing factor mediated dilation in MCAs when the antagonist is administered while hypertension develops. Intriguingly, the improved endothelial function persists even after several weeks of treatment withdrawal suggesting there may be a critical time window during which endothelial function can be permanently improved in cerebral arteries from SHRSP.
- © 2013 by American Heart Association, Inc.