title: Temporary mineralocorticoid receptor antagonism during the development of hypertension improves cerebral artery dilation.
abstract: 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 middle cerebral artery (MCA) structure and function in stroke-prone spontaneously hypertensive rats (SHRSP), even after treatment withdrawal. Six-week-old SHRSP were treated with spironolactone (25 mg/kg/day) from 6 to 12 weeks and when aged to 18 weeks, these rats were compared to age-matched untreated SHRSP. Surprisingly, temporary spironolactone treatment reduced the MCA outer and lumen diameter but had no effect on the wall thickness. Temporary spironolactone treatment improved nitric oxide and endothelium-derived hyperpolarizing factor mediated dilation but had no effect on blood pressure. Spironolactone treatment caused a very small reduction in the damage caused by permanent focal cerebral ischemia. These results suggest that temporary MR antagonism during the development of hypertension has divergent effects on the MCA, in that it causes a potentially detrimental reduction in the lumen diameter while improving vasodilation.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Jonathon L
authors.initials: JL
authors.lastname: McClain
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dorrance
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D051381:Rats; D011918:Rats, Inbred SHR; D013148:Spironolactone / Q000008:administration & dosage
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone
keywords: Hypertension; aldosterone; endothelium-dependent vasodilation; middle cerebral artery; vascular remodeling