Effects of spironolactone on cerebral vessel structure in rats with sustained hypertension

Spironolactone prevents eutrophic middle cerebral artery (MCA) remodeling in young stroke-prone spontaneously hypertensive rats (SHRSP). Clinically, it is more relevant to identify treatments that improve vessel structure after hypertension and remodeling has developed. We hypothesized that spironolactone would increase the MCA lumen diameter and reduce the wall/lumen ratio in SHRSP treated from 12 to 18 weeks of age.

Twelve-week-old male SHRSP were treated with spironolactone (SHRSP + spir: 25 mg/kg/day) for 6 weeks and were compared at 18 weeks to age matched untreated SHRSP and Wistar Kyoto (WKY) rats. MCA structure was assessed by pressure myography. The WKY rats were included to provide an indication of the magnitude of the hypertensive MCA remodeling.

Spironolactone had no effect on blood pressure as measured by telemetry. MCA myogenic tone was enhanced in the SHRSP + spir. Spironolactone increased the MCA lumen diameter (SHRSP: 223.3 ± 9.7 µm, SHRSP + spir: 283.7 ± 10.1 µm, WKY: 319.5 ± 8.8 µm, analysis of variance (ANOVA) P < 0.05) and reduced the wall/lumen ratio (SHRSP: 0.107 ± 0.007, SHRSP + spir: 0.078 ± 0.006, WKY: 0.047 ± 0.002, ANOVA P < 0.05). Vessel wall stiffness was unchanged by spironolactone. Collagen 1 and 4 mRNA expression was increased in cerebral vessels from SHRSP compared to WKY rats; collagen 1 was reduced by spironolactone. Western blot analysis showed that active matrix metalloproteinase (MMP)-13 expression was increased by spironolactone treatment. The expression of intercellular adhesion molecule 1 (ICAM-1), a marker of inflammation, was increased in SHRSP and reduced by spironolactone.

These studies provide evidence that chronic mineralocorticoid receptor (MR) antagonism improves cerebral vessel structure after remodeling has developed in a model of human essential hypertension.