Mineralocorticoid receptor antagonism improves transient receptor potential vanilloid 4-dependent dilation of cerebral parenchymal arterioles and cognition in a genetic model of hypertension.

Abstract

In a model of secondary hypertension, mineralocorticoid receptor (MR) antagonism during the development of hypertension prevents the impairment of transient receptor potential vanilloid 4 (TRPV4) activation in parenchymal arterioles (PAs) and cognitive impairment. However, it is unknown whether MR antagonism can improve these impairments when treatment begins after the onset of essential hypertension. We tested the hypothesis that MR activation in stroke-prone spontaneously hypertensive rats (SHRSP) leads to impaired TRPV4-mediated dilation in PAs that is associated with cognitive dysfunction and neuroinflammation. 20-22-week-old male SHRSP ± eplerenone (EPL; 100 mg/kg daily for 4 weeks) were compared to normotensive Sprague-Dawley (SD) rats. Pressure myography was used to assess PA function. Cognition was tested using Y-maze. Neuroinflammation was assessed using immunofluorescence and qRT-PCR. Carbachol-mediated endothelium-dependent dilation was impaired in SHRSP, and MR antagonism improved this without affecting myogenic tone. Dilation to TRPV4 agonist GSK1016790A was impaired in SHRSP, and ELP treatment restored this. Intermediate conductance potassium channel (IKCa)/small conductance potassium channel (SKCa)-mediated dilation was impaired by hypertension and unaffected by EPL treatment. TRPV4 and IKCa/SKCa channel mRNA expression were reduced in PAs from hypertensive rats, and EPL did not improve this. Impairments in PA dilation in SHRSP were associated with cognitive decline, microglial activation, reactive astrogliosis, and neuroinflammation; cognitive and inflammatory changes were improved with MR blockade. These data advance our understanding of the effects of hypertension on cerebral arterioles using a clinically relevant model and treatment paradigm. Our studies suggest TRPV4 and the MR are potential therapeutic targets to improve cerebrovascular function and cognition during hypertension.