A sexually dimorphic response to aldosterone antagonism in the kidney of spontaneously hypertensive rat

INTRODUCTION. Hypertension remains a major public health problem, affecting nearly half of the adults in the USA. In most cases there is no readily identifiable cause and hypertension is referred to as essential. Spontaneously hypertensive rat (SHR) is a model of essential hypertension. The existing data on the mechanisms underlying blood pressure (BP) increase in SHR are often contradictory, yet some studies indicate that BP elevation in SHR is dependent on mineralocorticoid, aldosterone, and positively correlates with the expression and activity of the amiloride-sensitive epithelial Na+ channel (ENaC) in the kidney. Here, we tested if inhibition of mineralocorticoid receptors (MR) affects BP and renal electrolyte handling in SHR. METHODS. We compared BP, plasma renin activity, circulating aldosterone levels, plasma and urinary electrolytes, expression of genes related to MR signaling in the kidney and renal ENaC activity in 10–15-week-old male and female SHR treated with vehicle or MR inhibitor, spironolactone for 3 weeks. RESULTS. We found that spironolactone administration was followed by a transient elevation of plasma K+ and reduced urinary K+ excretion in SHR females, but not in males. This sex-specific effect of MR blockade was marginal after 1 week of treatment and at the end of the 3rd week urinary Na+ and K+ levels were not different in treated and nontreated SHR of the same sex. Serum aldosterone levels in nontreated SHR were relatively low, comparable to those in normotensive Wistar-Kyoto rats. SHR females, but not males, responded to spironolactone with a more than twofold elevation in circulating aldosterone, while plasma renin activity was low (~5 ng/ml·hr) in SHR rats of both sexes regardless of the treatment status. MR expression was comparable in male and female SHR and was not altered by spironolactone. However, SHR females had a ~50% higher expression of HSD11β2, an enzyme that inactivates corticosterone allowing the interaction of MR with aldosterone or its antagonists. Renal ENaC activity was low in SHR of both sexes, comparable to that observed in other normotensive rodent strains. Upon 3 weeks of treatment, spironolactone did not reduce ENaC channel activity or a-ENaC subunit expression. Renal MR expression was higher in SHR than in Sprague-Dawley rats infused with angiotensin II, where excessive ENaC activity is sensitive to spironolactone. At the systemic level, spironolactone did not affect amiloride-sensitive Na+ or K+ excretion and BP in SHR of both sexes. CONCLUSIONS. We conclude that higher levels of HSD11β2 in SHR females, likely, increase MR availability to aldosterone or its antagonists. Inhibition of MR in SHR females leads to a transient elevation in plasma K+ that is later compensated by increased aldosterone. MR blockade is not an effective antihypertensive strategy in 10-15 weeks old SHR of both sexes, due to low activity of systemic RAAS and renal ENaC. This research was supported by NIH-NIDDK R01DK125464 grant (to M. Mamenko). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.