Acid‐sensing ion channel 1a deficiency drives endocrine hypertension in male mice

Acid-sensing ion channel 1a (ASIC1a) is a proton-gated cation channel activated by extracellular acidosis, a condition often associated with ischaemia, inflammation and metabolic stress. Our laboratory has previously demonstrated that ASIC1a contributes to systemic endothelium-dependent vasodilatation; however, the role of ASIC1a in blood pressure regulation remains unclear. The objective of this study was to investigate the role of ASIC1a in blood pressure regulation using a model of angiotensin II-induced hypertension. We further determined the effects of age and sex, as these are non-modifiable risk factors for hypertension. Radiotelemeters were implanted in 6- and 18-month-old male and female wild-type (Asic1a^+/+) and ASIC1a knockout (Asic1a^-/-) mice to continuously measure blood pressure and heart rate under baseline conditions and following angiotensin II. Blood gases, electrolytes, hormones and indices of end-organ injury were also assessed. Deletion of ASIC1 did not significantly alter blood pressure in 6-month-old male or female mice. However, aged male Asic1a^-/- mice develop hypertension, whereas female Asic1a^-/- mice remain unaffected. This hypertension was associated with aldosterone excess, increased sympathetic activity, and evidence of aortic fibrosis, left ventricular hypertrophy and renal injury. Importantly, hyperaldosteronism occurred independently of the renin-angiotensin system and was associated with blunting of angiotensin II-induced hypertension. Prior to the onset of hypertension, 6-month-old male Asic1a^-/- mice exhibit elevated corticosterone, hypokalaemia, reduced urine osmolality, increased pulse pressure and cardiomyocyte hypertrophy. Together, these findings identify ASIC1a as a novel, sex-specific regulator of cardiovascular function, suggesting that ASIC1a deficiency may be a potential driver of endocrine-related hypertension. KEY POINTS: Extracellular acidosis, which occurs during pathological conditions such as ischaemia, inflammation and metabolic stress, contributes to the pathogenesis of cardiometabolic disease. Acid-sensing ion channels (ASICs) are key sensors of acidosis and important mediators of endothelium-dependent vasodilatation; however, the role of ASIC1a in blood pressure regulation remains poorly understood. Here we report that ASIC1a deficiency causes hypertension in aged male mice that is driven by an excess of aldosterone and increased sympathetic activity, while female mice remain unaffected. Hyperaldosteronism occurs independently of angiotensin II but is associated with elevated corticosterone that precedes the development of hypertension. We further show that male, but not female, ASIC1a knockout mice have a reduced sensitivity to angiotensin II-induced hypertension. These findings identify ASIC1a as a novel, sex-specific regulator of cardiovascular function, suggesting that ASIC1a deficiency contributes to endocrine-related hypertension.