Primary aldosteronism (PA) is the most common cause of secondary hypertension. The paucity of good animal models hinders our understanding of the pathophysiology of PA and the hypertensive mechanism of PA remains incompletely known. It was recently reported that genetic deletion of TWIK-related acid-sensitive potassium-1 and potassium-3 channels from mice (TASK-/-) generates aldosterone excess and mild hypertension. We addressed the hypertensive mechanism by assessing autonomic regulation of cardiovascular activity in this TASK-/- mouse line that exhibits the hallmarks of PA. Here, we demonstrate that TASK-/- mice were hypertensive with 24-h ambulatory arterial pressure. Either systemic or central blockade of the mineralocorticoid receptor (MR) markedly reduced elevated arterial pressure to normal level in TASK-/- mice. The response of heart rate to the muscarinic cholinergic receptor blocker atropine was similar between TASK-/- and wild-type mice. However, the responses of heart rate to the β-adrenergic receptor blocker propranolol and of arterial pressure to the ganglion blocker hexamethonium were enhanced in TASK-/- mice relative to the counterparts. Moreover, the bradycardiac rather than tachycardiac gain of the arterial baroreflex was significantly attenuated and blockade of MRs to a large degree rescued the dysautonomia and baroreflex gain in TASK-/- mice. Overall, the present study suggests that the MR-dependent dysautonomia and reduced baroreflex gain contribute to the development of hyperaldosteronism-related hypertension.

The goal of this paper is to elucidate the effects of sodium restriction on hypertension and left ventricular (LV) hypertrophy in a mouse model with primary aldosteronism (PA). Mice with genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels (TASK-/-) were used as the animal model of PA. Parameters of the LV were assessed using echocardiography and histomorphology analysis. Untargeted metabolomics analysis was conducted to reveal the mechanisms underlying the hypertrophic changes in the TASK-/- mice. The TASK-/- adult male mice exhibited the hallmarks of PA, including hypertension, hyperaldosteronism, hypernatremia, hypokalemia, and mild acid-base balance disorders. Two weeks of low sodium intake significantly reduced the 24-h average systolic and diastolic BP in TASK-/- but not TASK+/+ mice. In addition, TASK-/- mice showed increasing LV hypertrophy with age, and 2 weeks of the low-sodium diet significantly reversed the increased BP and LV wall thickness in adult TASK-/- mice. Furthermore, a low-sodium diet beginning at 4 weeks of age protected TASK-/- mice from LV hypertrophy at 8-12 weeks of age. Untargeted metabolomics demonstrated that the disturbances in heart metabolism in the TASK-/- mice (e.g., Glutathione metabolism; biosynthesis of unsaturated fatty acids; amino sugar and nucleotide sugar metabolism; pantothenate and CoA biosynthesis; D-glutamine and D-glutamate metabolism), some of which were reversed after sodium restriction, might be involved in the development of LV hypertrophy. In conclusion, adult male TASK-/- mice exhibit spontaneous hypertension and LV hypertrophy, which are ameliorated by a low-sodium intake.