Effect Of Genetic Deletion Of TASK Channel On Arterial Barorereflex

Hypertension is one of the most common non-infectious diseases,as well as high risk factors for cerebrovascular diseases.Primary aldosteronism(PA)is a direct consequence of autonomous aldosterone overproduction,manifesting increased blood volume,sodium retention and hypokalemia,metabolic alkalosis.PA,the common cause of secondary hypertension,accounts for 10% of hypertensive patients and for 20% of refractory hypertension.However,the neurogenic mechanism of hypertension elicited by hypercholesterolemia remains controversial.When focusing on the role of aldosterone in the onset and development of hypertension,the majority of prior experiments were carried out in normotensive animal models treated chronically with aldosterone,or in other types of hypertensive animals.It remains uncertain whether the findings obtained in these animal models reflex truly the pathogenesis of hypertension in the PA,particularly idiopathic aldosteronism.It is therefore necessary to establish an ideal animal model to investigate the relationship between hyperaldosterone and hypertension systematically,comprehensively and accurately.TWIK-related acid-sensitive K(TASK)channel knockout mice(TASK-/-)exhibit hypercholesterolemia,hypertension,low renin,and failure in inhibition of overproduction of aldosterone by saline loading experiments or angiotensin II receptor blockers,which is very similar to idiopathic aldosteronism in patients.At present,TASK knockout mice have been recognized as a good animal model of PA.This compact study mainly examined whether the arterial baroreflex was impaired in genetic deletion of TASK channel mice.Objective: To investigate the effect of deletion of TASK channel/ hyperaldosteronism on arterial baroreceptor reflex in mice using radio telemetry,plethysmography and Western blot.Method:1 Blood pressure and heart rate were measured in conscious TASK-/-mice and counterparts using radio telemetry system.The sympathetic-vagal balance was assessed by comparing the difference between both genotypes in blood pressure and heart rate when challenged by intraperitoneal injections of propranolol,atropine and hexamethonium bromide.2 Assessment of cardiovascular activity during exposure to hypoxia and hypercapnia in two groups of conscious mice.3 Quantitative analysis of mineralocorticoid receptors in the rostral ventrolateral medulla of two genotypes.Result:1 The systolic blood pressure,diastolic blood pressure and mean arterial pressure are significantly higher in TASK-/-mice than those in counterparts,but there is no significant difference in heart rate between both genotypes.2 No significant change has been found in blood pressure between two groups when challenged by hypercapnia,whereas acute exposure to hypoxia produces a decrease in heat rate in TASK-/-mice.3 Acute administration of Atropine speeds up heart rate but the incremental change is similar between two genotypes,suggesting that genetic deletion of TASK channels fails to affect parasympathetic outflows.4 Injection of Propranolol slows down heart rate in the two groups of mice,but the decrement of heart rate is greater in TASK-/-mice compared with controls,in favor of enhanced sympathetic overactivation in knockouts.5 Hexamethonium bromide reduces the arterial blood pressure in the two groups,but a deeper fall occurs in TASK-/-mice,suggesting that sympathetic nerve tension is reinforced.6 The overexpression of mineralocorticoid receptors was revealed in rostral ventrolateral medulla of TASK-/-mice in relative to controls.Conclusion: Genetic deletion of TASK channels in mice produces hypertension,which is likely associated with attenuated baroreflex,sympathetic overactivation and overexpression of mineralocorticoid receptors in rostral ventrolateral medulla.