Characterising the role of Vascular ENaC for Blood Pressure Regulation
Hypertension is characterised by extracellular fluid volume expansion and increased vascular tone. The epithelial sodium channel (ENaC) in the kidney has a central role in maintenance of extracellular fluid volume. In the vasculature, ENaC has been implicated in mediating both endothelium-dependent vasodilation and the VSMC-induced myogenic constriction in response to intraluminal pressure, which places ENaC in a pivotal position for the control of vascular function and thus, a potential mediator of vascular tone. It is not known whether ENaC subunit expression in the vasculature is changed in hypertension and whether ENaC plays a role in the regulation of vascular tone in the pathogenesis of hypertension. Hypotheses: 1) Vascular ENaC subunit expression is increased in hypertension. 2) The increased ENaC leads to vascular dysfunction contributing to the development of hypertension. 3) Antihypertensive treatment leads to decreases in vascular ENaC expression in hypertension. 4) Vascular ENaC expression is associated with myocardial infarction, a risk factor of hypertension. Methods: mRNA and protein expression of all three ENaC subunits was investigated in different arteries from normotensive and hypertensive Cyp1a1Ren2 rats. Effect of ENaC on vascular function was assessed by addition of amiloride in arteries from normotensive and hypertensive animals. Spironolactone treatment was used as the antihypertensive to evaluate the changes in ENaC expression. Major findings: The mRNA and protein level of α ENaC is upregulated in hypertensive arteries. Amiloride-mediated ENaC blockade increases the vasodilation indicating that increases in vascular ENaC are potentially mediating the loss of endothelium-dependent vasodilation. Another major finding is the presence of proteolytic cleavage of ENaC in the vasculature and a potential increase of this cleavage in hypertension. The antihypertensive treatment with SP decreases the vascular ENaC expression in hypertension, providing evidence of vascular ENaC as a therapeutic target. Further, this study revealed an association of altered vascular ENaC expression with myocardial infarction. Main conclusion: Increased ENaC expression in the vasculature is involved in mediating vascular tone, which potentially leads to the development of hypertension. The changes in function can be attributed to proteolytic cleavage of vascular ENaC.
Advisor: Fronius, Martin; McDonald, Fiona
Degree Name: Doctor of Philosophy
Degree Discipline: Physiology
Publisher: University of Otago
Keywords: ENaC; Hypertension; Arteries; MyocardialInfarction; Spironolactone; BloodPressure
Research Type: Thesis