Abstract
Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na+) to high salt (3% Na+) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure-depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.
Highlights
Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association
Salt-sensitive blood pressure (BP) was not caused by renal sodium retention and the pressure natriuresis relationship was enhanced, not attenuated
We found salt-sensitivity in commercially sourced male C57BL6/J mice, reflecting sympathetic overactivity and not sodium retention or attenuation of the acute pressure natriuresis response
Summary
Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Changing from control (0.3% Na+) to high salt (3% Na+) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch This hypertensive response was maintained over the 3-week study period. Individual salt (sodium chloride) intake is estimated at >8 g/day,[1,2,3] more than twice the upper limit recommended by the American Heart Association.[4] This habitual salt excess is associated with a range of poor health outcomes, including autoimmunity,[5] cardiovascular and chronic kidney disease,[6] dementia,[7] and gastrointestinal cancers.[8] Hypertension makes an important contribution to many of these and the association between salt intake and blood pressure (BP) is well documented.[9] There is an exaggerated rise in BP in response to salt in ≈30% of people, who are categorized as salt-sensitive.[10] Even if BP is within the normal range, salt-sensitivity increases mortality risk[11] and is an independent cardiovascular risk factor.[12]. Salt-sensitive BP was not caused by renal sodium retention and the pressure natriuresis relationship was enhanced, not attenuated
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