Hypothesis: reactive increases in plasma renin activity attenuate the fall in blood pressure caused by salt depletion and renin-angiotensin system inhibition.

Abstract

There are inconsistencies in the effect of raising or lowering body salt on blood pressure (BP). We hypothesize that they are caused in part by differences in plasma renin activity (PRA). PRA changes reciprocally with body salt. PRA is the rate limiting step in the formation of the vasoconstrictor peptide angiotensin II (Ang II) in the circulation where it cleaves Ang I from plasma angiotensinogen, and then Ang I is rapidly converted to Ang II by angiotensin-converting enzyme in plasma and vascular endothelial cells. We hypothesize that PRA levels above 0.65 ng/ml/h lead to sufficient Ang II production to cause vasoconstriction, whereas lower levels do not. PRA is usually more than 0.65 in normotensives who are not on a high-salt diet; in them, the increase in PRA/Ang II vasoconstriction caused by reduction in body salt (low-salt diet, diuretic use) is large enough to prevent BP from falling. By contrast, a similar reduction in body salt lowers BP in the 30% of hypertensive patients with low baseline PRA (<0.65 ng/ml/h), because vasoconstriction does not increase in that range. A similar reduction in body salt also lowers BP in the 60% of hypertensive patients with baseline PRA between 0.65 and 4.5 ng/ml/h, but for a different reason; the rise in PRA and the increase in vasoconstriction is too small to prevent BP from falling. However, after body salt has been reduced enough to raise PRA above 4.5 ng/ml/h, further salt depletion increases PRA to a greater extent, and BP does not fall. Renin-angiotensin system (RAS) inhibitors leave a small amount of renin unblocked. In salt-depleted hypertensive patients, they also raise PRA enough to prevent BP from falling significantly. We propose that this PRA/Ang II vasoconstrictor effect related to reactive increases in PRA can prevent or attenuate the decrease in BP caused by excessive salt depletion, even during concurrent RAS inhibition. This phenomenon, if confirmed, could inform new strategies to optimize the treatment of hypertension, cardiovascular disease (CVD) and chronic kidney disease (CKD).