Natriuretic peptides buffer renin-dependent hypertension

Abstract

The renin-angiotensin-aldosterone system and cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are opposing control mechanisms for arterial blood pressure. Accordingly, an inverse relationship between plasma renin concentration (PRC) and ANP exists in most circumstances. However, PRC and ANP levels are both elevated in renovascular hypertension. Because ANP can directly suppress renin release, we used ANP knockout (ANP(-/-)) mice to investigate whether high ANP levels attenuate the increase in PRC in response to renal hypoperfusion, thus buffering renovascular hypertension. ANP(-/-) mice were hypertensive and had reduced PRC compared with that in wild-type ANP(+/+) mice under control conditions. Unilateral renal artery stenosis (2-kidney, 1-clip) for 1 wk induced similar increases in blood pressure and PRC in both genotypes. Unexpectedly, plasma BNP concentrations in ANP(-/-) mice significantly increased in response to two-kidney, one-clip treatment, potentially compensating for the lack of ANP. In fact, in mice lacking guanylyl cyclase A (GC-A(-/-) mice), which is the common receptor for both ANP and BNP, renovascular hypertension was markedly augmented compared with that in wild-type GC-A(+/+) mice. However, the higher blood pressure in GC-A(-/-) mice was not caused by disinhibition of the renin system because PRC and renal renin synthesis were significantly lower in GC-A(-/-) mice than in GC-A(+/+) mice. Thus, natriuretic peptides buffer renal vascular hypertension via renin-independent effects, such as vasorelaxation. The latter possibility is supported by experiments in isolated perfused mouse kidneys, in which physiological concentrations of ANP and BNP elicited renal vasodilatation and attenuated renal vasoconstriction in response to angiotensin II.

Optimum AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade alone in hypertensive rats

“…The beneficial effects of NEP inhibition on top of AT 1 receptor blockade do not seem to be due to RAS suppression, for example, by preventing the rise in renin release that normally accompanies RAS blockade. Indeed, Demerath et al, 43 in the isolated perfused mouse kidney, were unable to demonstrate any suppressant effect of either ANP or BNP on renin secretion, despite earlier reports suggesting that natriuretic peptides inhibit renin release. 31 They therefore concluded that natriuretic peptides buffer renin-dependent hypertension, for example, by directly attenuating Ang II-mediated constriction.…”

Salt feedback on the renin-angiotensin-aldosterone system

“…Activation of GC-A by ANP not only induces natriuresis and vasorelaxation and raises the glomerular filtration rate but also has the capacity to directly suppress renin release from JGE cells [68,109]. Due to the major contribution of GC-A to blood pressure control, GC-A knockout mice are hypertensive [25,70]. The plasma levels of ANP are higher than those of BNP in healthy individuals and the cardiovascular phenotype of ANP knockout mice largely resembles that of GC-A knockout mice [25,54], but the phenotype of BNP knockout mice does not [117]; therefore, ANP is considered the more relevant natriuretic peptide under physiological circumstances.…”

“…Due to the major contribution of GC-A to blood pressure control, GC-A knockout mice are hypertensive [25,70]. The plasma levels of ANP are higher than those of BNP in healthy individuals and the cardiovascular phenotype of ANP knockout mice largely resembles that of GC-A knockout mice [25,54], but the phenotype of BNP knockout mice does not [117]; therefore, ANP is considered the more relevant natriuretic peptide under physiological circumstances. Because ANP plasma levels are elevated under significant salt load and ANP can suppress renin release, a functional role of ANP in the salt-dependent regulation of PRA appears plausible.…”

NT-proBNP and the risk of incident hypertension

“…Among many others, the main effects of BNP are vasodilation as well as natriuresis, both representing key mechanisms in arterial pressure control and in the cardio-renal cross-talk. Opposite effects are exerted by the renin-angiotensin-aldosterone system, and it has been recently shown that natriuretic peptides buffer renal vascular hypertension via reninindependent effects [25]. BNP is released by ventricular cardiomyocytes as a result of 'spontaneous' and 'inducible' production, the former being largely under genetic control and the latter being stimulated by mechanical stretch, as well as by direct or indirect toxic effects.…”