ANP Peptide and the RAAS: A Counter-Regulatory Relationship

The most cited connection between anp and raas is the suppression of renin release, and even that has two competing explanations. The indirect one runs through the macula densa: if the peptide increases delivery of sodium chloride to the distal nephron, the macula densa senses it, adenosine signalling increases, and renin secretion from the granular cells falls. The direct one is that cGMP acts on the granular cells themselves. Papers that attempt to block the macula densa pathway still find suppression, which is why most authors accept a direct component alongside the tubular one.

The direct component has a famous puzzle attached to it. In juxtaglomerular granular cells, cyclic AMP stimulates renin secretion and intracellular calcium inhibits it, so anything that lowers calcium ought, by that logic, to raise renin. cGMP lowers calcium, yet renin falls. The resolution usually offered is that cGMP is not acting through calcium at all: a cGMP stimulated phosphodiesterase degrades the cyclic AMP pool that drives renin synthesis and release. Once I understood that, the literature stopped contradicting itself for me, and anp and raas stopped looking like a simple see saw.

One caution I have learned to apply here is about preparation. Isolated granular cells, isolated perfused kidneys and intact animals give different answers, in part because the intact animal has baroreflex and macula densa loops switched on that the reduced preparation does not. When a paper reports a large suppression of renin, my first question is whether renal perfusion pressure was controlled. The tubular side of that question is covered in my anp peptide notes.

Atrial natriuretic peptide lowers aldosterone, and it does so through more than one door. The first is simply that less angiotensin II reaches the zona glomerulosa when renin falls. The second is a direct action on the adrenal cell itself: glomerulosa cells carry guanylyl cyclase coupled receptors, cGMP rises, and steroidogenesis falls at the early steps of cholesterol mobilisation as well as at the terminal enzyme that converts its immediate precursor to aldosterone. Reports differ on which step dominates, and I have not been able to settle that from reading alone.

The connection also runs backwards, which is the part that complicates the counter regulatory story. Angiotensin II has been reported to stimulate atrial natriuretic peptide secretion through AT1 receptors on atrial myocytes, apparently independently of stretch. So a rise in angiotensin II can raise the natriuretic peptide that will in turn oppose it, which is a negative feedback loop with the peptide as the effector rather than the initiating stimulus. Anp and raas are therefore better described as mutually connected than as simply opposed.

Downstream of the receptors there is a second layer of interaction. Protein kinase G and protein kinase C phosphorylate overlapping substrates in vascular smooth muscle and in transporting epithelia, and there are reports of receptor level cross talk between the angiotensin and natriuretic peptide systems. The practical consequence for a reader is that a peptide concentration measured in isolation tells you very little about the balance of signalling at the tissue level, which is why anp and raas cannot be read as a simple balance. The vascular angle on this sits in anp peptide.

The sympathetic limb of anp and raas interaction is the one I find hardest to read. Atrial natriuretic peptide has been reported to reduce muscle sympathetic nerve activity in human studies, to blunt baroreflex mediated vasoconstriction, and to reduce noradrenaline release from sympathetic nerve endings in some preparations. Proposed sites include circumventricular organs accessible to circulating peptide and the afferent side of the baroreflex itself. The findings are not uniform, and I suspect the discrepancy reflects differences in how much the peptides changed filling pressure in each protocol.

The renal nerves deserve a separate note, because they sit right where the two systems meet. Renal sympathetic activation raises renin through beta adrenergic signalling on granular cells and simultaneously reduces sodium excretion, both of which oppose the peptide. Conversely, renal denervation has been reported to change the natriuretic response to the peptide, which means the sympathetic input is not background noise but part of the gain of the system. Any account of anp and raas that ignores the renal nerves is incomplete in my view.

Finally there is the fluid shift. Atrial natriuretic peptide increases haematocrit in many studies, which is read as movement of fluid out of the vascular compartment into the interstitium. Reduced plasma volume means reduced venous return and reduced cardiac filling, and the baroreflex responds to that. So a peptide described as a vasodilator also lowers preload by moving volume, and the sympathetic response to that shift may partly offset the arterial effect. I have tried to keep these separate in my anp peptide notes.

The straightforward answer is that both systems regulate the same integrated variable, and they read it in opposite directions. Arterial pressure and the fullness of the circulating volume are sensed by atrial stretch receptors, by baroreceptors, by the juxtaglomerular apparatus and by the macula densa, and the outputs are then combined. A study that changes one limb without measuring the other is, in practice, measuring a partially open loop, which is why most careful papers report renin, aldosterone and natriuretic peptide concentrations together.

There is also a shared clearance machinery that makes the two harder to separate than they look. Neutral endopeptidase degrades atrial natriuretic peptide readily and angiotensin peptides as well, so anything that alters that enzyme moves both sides of the balance at once. On the processing side, the prohormone is cleaved by corin before it becomes the circulating peptide, and defects in that step change what an assay detects. That methods layer is why I cross reference atrial natriuretic peptide here.

What I still find unclear after all this reading is how the balance is set in a steady state rather than in an acute experiment. Most of the mechanistic work involves acute perturbation, while the interesting physiological questions concern days and weeks. Anp and raas may interact differently on those two timescales, and the literature has more to say about the first than the second. I keep a list of the longitudinal and balance studies I have found, with my objections to each, in my research journal.