Endogenous cardiotonic steroids in kidney failure: a review and an hypothesis

Abstract

In response to progressive nephron loss, volume and humoral signals in the circulation have increasing relevance. These signals, including plasma sodium, angiotensin II, and those related to volume status, activate a slow neuromodulatory pathway within the central nervous system (CNS). The slow CNS pathway includes specific receptors for angiotensin II, mineralocorticoids, and endogenous ouabain (EO). Stimulation of the pathway leads to elevated sympathetic nervous system activity (SNA) and increased circulating EO. The sustained elevation of circulating EO (or ouabain) stimulates central and peripheral mechanisms that amplify the impact of SNA on vascular tone. These include changes in synaptic plasticity in the brain and sympathetic ganglia that increase preganglionic tone and amplify ganglionic transmission, amplification of the impact of SNA on arterial tone in the vascular wall, and the reprogramming of calcium signaling proteins in arterial myocytes. These increase SNA, raise basal and evoked arterial tone, and elevate blood pressure (BP). In the setting of CKD, we suggest that sustained activation/elevation of the slow CNS pathway, plasma EO, and the cardiotonic steroid marinobufagenin, comprises a feed-forward system that raises BP and accelerates kidney and cardiac damage. Block of the slow CNS pathway and/or circulating EO and marinobufagenin may reduce BP and slow the progression to ESRD.

Keywords: Brain; Dialysis; Hypertension; Marinobufagenin; Ouabain.

Figure 1. Proposed feed-forward pathway that raises vascular resistance and blood pressure in chronic kidney disease

In CKD, progressive loss of nephrons generates humoral signals that activate a slow neuromodulatory pathway in the brain. The slow pathway raises preganglionic SNA and circulating EO. The sustained elevation of circulating EO (red dashed lines) amplifies ganglionic function [1] and raises postganglionic sympathetic nerve activity, enhances the effect of sympathetic nerve activity [2] in the vascular wall, and directly amplifies Ca²⁺ signaling [3] in arterial myocytes. Block of angiotensin II receptors, or MR, or EO in the brain may normalize downstream events. Elements of the pathway have been demonstrated in rodents and portions have been shown in human tissue. The mechanism by which activation of the CNS slow pathway raises plasma EO may involve ACTH. The relative contribution of adrenal and brain EO to the elevated circulating EO in CKD is not known. Elevated circulating MBG is shown as secondary to volume expansion (no data demonstrate CNS control of MBG); renal ischemia may trigger MBG. In the scheme presented, sustained increases in MBG and EO elevate BP and also promote renal and cardiac damage that enhances the progression of renal failure. The signaling pathways for the fibrotic effects have been described elsewhere^,. This feed-forward mechanism provides further stimulus to circulating EO and MBG and may accelerate progression to complete failure. Maneuvers that block EO and MBG ameliorate this cycle of events^,,. Yellow horizontal bars: potential sites for acute antagonism by canrenone. White stars: sites of synaptic plasticity. The same overall pressor mechanism may be active among some patients with essential hypertension and in heart failure, and also where there are sustained increases in angiotensin II (e.g., low salt intake). Abbreviations: AT1R, angiotensin type I receptor. CKF, chronic kidney failure. CNS, central nervous system. EO, endogenous ouabain, GFR, glomerular filtration rate. MR, mineralocorticoid receptor. MT, myogenic tone. NCX1, sodium calcium exchanger type 1. SERCA, sarcoplasmic reticulum calcium ATPase. SNA, sympathetic nerve activity. TPVR, total peripheral vascular resistance. TRPC6, transient receptor potential cation channel, subfamily C, member 6.

Figure 2. Circulating EO as a function of estimated GFR in CKD (Stage III to V)

The trend to increasing EO as GFR declines is significant. Simonini and Manunta, unpublished observations.