Endogenous ouabain and the renin–angiotensin–aldosterone system: distinct effects on Na handling and blood pressure in human hypertension

Abstract

Objective To evaluate whether the renin–angiotensin–aldosterone system (RAAS) and endogenous ouabain system differently affect renal Na handling and blood pressure. Methods Three hundred and one patients in whom we compared blood pressure, and renal Na tubular reabsorption in the basal condition and 2 h (T120) after saline infusion. Results Following multivariate-adjusted linear and quartiles analysis, baseline mean blood pressure (MBP) was significantly higher (113.7 ± 1.33 mmHg) in the fourth versus the first endogenous ouabain quartile (103.8 ± 1.04 mmHg) and the trend across the quartiles was highly significant (β=0.23, P =3.53e-04). In contrast, an inverse relationship was present in the renin activity (PRA) quartiles with MBP highest in the first (112.5 ± 1.26) and lowest in the fourth PRA quartile (107.6 ± 1.48, P =0.039). Following an acute saline load, changes in MBP and the slope of the pressure–natriuresis relationship were inversely related across the PRA quartiles. The fractional excretion of sodium (FENa) showed a negative linear trend going from the first to the third endogenous ouabain quartiles (2.35 ± 0.17 and 1.90 ± 0.14%, P =0.05). Patients in the fourth endogenous ouabain quartile (>323 pmol/l) showed increased FENa T120 (2.78 ± 0.18%, P < 0.01) and increased Na tubular rejection fraction (P =0.007) after Na load. After the saline load, there was a biphasic relationship between plasma endogenous ouabain and FENa favoring Na retention at low endogenous ouabain and Na excretion at high endogenous ouabain levels. Conclusion The RAAS and endogenous ouabain system are two independent and complementary systems having an inverse (RAAS) or a direct (endogenous ouabain system) relationship with hemodynamic parameters.

Endogenous Ouabain Is Not Ouabain

“…28 Furthermore, plasma EO levels were reported to be higher in the offspring of families with a positive history of hypertension than in subjects with no such family history, to correlate with blood pressure levels, and relate to some indices of diastolic left ventricular structure and function. 29 Whereas review articles in several high-profile journals, often but not uniquely from the University of Maryland and Milan workers, have taken for granted that EO exists and is of pathophysiological importance, 24,25,[29][30][31][32] questions have been raised by us and several other research groups. At an Endocrine Society meeting in 1995, opinions were divided as to whether authentic ouabain circulates in human plasma and is of adrenocortical origin.…”

Nanomolar ouabain increases NCX1 expression and enhances Ca2+signaling in human arterial myocytes: a mechanism that links salt to increased vascular resistance?

“…Moreover, exposure of primary cultured rodent arterial myocytes to nanomolar ouabain for 48 -72 h also increases expression of NCX1 and TRPC6 proteins (49). In this context, it is noteworthy that plasma EO levels are significantly elevated in several rodent hypertension models (15,16,29), as well as in 40 -50% of humans with essential hypertension and in most patients with aldosterone-linked hypertension (40,43,51). We suggested that the increased peripheral vascular resistance in the rodent hypertension models results, in part, from the augmented Ca 2ϩ signaling and vasoconstriction as a consequence of the Ca 2ϩ transporter upregulation in the arterial myocytes (7,34).…”

“…The main conclusion from these studies is that the same ouabain-dependent long-term mechanisms that augment Ca 2ϩ signaling and vascular tone in rodent arterial myocytes (49) are also functional in human arterial myocytes. The implication is that in human hypertension, including a large fraction of patients with essential hypertension and those with hypermineralocorticoid syndromes, in whom plasma EO is elevated (40,43,51), these Na ϩ and Ca 2ϩ transport mechanisms promote the increased vascular tone. They also augment responses to (enhanced) sympathetic drive and to humoral vasoconstrictors and, thereby, elevate BP.…”

“…We have speculated that similar mechanisms are involved in human hypertension (6, 7). This view is based, in part, upon the evidence that plasma EO levels are elevated in Ϸ45% of patients with essential hypertension, and in a majority of patients with aldosterone-producing adenomas, i.e., those with a high level of the salt-retaining hormone aldosterone (40,45,51). Na ϩ pumps are ␣␤-dimers.…”

Endogenous Ouabain Changes Rapidly During Cardiac Pulmonary by Pass

“…Prolonged ouabain infusion in rats causes an increase in plasma creatinine, blood pressure and tubular Na reabsorption. [7], Recently [14], we have shown the relationship between EO and impaired glomerular filtration rate as direct consequence of long exposure to increased level of plasma EO in hypertensives. Therefore, we conducted these prospective observational studies to test the time course of circulating EO changes during cardio pulmonary bypass (CPB), where acute volume and blood pressure modification occurs.…”