Abstract-An ouabain-like factor has been implicated repeatedly in salt-sensitive hypertension as a natriuretic agent.However, the response of plasma ouabain-like factor to acute and chronic variation of body sodium is unclear. We studied 138 patients with essential hypertension who underwent an acute volume expansion/contraction maneuver (2 days) and 20 patients who entered a blind randomized crossover design involving chronically controlled sodium intake and depletion (170 to 70 mmol/d; 2 weeks each period). In both studies, plasma levels of ouabain-like factor were higher during sodium depletion (acute: 338.8Ϯ17.4 and 402.7Ϯ22.8 pmol/L for baseline and low sodium, respectively, PϽ0.01; chronic: 320.4Ϯ32.0 versus 481.0Ϯ48.1 pmol/L, Pϭ0.01). No significant change in plasma ouabain-like factor was observed after a 2-hour saline infusion (333.4Ϯ23.9 pmol/L) or controlled sodium (402.1Ϯ34.9 pmol/L). When patients were divided into salt-sensitive or salt-resistant groups, no differences in plasma ouabain-like factor were observed in the 2 groups at baseline or in response to the 2 protocols: salt resistant (nϭ69, 340.1Ϯ25.9 pmol/L) versus salt sensitive (nϭ69, 337.4Ϯ23.6 pmol/L) and chronic salt resistant (nϭ11, 336.0Ϯ53.2) versus salt sensitive (nϭ9, 301.1Ϯ331.4 pmol/L). However, circulating ouabain-like factor was increased by sodium depletion in both groups. These results demonstrate that circulating ouabain-like factor is raised specifically by maneuvers that promote the loss of body sodium. Acute expansion of body fluids with isotonic saline is not a stimulus to plasma ouabain-like factor. Moreover, basal levels of plasma ouabain-like factor do not differ among patients with salt-sensitive or salt-resistant hypertension. Taken together, these new results suggest that ouabain-like factor is involved in the adaptation of humans to sodium depletion and argue against the hypothesis that ouabain-like factor is a natriuretic hormone. Key Words: sodium pump inhibitor Ⅲ endogenous Ⅲ salt sensitivity Ⅲ high blood pressure T he involvement of a natriuretic hormone in the control of sodium homeostasis was hypothesized Ϸ40 years ago.
Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we furnished data from rodents and human cells demonstrating two hypertension-triggering mechanisms-variants of adducin and elevated concentrations of endogenous ouabain (within a particular range)-and their selective inhibition by the drug rostafuroxin. Here, we have investigated the relationship between variants of genes encoding enzymes for ouabain synthesis [LSS (lanosterol synthase) and HSD3B1 (hydroxy-d-5-steroid dehydrogenase, 3b-and steroid d-isomerase 1)], ouabain transport {MDR1/ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1]}, and adducin activity [ADD1 (adducin 1) and ADD3], and the responses to antihypertensive medications. We determined the presence of these variants in newly recruited, never-treated patients. The genetic profile defined by these variants predicted the antihypertensive effect of rostafuroxin (a mean placebo-corrected systolic blood pressure fall of 14 millimeters of mercury) but not that of losartan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive effect was twice that of antihypertensive drugs recently tested in phase 2 clinical trials. One-quarter of patients with primary hypertension display these variants of adducin or concentrations of endogenous ouabain and would be expected to respond to therapy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin also underlie hypertensionrelated organ damage, this drug may also reduce the cardiovascular risk in these patients beyond that expected by the reduction in systolic blood pressure alone.
The importance of excess salt intake in the pathogenesis of hypertension is widely recognized. Blood pressure is controlled primarily by salt and water balance because of the infinite gain property of the kidney to rapidly eliminate excess fluid and salt. Up to fifty percent of patients with essential hypertension are salt-sensitive, as manifested by a rise in blood pressure with salt loading. We conducted a two-stage genetic analysis in hypertensive patients very accurately phenotyped for their salt-sensitivity. All newly discovered never treated before, essential hypertensives underwent an acute salt load to monitor the simultaneous changes in blood pressure and renal sodium excretion. The first stage consisted in an association analysis of genotyping data derived from genome-wide array on 329 subjects. Principal Component Analysis demonstrated that this population was homogenous. Among the strongest results, we detected a cluster of SNPs located in the first introns of PRKG1 gene (rs7897633, p = 2.34E-05) associated with variation in diastolic blood pressure after acute salt load. We further focused on two genetic loci, SLC24A3 and SLC8A1 (plasma membrane sodium/calcium exchange proteins, NCKX3 and NCX1, respectively) with a functional relationship with the previous gene and associated to variations in systolic blood pressure (the imputed rs3790261, p = 4.55E-06; and rs434082, p = 4.7E-03). In stage 2, we characterized 159 more patients for the SNPs in PRKG1, SLC24A3 and SLC8A1. Combined analysis showed an epistatic interaction of SNPs in SLC24A3 and SLC8A1 on the pressure-natriuresis (p interaction = 1.55E-04, p model = 3.35E-05), supporting their pathophysiological link in cellular calcium homeostasis. In conclusions, these findings point to a clear association between body sodium-blood pressure relations and molecules modulating the contractile state of vascular cells through an increase in cytoplasmic calcium concentration.
Objectives Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker. Rationale and Design Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis. Patients Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both “in vivo” and “in vitro.” Main Results In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4 ± 0.38, 1.7 ± 0.41, 2.4 ± 0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2 ± 0.09, 1.4 ± 0.23, 2.2 ± 0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (–18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (–29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain. Conclusions Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.
Increased visceral adipose tissue in obesity is associated with adverse cardiovascular events and hypertension. Visceral adipose tissue surrounds mesenteric arteries and may produce vasoactive substances that influence vascular contraction. We tested the hypothesis that perivascular adipose tissue modulates contraction of small, resistance-sized mesenteric artery ring preparations. We studied mesenteric rings surrounded by periadventitial adipose tissue from adult male Sprague-Dawley rats. The contractile response to serotonin, phenylephrine, and endothelin I was markedly reduced in intact vessels compared to vessels without periadventitial fat. The contractile response to U46619 or depolarizing high Kϩ containing solutions (60 mM) was similar in vessels with and without periadventitial fat. The Kϩ channel opener cromakalim induced relaxation of vessels precontracted by serotonin but not by U46619 or high Kϩ containing solutions (60 mM), suggesting that Kϩ channels are involved. The intracellular membrane potential of smooth muscle cells was more hyperpolarized in intact vessels than in vessels without periadventitial fat. Both the anti-contractile effect and membrane hyperpolarization of periadventitial fat were abolished by inhibition of delayedrectifier Kϩ channels with 4-aminopyridine (2 mM). Blocking other Kϩ channels with glibenclamide (3 mM), apamin (1 M), TEA (1 mM), TPeA (10 M) did not restore the vascular response in intact vessels. Longitudinal removal of 50% of perivascular tissue reduced the anticontractile effect to serotonin by almost 50% while removal of the endothelium did not affect the anti-contractile effect. Using Vivaspin filters, we separated and isolated the visceral adventitia-derived relaxing factor. We suggest that visceral perivascular adipose tissue controls mesenteric arterial tone locally. It induces vasorelaxation by activating delayed-rectifier Kϩ channels in vascular smooth muscle cells.Key Words: ion channels, adipocytes, arterial tone High NaC1 diets raise blood pressure (BP) and thereby accelerate arterial lesions. Study I: 100 uninephrectomized Dahl salt-resistant rats were given DOCA implants (250 mg/kg) and drink 1% NaC1 water for 6 weeks. Following 4 weeks of recovery after removal of the DOCA and NaC1, rats were divided into 2 matched groups with BP160 mm Hg (0.3% low vs 8% high NaC1). After 5 weeks on these diets, BP averaged 158 in both groups. Although the 8% high NaC1 produced no further rise in BP, 51% of the rats had died after 8 weeks on 8% NaC1 vs. none in 3% low NaC1 (pϽ0.001). The chief cause of death appears to be cerebral arterial injuries although they had no further rise in BP. Seemingly, salt's infany goes beyond BP. Study II: Following a true or sham aqueductal block on 4 week old Sprague Dawley rats, DOCA hypertension was induced by DOCA (150mg/kg) and 6% high NaC1 for 5 weeks, showed similar BPs, 175 vs 171. After 7 weeks, 27 sham BP averaged 189Ϯ2.5 vs 175Ϯ3.6 mm Hg in 25 blocked rats (pϽ0.005). In 14 weeks, 20 sham rats averaged much higher BP than th...
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