Na+,K(+)-ATPase.

Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain-Na,K-ATPase (Na(+)- and K(+)-dependent adenosine triphosphatase) complex can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interaction with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain-Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper.

/pdf/adducin-and-ouabain-related-gene-variants-predict-the-fw7ztvycxf.pdf

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin–angiotensin–aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na+–ENaC–RAAS–EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents.

/pdf/the-central-mechanism-underlying-hypertension-a-review-of-56isaolh5a.pdf

The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain.

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach.

Towards Precision Medicine for Hypertension: A Review of Genomic, Epigenomic, and Microbiomic Effects on Blood Pressure in Experimental Rat Models and Humans.

In this brief article, we summarize recent reports about endogenous ouabain (EO), a cardiotonic steroid hormone. This includes analysis of mammalian EO, the discovery of EO isomers, regulation of intracellular signaling by EO, and the roles of EO in hypertension, pregnancy, and heart and kidney diseases. Novel ouabain-resistant mice that elucidate the key roles of α2 Na+ pumps and their cardiotonic steroid-binding site are also discussed.

EO was first identified in human plasma 25 years ago.1,2 Despite confirmation in humans and other mammals with mass spectrometry (MS; Figure; Figures S1–S6 in the online-only Data Supplement), nuclear magnetic resonance, and combined liquid chromatography (LC)–immunology methods,3–6 human EO has remained controversial.7 New analytic studies and related findings should allay skepticism. For example, employment of multistage MS (MS–MS and MS–MS–MS) to examine the effects of pregnancy and of central angiotensin (Ang) II infusion on EO in rat plasma led to the discovery of 2 novel EO isomers.8,9 Isomer 1 has MS–MS and MS–MS–MS product ion spectra indistinguishable from those of EO, but is slightly more polar than EO; it binds to the antibody used in our radioimmunoassay. Isomer 2 is slightly less polar than EO, has a distinct MS–MS–MS spectrum, and cross reacts weakly in our radioimmunoassay. The primary structural difference(s) between EO and these isomers may involve the steroid nucleus. Importantly, neither isomer was previously described or is detectable in commercial (plant) ouabain.8,9



Figure. 
Endogenous ouabain determined by liquid chromatography (LC)–mass spectrometry (MS)–MS in plasma from patients with cardiomyopathy. A , Capillary LC–MS–MS product ion chromatogram for a plasma extract from a patient with cardiomyopathy. The ion current peaks represent positively charged molecular product ions with an M+Li+/z ratio equivalent to the lithiated aglycone of ouabagenin …

Endogenous Ouabain: Recent Advances and Controversies.

The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans.

/pdf/main-results-of-the-ouabain-and-adducin-for-specific-1bs1orlb7t.pdf

Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Objective. To compare the efficacy and safety of olmesartan medoxomil (O) and ramipril (R) in elderly patients with essential arterial hypertension. Methods. After a 2-week placebo washout, 351 elderly hypertensive patients aged 65–89 years (office sitting diastolic blood pressure, DBP, 90–109 mmHg and office sitting systolic blood pressure, SBP, 140–179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once daily. After the first 2 and 6 weeks, doses could be doubled in non-normalized (blood pressure <140/90 mmHg for non-diabetic and <130/80 mmHg for diabetic) subjects, up to 40 mg for O and 10 mg for R. Office blood pressures were assessed at randomization, after 2, 6 and 12 weeks of treatment; 24-h ambulatory blood pressure (ABP) was recorded at randomization and after 12 weeks. Results. At week 12, in the intention-to-treat population (170 patients O and 175 R) the rate of normalized subjects was significantly larger in the O group (38.8% vs 26.3% R; p = 0.013). ...

Antihypertensive efficacy and safety of olmesartan and ramipril in elderly patients with mild to moderate systolic and diastolic essential hypertension.

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Main results of the Ouabain and Adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin

Antihypertensive efficacy and safety of olmesartan and ramipril in elderly patients with mild to moderate systolic and diastolic essential hypertension.