Chronic ouabain treatment induces Rho kinase activation

Abstract

Ouabain is an endogenous Na(+)/K(+)-ATPase inhibitor whose chronic administration induces hypertension. Endogenous ouabain levels increase in human essential hypertension. On the other hand, Rho/Rho kinase (ROCK) pathway has been implicated in various animal models of hypertension. In the current work, we evaluated the possible involvement of Rho kinase in ouabain-induced hypertension. Ouabain was administered daily (20 µg/kg, i.p.) to Wistar rats for 6 weeks. After the ouabain treatment, we evaluated the possible changes in vascular responses to KCl and phenylephrine alone and in the presence of Rho kinase inhibitor Y27632. We also determined the expressions of ROCKs, Rho A and phosphorylation of myosin binding subunit of myosin light chain phosphatase (pMYPT) and activation of Rho A. Agonist-induced contractions in the presence of Y27632 are significantly decreased and Y27632-induced relaxations in aortas precontracted with phenylephrine are significantly enhanced with the chronic treatment of ouabain. Although the expressions of ROCK I and ROCK II remained unchanged, pMYPT expression was significantly increased in ouabain-treated group. Moreover, Rho A expression and activation were decreased after treatment with ouabain. Although Rho kinase expression did not change in aortas, increased basal Rho kinase activation may contribute to the development of ouabain-induced hypertension. Our current data present the first evidence that Rho kinase is involved in the development of ouabain-induced hypertension in rats.

Na+/K+ ATPase activity promotes invasion of endocrine resistant breast cancer cells

“…Furthermore, ouabain treatment in mice was shown to induce cochlear nerve degeneration [ 51 ] and glomerular podocytopathies and proteinuria through nephrin downregulation [ 52 ]. One report suggested that chronic administration of ouabain in Wistar rats induced hypertension in part through increased Rho kinase activity [ 53 ]. Therefore, more studies are needed to assess the long-term safety profile for ouabain as a possible therapeutic approach for breast cancer treatment.…”

Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps

“…Second, normal breast cell lines (MCF-10a) are more sensitive to cardiac glycoside-induced apoptosis than are some highly invasive lines, such as MDA-MB-231 [ 22 ], whereas the opposite is true of TOL. Third, the mechanism for cardiac glycosides to induce apoptosis involves activation of the Rho kinase [ 23 , 24 ] and/or SRC pathways [ 22 ], whereas TOL is induced by excess intracellular Na + concentration and the induction of osmotic lysis. The positive results observed in our in vitro studies, coupled with complementary results of the in vivo experiments provide evidence warranting further study of targeted osmotic lysis in experimental animals as a potential treatment for advanced stage carcinoma.…”

Endogenous Ouabain

“…This variable response, 7 even within a single strain, 68, 69 is neither strange nor surprising. When given high salt, excess mineralocorticoids or other hypertensinogenic substances, not all outbred rats develop hypertension; indeed, this phenotype variation was deliberately exploited to generate lines of rats with heightened or lowered susceptibility to hypertension.…”

“…68, 72 The sensitive strain exhibited altered ganglionic synapse plasticity that was normalized with in vivo captopril. 72 Some components of the pressor mechanism of ouabain that likely function in the sensitive strain have been partially elucidated, 28, 69 whereas elevated vagal tone and increased CGRP may underlie the ouabain-resistant phenotype. 67 …”