Sodium Pump Inhibitors In Blood Pressure Regulation

Aging

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Abstract

Two endogenous digitalis-like cardiotonic steroids (CTS), endogenous ouabain (EO) and marinobufagenin (MBG), coexist in mammalian tissues. MBG acts as a selective inhibitor of ouabain-resistant alpha-1 isoform of Na/K-ATPase (NKA), the main isoform in the kidney, vascular smooth muscle (VSM) and adult cardiomyocytes. In Dahl salt-sensitive rats (DS) on a high NaCl intake, brain EO triggers peripheral MBG, which raises the blood pressure (BP). In a rat model of preeclampsia (PE), the in vivo, administration of monoclonal antibody (Mab) lowers the BP. During the past year our research focused on (i) the relationship between central and peripheral CTS in DS, (ii) the development of a therapeutic anti-MBG monoclonal antibody (Mab), and (iii) studies of aging-related mechanisms of MBG-induced NKA-mediated cell signaling. [unreadable] [unreadable] (i) Pathogenesis of NaCl-sensitive hypertension.[unreadable] Following NaCl loading of DS, an initial transient rise of hippocampal EO, followed by an increase in EO in the supraoptic nucleus of the hypothalamus and pituitary, stimulates pituitary angiotensin II (AngII), and, via activation of sympathetic nervous system, activates the adrenocortical renin-angiotensin system (RAS). Adrenocortical AngII acting through AT1 receptors stimulates production of MBG. An increase in MBG production induces inhibition of the Na pump in renal tubules and in VSM. During the past year, we pharmacologically analyzed the sequence of events underlying NaCl-induced ouabain-mediated prohypertensive signaling. We studied effects of administration of anti-ouabain antibodies into hippocampus and supraoptical nucleus of hypothalamus in rats following acute NaCl loading and central administration of low doses of ouabain. Blockade of brain EO with a specific antibody prevented (a) stimulation of MBG production, (b) elevation of BP, and (c) natriuresis and activation of adrenocortical RAS induced by both centrally-administered ouabain and NaCl loading. [unreadable] [unreadable] (ii) Development of a therapeutic monoclonal anti-MBG antibody. [unreadable] Heightened levels of MBG are associated with elevations of BP in patients and laboratory rats with PE, in hypertensive subjects and in rats with end stage renal disease (ESRD), and in hypertensive DS. During the past year, we demonstrated that 3E9 anti-MBG Mab effectively lowers BP in hypertensive rats with ESRD, in rats with Ang II-induced hypertension. 3E9 Mab also ex vivo reversed inhibition of the sodium pump in erythrocytes obtained from patients with PE. Humanization of 3E9 Mab is in progress now.[unreadable] [unreadable] (iii) Aging, MBG-induced cell signaling and mechanisms of its modulation.[unreadable] Atrial Natriuretic Peptide (ANP), dephosphoprylates vascular smooth muscle (VSM) NKA via a cGMP-dependent mechanism, and markedly reduces its sensitivity to MBG. In renal medulla of rats, ANP exhibits an opposite effect, i.e., induces NKA phosphorylation and sensitizes the Na pump to the inhibitory effect of MBG. Since VSM and renal medulla express PKG1 and PKG2 isoforms, respectively, these two PKG isoforms are likely to mediate the opposing effects of ANP on NKA phosphorylation and MBG sensitivity. Therefore, a concurrent production of a vasorelaxant, ANP, and a vasoconstrictor, MBG, potentiate each other's natriuretic effects, but ANP may offset the vasoconstrictor effect of MBG. Aging is associated with heightened levels of CTS and with a decline in cGMP-PKG signaling in the kidney and VSM. Such a decline may shift the balance between effects of MBG and ANP on renal and cardiovascular NKA towards lesser inhibition of renal Na pump and greater inhibition of VSM NKA and thus contribute to the pathogenesis of hypertension. In aged Sprague-Dawley rats (S-D), acute NaCl loading produced greater pressor and MBG responses and lesser natriuretic response as compared to that in young rats, We also compared effects of ANP on MBG-induced NKA inhibition in VSM and renal medulla of young and old rats. While in young rats ANP potentiated MBG-induced inhibition of renal NKA, and reversed inhibition of VSM NKA, the effect in aged animals was opposite: ANP did not alter MBG-induced inhibition of renal NKA, and in VSM, ANP potentiated MBG-induced NKA inhibition. Thus, in aged rats, ANP is not capable of potentiation of the physiological effect of MBG, natriuresis, and, likewise, aging is associated with a loss in the ability of ANP to offset MBG-induced vasoconstriction.The phenotype of salt-sensitive hypertension in many aspects resembles that occurring during aging. In our experiments, NaCl loading of salt-sensitive DS and of normotensive S-D, in the presence of comparable MBG response, produces preferential inhibition of the Na pump in the vascular smooth muscle of DS and in the kidney of S-D. Accordingly, NaCl-loaded DS exhibited pressor response and sodium retention, while in S-D adequate natriuresis occurred in the absence of BP elevation. Therefore, in rats, salt-sensitivity of BP is associated with a loss in the responsiveness of renal Na pump to MBG, while vascular Na pump exhibits heightened MBG sensitivity.