OF WORK Our previous studies demontrated that two endogenous sodium pump ligands (SPL), ouabain-like compound (OLC) 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 sodium pump isoform in the kidney, vascular smooth muscle and adult myocardiocytes. In Dahl salt-sensitive rats (DS), in which the mutation of alpha-1 NKA underlies development of NaCl sensitive hypertension, plasma and urine MBG levels are increased in parallel to blood pressure elevations. In vivo administration of MBG antibody to hypertensive DS lowered the blood pressure. During last year our research efforts concentrated on the: (i) studies of relationship between MBG and OLC during the establishment of Dahl hypertension, (ii) establishment of profile of changes in SPL and NKA isoforms during development of compensatory left ventricular (LV) hypertrophy and congestive heart failure (CHF) in DS, and (iii) investigations of the possible roles of SPL in preeclampsia. (i) Pathogenesis of NaCl sensitive hypertension. In the course of development of NaCl hypertension in DS, an initial stimulation of pituitary OLC induced by NaCl loading stimulates brain angiotensin II (ATII), and triggers an MBG response via ATII sensitive pathway. Low concentrations of ATII stimulate production of MBG by primary adrenocortical cell cultures, and losartan blocks this effect. A sustained increase in MBG production occurs and induces inhibition of the sodium pump in renal tubules and in cardiovascular tissues. The later contributes to the chronic blood pressure elevation induced by a sustained high NaCl intake. The mechanism, by which a nanomolar concentration of MBG substantially inhibits sodium transport in renal tubules, appears to be complex, and, in addition to direct inhibition of the sodium pump, involves internalization of the NKA. Thus, two SPL, MBG and OLC, play an important role in the vicious circle, which underlies pathogenesis of NaCl sensitive hypertension. (ii) Cardiovascular remodeling. DS on a high NaCl intake developed hypertension and LV hypertrophy (LVH), which progressed to CHF. During development of LVH, the increases in blood pressure were accompanied by a 4-fold increase in plasma MBG, an increased sensitivity of LV sarcolemmal NKA to MBG at the level of high affinity binding sites, and an increase in alpha-1 NKA protein. In contrast, plasma levels of the alpha-3 NKA ligand, OLC, did not change during LVH, and the sensitivity of LV NKA to ouabain was decreased. The transition to CHF was accompanied by a decrease in alpha-1 NKA protein, a reduction in plasma MBG to control levels, and a decrease in LV NKA sensitivity to MBG. Conversely, following the transition to CHF the neonatal alpha-3 NKA was abundantly expressed within LV sarcolemma, plasma OLC increased 3-fold compared to control, and the sensitivity of LV NKA to ouabain enhanced 7-fold compared to control. Using MBG and OLC immunoassays developed in our laboratory, our collaborators in the Military Medical Academy (St. Petersburg, Russia) have shown that in hypertensive human subjects with mild-to-moderate CHF, MBG, but not OLC, exhibited progressive increases similar to atrial natriuretic peptide (ANP), varied with CHF severity and correlated with LV systolic function. We hypothesize that in CHF, the concurrent production of these two natriuretic hormones, a vasorelaxant, ANP, and a vasoconstrictor, MBG, potentiate each other's natriuretic effects, but may offset their vasoactive actions. However, in patients with severe CHF (LV ejection fraction less than 30%), renal excretion of OLC was twice as high as in patients with an ejection fraction of 40-60%. The regulatory switch of SPL in patients with CHF resembles that of an animal model in which CHF develops as a consequence of NaCl-sensitive hypertension. Thus, during LVH and CHF, a shift in endogenous NKA ligand production is linked to a shift in myocardial NKA isoforms and their sensitivity to SPL. (iii) Preeclampsia. Previously we have shown that dramatic increases in plasma MBG accompany preeclampsia. Interestingly, antibodies to digoxin (DIGIBIND), due to their ability to bind SPL are used in the treatment of preeclampsia clinically. Results of our collaborative experiments with investigators at the University of Montreal demonstrate, that normal pregnancy in rats was associated with increases in renal excretion of both MBG and OLC. However, in a rat model of preeclampsia, which develops in pregnant animals on a high NaCl intake, renal excretion of MBG, but not that of OLC, was significantly increased. This observation makes MBG a likely target for DIGIDBIND in preeclampsia. Taken together, these findings demonstrate that MBG is a novel factor in pathogenesis of hypertension, and may open new pharmacological possibilities in the treatment of hypertension, including blockade of circulating MBG with specific antibodies in preeclampsia, attenuation of NKA inhibitory effect of MBG on cardiovascualar NKA by inhibition of protein kinase C and resulting desensetization of the sodium pump to MBG (Sourcebook 2002; OV Fedorova, et al. Hypertension 2002, 39:298), and inhibition of adrenocortical MBG production by ACE inhibitors and/or angiotensin II receptor blockers.
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