| Alexei Y. Bagrov, M.D., Ph.D., Investigator Head, Hypertension Unit Laboratory of Cardiovascular Science E-mail: bagrova@mail.nih.gov |
| Biography: Dr. Bagrov received his M.D. at Ivan Pavlov Medical University and Ph.D. at I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Leningrad, USSR. He subsequently completed his cardiology training and held clinical and academic appointments in St. Petersburg, Russia. In 1992-1994 and 1998-2001, he worked at the NIA as a Visiting Associate and NRC Senior Associate. |
| Overview: Two endogenous digitalis-like inhibitors of the Na/K-ATPase (NKA), sodium pump ligands (SPLs), endogenous ouabain (EO) and marinobufagenin (MBG), coexist in mammalian tissues, are responsive to NaCl loading and plasma volume expansion, and differ with respect to their targets (a-3 and a-1 isoforms of NKA). SPLs play an important role in the pathogenesis of NaCl sensitive hypertension. In NaCl-loaded Dahl salt sensitive rats (DS), brain EO triggers peripheral production of MBG, a natriuretic and a vasoconstrictor, via an ATII sensitive pathway. Administration of anti-MBG antibodies to hypertensive DS lowers the blood pressure. |
| Pharmacological antagonism of SPLs may open new possibilities in the treatment of hypertension and its complications. Thus, PKC-induced phosphorylation sensitizes a-1 NKA to MBG. An interaction of PKC-dependent phosphorylation and MBG on NKA activity underlies the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension and is a target for antihypertensive therapy of hypertension. Accordingly, chronic treatment of hypertensive DS rats with cicletanine, a compound, which directly inhibits PKC, produces a marked antihypertensive effect that is associated with desensitization of a-1 NKA to MBG. |
| Changes in SPLs levels and myocardial NKA isoforms accompany development of compensatory left ventricular hypertrophy (LVH) and transition to chronic heart failure (CHF) in DS. Development of LVH was accompanied by elevated MBG, an increased sensitivity of cardiac NKA to MBG, and an up-regulation of a-1 NKA protein in the myocardium. The transition to CHF was accompanied by a decrease in a-1 NKA protein, a reduction in plasma MBG, and a decrease in the sensitivity of NKA to MBG. Conversely, neonatal a-3 NKA was produced within the failing myocardium, plasma EO rose, and the sensitivity of NKA to ouabain enhanced 7-fold compared to control. Thus, a shift in endogenous NKA ligands production is linked to a shift in myocardial NKA isoforms in DS during LVH and CHF. In patients with CHF, MBG exhibits progressive increases similar to ANP, varies with CHF severity, and correlates with LV systolic function. In CHF, the concurrent production of two natriuretic hormones, a vasorelaxant, ANP, and a vasoconstrictor, MBG, potentiate each other's natriuretic effects, but may offset their respective vasoactive actions. ANP differentially modulates the inhibitory effect of MBG on the sodium pump via PKG-induced phosphorylation/dephosphorylation of the NKA. |
| SPLs contribute to blood pressure elevation in preeclampsia, which complicates up to 10% of pregnancies, and is a major factor in worldwide maternal mortality. In three studies, DIGIBIND (i.e. Fab fragments of digoxin antibodies), due to its ability to bind circulating SPLs, decreased blood pressure in preeclamptic patients. Recently, we have shown that MBG (rather than EO) becomes elevated in preeclampsia. In collaboration with the University of Montreal and Tulane University (New Orleans, LA), we established that renal excretion of MBG increases in pregnant rats with experimental preeclampsia. Moreover, administration of anti-MBG antibodies to these rats was associated with a sustained decrease in blood pressure together with activation of the sodium pump in aorta. Thus, MBG is a novel factor in the pathogenesis of preeclampsia, and antibodies to MBG may be more effective than DIGIBIND in treatment of preeclampsia. |
| In conclusion, SPLs are important factors in the pathogenesis of and targets for intervention in NaCl-sensitive hypertension, preeclampsia, and hypertensive heart disease. |
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