Endogenous digitalis and impairment of vasorelaxation in preeclampsia

Previous studies implicated endogenous cardiotonic steroids (CTS) in the pathogenesis of preeclampsia (PE) and demonstrated that in PE, immunoneutralization of CTS by Digibind, Fab fragments of digoxin antibody, produces antihypertensive and renoprotective effects. Marinobufagenin (MBG) a bufadienolide CTS, induces vascular fibrosis in vivo and in vitro. Because levels of MBG in PE are markedly increased, anti-MBG monoclonal antibody reduces blood pressure (BP) in a rat model of PE, and MBG exerts profibrotic effects, we hypothesized that in PE, elevated placental MBG levels would be associated with development of fibrosis in feto-placental circulation, and with impairment of vascular relaxation. We studied 18 patients with PE (mean BP = 123 ± 2 mmHg; 29 ± 2 years, 36 weeks gest. age) and 12 gestational age-matched normal pregnant subjects (mean BP = 92 ± 2 mmHg). PE was associated with a two-fold rise in the levels of MBG in placentae, and with a 2-fold increase in the level procollagen-1 in the umbilical arteries. As compared to control vessels, isolated rings of umbilical arteries from subjects with PE, in the presence of unaltered responsiveness to endothelin-1 (EC₅₀ = 20 and 33 nmol/L), exhibited markedly impaired response to the relaxant effect of sodium nitroprusside (EC₅₀ = 141 vs. 0.9 nmol/L p < 0.001). These results demonstrate that in PE, elevated levels of MBG are associated with vascular fibrosis, and impairment of vasorelaxation, and suggest that MBG represents a potential target for therapy.

preeclampsia , endogenous cardiotonic steroids , vasorelaxation

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