Plasma Marinobufagenin-Like and Ouabain-Like Immunoreactivity in Adrenocorticotropin-Treated Rats

Abstract

Recently, an endogenous digitalis-like factor (EDLF) was shown to be stimulated in corticotropin (ACTH) hypertension in the rat. We have shown that mammalian plasma contains a vasoconstrictor Na,K-ATPase inhibitor, which cross-reacts with an antibody to amphibian EDLF, marinobufagenin. In the present experiment, the effect of 8 days of intramuscular ACTH treatment (0.5 mg/kg/day) of male Fisher 344؋ ؋NB rats on blood pressure, plasma ouabain-like and marinobufagenin-like immunoreactivity, and on the activity of Na,KATPase in aortic sarcolemma were studied.The C hronic administration of ACTH has been reported to raise the blood pressure of various mammalian species, including humans and rats.1,2 The hypertensinogenic effects of ACTH administration are dependent on the adrenal cortex and could be prevented by adrenalectomy.1,3 ACTH-induced hypertension has been attributed to the action of various adrenocorticosteroids, including aldosterone and progesterone derivatives in sheep, 4 cortisol in humans, 5 and corticosterone in the rat. 6 Several lines of evidence indicate the existence of digitalis-like immunoreactive endogenous inhibitors of Na,K-ATPase in mammalian tissues.7,8 Endogenous digitalis-like factors (EDLF) are believed to play an important role in sodium homeostasis and to contribute to several forms of human and animal hypertension.9,10 The adrenal cortex has been shown to be one of the major sources of EDLF in mammals.11,12 Endogenous ouabain was the first EDLF to be purified from human plasma, 13 and recent evidence indicates that Recently, we showed that a bufodienolide Na,KATPase inhibitor, marinobufagenin, elicits vasoconstrictor and Na,K-pump inhibitory effects in rat aorta. 19 Subsequently, it was established that mammalian plasma contains marinobufagenin-like immunoreactive material, which is responsive to saline volume expansion and is chromatographically indistinguishable from amphibian marinobufagenin. 15,20,21 When effects of marinobufagenin and ouabain were compared in membrane fractions prepared from rat aortae, marinobufagenin preferentially inhibited Na,KATPase in vascular smooth muscle membranes (␣-1 isoform), whereas ouabain demonstrated higher affinity toward Na,K-ATPase from vascular nerve endings (␣-3 isoform). 22In 1994, Li et al 23 showed that hypertension in rats occurring after 8 days of ACTH administration was associated with an increase in plasma digoxin-like immunoreactivity. Subsequently, Yamada et al 24 showed that ACTH treatment of rats for 15 days increased blood pressure and plasma levels and urinary release of an ouabain-like immunoreactive material.Recent observations suggest that mammalian plasma contains several substances with the ability to inhibit the sodium pump and to interact with digitalis antibodies, 8,25 and that different digoxin antibodies demonstrate wide variability in their capacity to detect EDLF. 7,26 The purpose of the present study was to investigate whether ACTH hypertension in the rat is associated with increased plasma levels of marinobufagenin-l...

Central Role for the Cardiotonic Steroid Marinobufagenin in the Pathogenesis of Experimental Uremic Cardiomyopathy

“…It is interesting to note that aldosterone-induced fibrosis only appears to develop in settings where salt loading and volume expansion also occur, 38 and these settings are likely to have increased circulating concentrations of MBG. 39,40 To be sure, we noted considerable cardiac fibrosis in our renal failure model as demonstrated by histological analysis and fibronectin expression. Fourth and perhaps most important, we observed that active immunization against MBG was associated with very substantial attenuation of cardiac hypertrophy, cardiac fibrosis, and the oxidant stress state.…”

Ouabain, a steroid hormone that signals with slow calcium oscillations

“…The concentrations of ouabain used in Fig. 1b are much higher than those reportedly observed in the blood (20)(21)(22). Ouabain binding to Na,K-ATPase may, under physiological conditions, be expected to increase as a function of time (23).…”

The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition

“…CTSs were discovered in digitalis plants and amphibian tissues (25,75). Recently, CTSs were found in the body fluids of mammals (5,23,29,73). Moreover, elevated levels of endogenous CTSs including marinobufagenin (MBG) have been associated with various pathological conditions: essential hypertension (4,24,73), preeclampsia (3,45,83), experimental diabetes (7), uremic cardiomyopathy (33), and cardiac failure (20,48,49,66,74).…”