Short communicationEndogenous bufadienolide mediates pressor response to ethanol withdrawal in rats
Introduction
Chronic excessive alcohol consumption is a risk factor for hypertension (Di Gennaro et al., 2002). Endogenous digitalis-like inhibitors of the Na/K-ATPase (cardiotonic steroids — CTS) are implicated in the mechanisms of NaCl-sensitive hypertension (Haddy, 2006) and in ethanol tolerance (Bagrov et al., 2002). In the hypertensives, levels of CTS increase with an adaptive role to induce natriuresis via inhibition of the sodium pump in renal tubuli (Haddy, 2006). In addition, CTS inhibit the Na/K-ATPase in the vascular smooth muscle and potentiate vasoconstriction (Haddy, 2006). Marinobufagenin (MBG), a CTS belonging to a class of bufadienolides, exhibits high affinity to ouabain-resistant α-1 Na/K-ATPase isoform, the main sodium pump isoform in vascular sarcolemma and an exclusive sodium pump isoform in renal epithelium (Fedorova et al., 2002, Fedorova et al., 2005). Accordingly, in vivo MBG acts as a natriuretic and as a vasoconstrictor (Fedorova et al., 2002, Fedorova et al., 2005).
MBG is also implicated in the development of ethanol addiction in rats. In our previous experiments, administration of MBG to rats reduced voluntary ethanol consumption (Kashkin et al., 2002), while active immunization of rats against MBG facilitated ethanol-seeking behavior (Bagrov et al., 1999).
In alcoholics, ethanol withdrawal is associated with a pressor response and renal sodium retention (Di Gennaro et al., 2002). Since MBG is a natriuretic and a vasoconstrictor (Fedorova et al., 2002, Fedorova et al., 2005), and since this hormone exhibits anti-addictive properties (Bagrov et al., 2002), we hypothesized that MBG may mediate ethanol withdrawal-induced pressor response.
Section snippets
Methods
The protocol of the study has been approved by the Animal Care and Use Committee of the National Institute on Aging, NIH. Thirty male Sprague–Dawley rats (251 ± 2 g) (Charles River Laboratories, Inc., Wilmington, MA) were housed in individual cages with free access to standard chow and drinking water and with a 12:12-hour light/dark cycle (t = 21 °C).
Ethanol withdrawal was induced as reported previously in detail (Spanagel et al., 1996). After a seven-day period of acclimation, 30 rats were divided
Results
As presented in Fig. 1A, systolic blood pressure did not exhibit significant changes in both “control” and “ethanol” groups during 9 days of observation, while in rats from “withdrawal” group, arterial pressure rose by 21 mm Hg within 48 h of replacement of 20% ethanol with water.
Levels of renal excretion of MBG, endogenous ouabain and sodium, and hematocrit assessed at day 9 of the experiment are illustrated in Fig. 1B–E. Forced ethanol ingestion did not significantly affect any of the
Discussion
The main observation of the present experiment is that in rats, acute ethanol withdrawal is associated with a rise in arterial pressure, with renal sodium retention, volume expansion, and a drop in hematocrit, and with an increase in renal excretion of MBG, an endogenous bufadienolide with natriuretic, vasopressor and anti-addictive properties.
The fact that, in a subset of rats, withdrawal-induced pressor response was prevented by in vivo administration of anti-MBG antibody, indicates that MBG
Role of funding source
The experiments described in this paper were supported by the National Institute on Aging, National Institutes of Health Intramural Research Program and by Russian Foundation for Fundamental Science (grant 06-04-48956).
Contributors
Drs. AY Bagrov, Zvartau, and YY Bagrov designed the study. Drs. AY Bagrov, OV Fedorova and VA Kashkin wrote the protocol. Drs. AY Bagrov, OV Fedorova, and EG Lakatta managed the literature searches and analyses. Drs. Kashkin and Fedorova, and AY Bagrov performed the experiments and undertook the statistical analysis. Drs. AY Bagrov and VA Kashkin wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All the authors do not have any conflicts of interest.
Acknowledgements
The authors gratefully acknowledge excellent editorial assistance by Marinella Macri, and excellent technical support by Chad Boily BA, and Danielle Joseph, AA.
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