title: Oxidative stress and autonomic dysregulation contribute to the acute time-dependent myocardial depressant effect of ethanol in conscious female rats.
abstract: BACKGROUND
  The molecular mechanisms of the acute hypotensive and indirectly assessed cardiac depressant effect of ethanol (EtOH)-evoked myocardial depression and hypotension in female rats are not known. We tested the hypothesis that a time-dependent myocardial depression caused by EtOH is initiated by its direct and indirect (cardiac vagal dominance) effects and is exacerbated by gradual development of oxidative stress.
  
  
  METHODS
  In conscious female rats, we directly measured left ventricular developed pressure (LVDP), the maximal rise of ventricular pressure over time (dP/dtmax ), blood pressure (BP), heart rate (HR), and sympathovagal activity following intragastric EtOH (1 g/kg) or water over 90 minutes. Catalytic activity of acetaldehyde (ACA)-generating (alcohol dehydrogenase [ADH] and catalase) and eliminating aldehyde dehydrogenase [ALDH2] enzymes along with mediators of oxidative stress were measured in myocardial tissues collected at 30, 60, or 90 minutes after EtOH or water.
  
  
  RESULTS
  EtOH reduced myocardial function (LVDP and dP/dtmax ) within 5 to 10 minutes before the steady fall in BP in conscious proestrus rats. Further, EtOH shifted the sympathovagal balance, analyzed by spectral analysis of high frequency and low frequency of interbeat intervals, toward vagal dominance. Prior vagal blockade (atropine) or antioxidant (tempol) treatment attenuated EtOH-evoked myocardial depression and hypotension. Ex vivo studies revealed time-dependent: (i) enhancement of ADH, but not ALDH2 activity (indicative of elevated ACA levels), (ii) increases in phosphorylated Akt and ERK1/2, NADPH-oxidase activity, reactive oxygen species, malondialdehyde, and 4-hydroxy-2-nonenal-modified proteins. These molecular responses along with reduced myocardial catalase activity were most evident at 90 minutes post-EtOH when the reductions in cardiac function and BP reached their nadir.
  
  
  CONCLUSIONS
  Vagal dominance and time-dependent myocardial oxidative stress along with the accumulation of cardiotoxic aldehydes mediate EtOH-evoked myocardial dysfunction and hypotension in conscious proestrus female rats.
authors.affiliation: Department of Pharmacology and Toxicology (BMI, MF, AAR-R), Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Badr M
authors.initials: BM
authors.lastname: Ibrahim
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000032:analysis; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000032:analysis; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D024101:Mitochondrial Proteins; D000431:Ethanol; D002374:Catalase; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat
keywords: Ethanol; Female Rats; Hypotension; Myocardial Dysfunction; Reactive Oxygen Species
references.citation: J Mol Cell Cardiol. 2006 Feb;40(2):283-94
references.pmid: 16403513
references.citation: JAMA. 1995 Jul 12;274(2):149-54
references.pmid: 7596003
references.citation: Diabetes Obes Metab. 2011 May;13(5):465-73
references.pmid: 21272185
references.citation: Hum Exp Toxicol. 2012 Jun;31(6):626-36
references.pmid: 22144729
references.citation: Am J Physiol Heart Circ Physiol. 2007 Mar;292(3):H1398-403
references.pmid: 17085535
references.citation: Am J Respir Cell Mol Biol. 2007 Jan;36(1):68-77
references.pmid: 16931806
references.citation: J Pharmacol Exp Ther. 2005 Sep;314(3):1328-37
references.pmid: 15937146
references.citation: Res Commun Chem Pathol Pharmacol. 1986 Feb;51(2):195-203
references.pmid: 3754347
references.citation: Alcohol Clin Exp Res. 2005 Feb;29(2):221-34
references.pmid: 15714045
references.citation: Alcohol Clin Exp Res. 2006 Sep;30(9):1500-5
references.pmid: 16930212
references.citation: Alcohol Clin Exp Res. 1999 Apr;23(4):624-32
references.pmid: 10235298
references.citation: Exp Physiol. 2012 Jun;97(6):719-29
references.pmid: 22366563
references.citation: J Pharmacol Exp Ther. 2010 Oct;335(1):149-54
references.pmid: 20610621
references.citation: J Am Coll Cardiol. 2009 Nov 10;54(20):1891-8
references.pmid: 19892241
references.citation: J Pharmacol Exp Ther. 2012 Aug;342(2):461-71
references.pmid: 22580349
references.citation: Eur J Pharmacol. 2011 Jan 10;650(1):317-23
references.pmid: 20970417
references.citation: Alcohol Clin Exp Res. 1996 Oct;20(7):1192-5
references.pmid: 8904969
references.citation: Am J Physiol Heart Circ Physiol. 2002 Apr;282(4):H1216-22
references.pmid: 11893554
references.citation: Eur J Pharmacol. 2012 Mar 15;679(1-3):95-100
references.pmid: 22305881
references.citation: J Clin Invest. 1976 Sep;58(3):751-60
references.pmid: 956400
references.citation: Mech Ageing Dev. 2007 Mar;128(3):276-85
references.pmid: 17250874
references.citation: Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H903-11
references.pmid: 21724868
references.citation: Toxicol Sci. 2006 Feb;89(2):386-98
references.pmid: 16291827
references.citation: J Pharmacol Exp Ther. 1999 Nov;291(2):766-72
references.pmid: 10525098
references.citation: J Sex Med. 2010 Sep;7(9):3023-32
references.pmid: 20626609
references.citation: Free Radic Biol Med. 2008 Dec 1;45(11):1542-50
references.pmid: 18845238
references.citation: Int J Mol Sci. 2012 Nov 05;13(11):14311-25
references.pmid: 23203066
references.citation: J Biol Chem. 2008 Oct 3;283(40):27038-47
references.pmid: 18622039
references.citation: J Biol Chem. 2008 Mar 21;283(12):7864-76
references.pmid: 18070887
references.citation: Comp Biochem Physiol A Mol Integr Physiol. 2003 Mar;134(3):607-14
references.pmid: 12600669
references.citation: Alcohol Clin Exp Res. 1984 Jul-Aug;8(4):352-8
references.pmid: 6091490
references.citation: Am J Physiol. 1995 Apr;268(4 Pt 2):H1606-12
references.pmid: 7733361
references.citation: Am J Physiol Heart Circ Physiol. 2004 Feb;286(2):H806-14
references.pmid: 14512276
references.citation: Clin Exp Pharmacol Physiol. 2009 Oct;36(10):1002-9
references.pmid: 19413598
references.citation: Clin Exp Hypertens. 1999 Nov;21(8):1429-45
references.pmid: 10574422
references.citation: Life Sci. 2007 Aug 23;81(11):895-905
references.pmid: 17765928
references.citation: Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H837-44
references.pmid: 22159996
references.citation: Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1614-24
references.pmid: 22307672
references.citation: Free Radic Biol Med. 2006 Dec 15;41(12):1847-59
references.pmid: 17157187
references.citation: Cell Mol Biol (Noisy-le-grand). 1997 Sep;43(6):825-34
references.pmid: 9359629
references.citation: Alcohol Clin Exp Res. 2009 Jul;33(7):1158-68
references.pmid: 19389198
references.citation: Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H860-6
references.pmid: 18567712
references.citation: J Pharmacol Exp Ther. 2012 Jan;340(1):11-8
references.pmid: 21946192
references.citation: J Mol Cell Cardiol. 2010 Apr;48(4):757-64
references.pmid: 19913552
references.citation: PLoS One. 2011;6(9):e25213
references.pmid: 21980400
references.citation: Am J Physiol. 1978 Dec;235(6):H701-6
references.pmid: 736158
references.citation: Nutr Metab Cardiovasc Dis. 2005 Aug;15(4):316-28
references.pmid: 16054557
references.citation: J Neurosci Res. 2011 Nov;89(11):1859-68
references.pmid: 21800350
references.citation: Antioxid Redox Signal. 2008 Jun;10(6):1115-26
references.pmid: 18321209
references.citation: Am J Physiol. 1999 Apr;276(4):H1245-52
references.pmid: 10199849
references.citation: Mol Pharmacol. 2004 Jul;66(1):187-96
references.pmid: 15213311
references.citation: J Biol Chem. 2006 Apr 7;281(14):9460-70
references.pmid: 16431921