Chronic ethanol intake modulates vascular levels of endothelin‐1 receptor and enhances the pressor response to endothelin‐1 in anaesthetized rats

• Published in: British journal of pharmacology Vol. 154; no. 5; pp. 971 - 981
• Main Authors: Tirapelli, C R, Legros, E, Brochu, I, Honoré, J‐C, Lanchote, V L, Uyemura, S A, De Oliveira, A M, D'Orléans‐Juste, P
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2008; Nature Publishing; Nature Publishing Group
• Subjects: Acetylcholine - pharmacology; Addictive behaviors; Adult and adolescent clinical studies; Alcohol Drinking - adverse effects; Alcohol Drinking - metabolism; Alcohol Drinking - physiopathology; Alcoholism; Alcoholism and acute alcohol poisoning; Animals; Aorta - drug effects; Aorta - metabolism; Biological and medical sciences; blood pressure; Blood Pressure - drug effects; Cardiovascular Diseases - etiology; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - physiopathology; chronic ethanol consumption; Endothelin-1 - metabolism; Endothelins - pharmacology; ETA receptors; Ethanol - administration & dosage; Ethanol - blood; Ethanol - toxicity; ET‐1; Heart Rate - drug effects; Kidney - drug effects; Kidney - metabolism; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - metabolism; Myocardium - metabolism; Oligopeptides - pharmacology; Peptide Fragments - pharmacology; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Phenylephrine - pharmacology; Piperidines - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Wistar; Receptor, Endothelin A - drug effects; Receptor, Endothelin A - metabolism; Receptor, Endothelin B - drug effects; Receptor, Endothelin B - metabolism; Research Papers; Self Administration; Toxicology; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - pharmacology; Ethanol; Rat; ETA receptors; Alcoholism; Rodentia; Endothelin 1; ETA endothelin receptor; Vertebrata; Mammalia; ET-1; chronic ethanol consumption; Animal; Arterial pressure; Blood pressure; Hemodynamics; Endothelin receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.157

Background and purpose:
The contribution of endothelin‐1 (ET‐1) to vascular hyper‐reactivity associated with chronic ethanol intake, a major risk factor in several cardiovascular diseases, remains to be investigated.
Experimental approach:
The biphasic haemodynamic responses to ET‐1 (0.01–0.1 nmol kg−1, i.v.) or to the selective ETB agonist, IRL1620 (0.001–1.0 nmol kg−1, i.v.), with or without ETA or ETB antagonists (BQ123 (c(DTrp‐Dasp‐Pro‐Dval‐Leu)) at 1 and 2.5 mg kg−1 and BQ788 (N‐cis‐2,6‐dimethyl‐piperidinocarbonyl‐L‐γ‐methylleucyl1‐D‐1methoxycarbonyltryptophanyl‐D‐norleucine) at 0.25 mg kg−1, respectively) were tested in anaesthetized rats, after 2 weeks' chronic ethanol treatment. Hepatic parameters and ET receptor protein levels were also determined.
Key results:
The initial hypotensive responses to ET‐1 or IRL1620 were unaffected by chronic ethanol intake, whereas the subsequent pressor effects induced by ET‐1, but not by IRL1620, were potentiated. BQ123 at 2.5 but not 1 mg kg−1 reduced the pressor responses to ET‐1 in ethanol‐treated rats. Conversely, BQ788 (0.25 mg kg−1) potentiated ET‐1‐induced increases in mean arterial blood pressure in control as well as in ethanol‐treated rats. Interestingly, in the latter group, increases in heart rate, induced by ET‐1 at a dose of 0.025 mg kg−1 were enhanced following ETB receptor blockade. Finally, we observed higher levels of ETA receptor in the heart and mesenteric artery and a reduction of ETB receptor protein levels in the aorta and kidney from rats chronically treated with ethanol.
Conclusions and implications:
Increased vascular reactivity to ET‐1 and altered protein levels of ETA and ETB receptors could play a role in the pathogenesis of cardiovascular complications associated with chronic ethanol consumption.
British Journal of Pharmacology (2008) 154, 971–981; doi:10.1038/bjp.2008.157; published online 12 May 2008