Tahir Siddiq

Ethanol toxicity and cardiac protein synthesis in vivo

Long- and short-term alcohol consumption induce a variety of cardiovascular changes, including alterations in hemodynamic variables and tissue biochemistry. In many instances some of the perturbations may be considered as compensatory adjustments, and indeed, there is some controversy that moderate long-term consumption may cause alterations in plasma lipid profiles, conferring cardiovascular protection by reducing the incidence of coronary artery disease. In the long term, however, ethanol misuse may induce a specific disease entity, namely alcoholic heart muscle disease, and short-term ethanol exposure may also perturb tissue contractility and hemodynamic indices. The mechanisms of these changes are unknown, but central to many of the metabolic and functional disturbances are alterations in tissue protein synthesis, perhaps precipitated or exacerbated by free radial formation or by the formation of protein-acetaldehyde adducts. Methods for measuring protein synthesis in vivo are reviewed, and their application to elucidating the mechanisms involved in cardiac abnormalities is described, including the effects of ethanol. Our results demonstrate that the effects of alcohol toxicity also occur at the subcellular level, and the synthesis of mitochondrial proteins are reduced in vivo, perhaps even contribution to defects in energy generation, the normal function of which is required to maintain contractility.

Gastrointestinal protein turnover and alcohol misuse

Acute and chronic ethanol ingestion causes a variety of pathological changes in the gastrointestinal tract, including gross morphological lesions and functional changes. We review whether these alterations also include changes in protein turnover, to explain the frequently observed villus atrophy and smooth muscle myopathy. The possibility that different regions of the gastrointestinal tract express diverse sensitivities is explored. Acute ethanol dosage profoundly reduced the synthesis of proteins in proximal regions of the rat gastrointestinal tract, but distal regions were less affected. In response to chronic ethanol exposure, similar regional sensitivities of the intestine were observed. In chronic studies the small intestine effects were characterised by selective losses of RNA, principally from the stomach and jejunum. We speculate whether the effects on protein synthesis were primarily due to ethanol or the consequence of acetaldehyde formation. We also determined whether changes in protein synthesis occurred secondary to alterations in nucleotide composition. The possible mediation by free-radical formation or impaired antioxidant status are also discussed. The overall results indicate that both acetaldehyde and ethanol are potent protein synthetic inhibitors and may contribute to the genesis of intestinal myopathy, possibly contributing towards motility disturbances and secondary malnutrition via malabsorption.

Effects of acute ethanol on ventricular myofibrillary protein synthesis in vivo in normotensive and hypertensive rats

Abstract The acute inhibitory effects of ethanol (75 mmol/kg body weight; i.p.; 2.5 hour) on the synthesis of the myofibrillary and other protein fractions in normotensive and hypertensive rats were investigated. Male Wistar rats were subjected to 30 days aortic constriction to induce hypertension. Controls were sham‐operated and subjected to controlled feeding so that both groups of rats received identical food intakes. At the end of the study the left ventricles were analysed. Hypertension was associated with a significant increase in the content of myofibrillary and non‐contractile proteins with slightly reduced protein synthesis. A marked decrease in the rates of contractile and non‐contractile protein synthesis occurred in response to ethanol dosage in sham‐operated control rats. The decline in myofibrillary protein synthesis was greater in the hypertensive animals. A reduction in the synthesis of contractile proteins will compromise the formation of new contractile elements and contribute to the impaired contractility of hypertensive ethanol misusers.

Alcohol and Protein Turnover

Ethanol administration induces a variety of pathological responses which in many tissues are manifested as reductions in tissue protein content. These alterations must be due to changes in protein turnover. This review is, therefore, primarily concerned with investigating the mechanisms whereby tissue protein synthesis or degradation is altered as a consequence of ethanol toxicity. Attention will be focused on the various muscle types (i.e. skeletal, cardiac and smooth muscle) and bone.

Effects of the dihydropyridine calcium channel blocker amlodipine on ventricular and atrial protein synthesis in an aortic constriction model of hypertension and, following chronic treatment, in the left ventricle of SHR rats

The dihydropyridine calcium channel blocking agent amlodipine is an effective anti-hypertensive agent and its use (in doses of 5 or 10 mg/day/kg body weight) was investigated in male Wistar rats with hypertension induced by aortic constriction. Controls were sham-operated and pair-fed. At the end of the study, rates of protein synthesis were measured with radiolabelled phenylalanine to calculate fractional rates of protein synthesis (ks), absolute rates of protein synthesis (Vs) and synthesis rates relative to RNA (kRNA). After 30 days of aortic constriction, weights of the left ventricle and left atrium were significantly increased by hypertension. The weights of the right ventricle and right atrium were relatively unaffected. Hypertension was accompanied by significant increases in the protein and RNA contents of the left ventricle and left atrium. The contractile and non-contractile protein contents were also increased in the left ventricles of hypertensive rats as were total proteins and total RNA. In the myofibrillary fraction, ks decreased. The right ventricle and right atrium were generally unaffected except for a decline in mixed protein ks. Many of these changes in hypertension were ameliorated by treatment with amlodipine, particularly at the higher dose (i.e. 10 mg/kg body weight/day) implicating an effect on protein metabolism. In the left ventricle these included amelioration of the increases in mixed and contractile proteins, total RNA contents, mixed Vs and Vs for sarcoplasmic and stromal proteins. The ameliorating effects of amlodipine were moderate in the left atrium. Furthermore, amlodipine also retarded the hypertension-induced reduction in right ventricule rates of protein synthesis. Although the preceding study emphasises the preventative aspects of amlodipines efficacy, an additional study was carried out in SHR rats to ascertain the applicability for regression per se. Amlodipine (10 mg/kg/body weight) therapy for 30 weeks caused regression of LV mass, total protein, RNA and DNA contents. We conclude that amlodipine, is an efficient agent in ameliorating the hypertension-induced changes in protein metabolism in an aortic constriction model.