Chronic effects of ethanol on pharmacokinetics and left ventricular systolic function in rats

BACKGROUND: Observational clinical studies have demonstrated that there is a U-shaped relationship between ethanol consumption and all-cause mortality or risk of ischemic stroke. Although the exact cause of the U-shaped relationship is unclear, the pharmacokinetics of ethanol during the time course of chronic intake of ethanol may be involved, in relation to its cardiotoxic effects. The present study has assessed the cause of the U-shaped relationship between the ethanol consumption and left ventricular (LV) systolic dysfunction in a pharmacokinetic way. METHODS: Male Wistar rats were paired, and either ethanol or control liquid diet was chronically administered for 7 weeks. Then, these rats were subdivided into 3 groups: control liquid-diet-fed rats [EtOH (-)], 3 g/dL ethanol liquid-diet-fed rats (3%EtOH), and 5 g/dL ethanol liquid-diet-fed rats (5%EtOH). Ethanol's cardiotoxicity on LV systolic function was investigated by echocardiography. Ethanol concentration in blood, ethanol pharmacokinetics, and hepatic alcohol dehydrogenase (ADH) activity were evaluated simultaneously. RESULTS: The 5%EtOH group revealed LV systolic dysfunction, associated with a higher ethanol concentration in blood, and lower hepatic ADH activity than the EtOH (-) group; however, the 3%EtOH group did not show LV systolic dysfunction. During the acute ethanol stress, LV systolic dysfunction appeared in both EtOH (-) and 5%EtOH groups, with a higher ethanol concentration in blood and lower hepatic ADH activity than the 3%EtOH group. The 3%EtOH group showed a higher ethanol washout rate, less time-integral of ethanol concentration, and shorter mean residence time of ethanol in blood than the EtOH (-) or 5%EtOH group. CONCLUSIONS: The U-shaped relationship between chronic ethanol consumption and LV systolic dysfunction may be closely related to the pharmacokinetic characteristics of ethanol in blood, which depends on the quantity of chronically drinking alcohol.