Abstract
Evidence suggests that ethanol-induced hypertension is associated with increased cardiovascular responsiveness to vasopressors in vivo and enhanced reactivity of isolated arteries to vasopressors ex vivo. The underlying mechanisms are not well understood and the contribution of ethanol metabolites to vascular effects induced by ethanol consumption are unclear. Mesenteric resistance arteries were harvested from Sprague-Dawley rats. Pressure myography was utilized to test effects of ethanol, acetaldehyde and phosphatidylethanol on myogenic tone and on vasoconstriction induced by phenylephrine, arginine vasopressin (aVP), endothelin-1 and KCl. Ethanol, acetaldehyde and phosphatidylethanol concentrations were monitored during the experiments. Ethanol concentrations in the vessel bath decreased with a half-life of 25min; acetaldehyde and phosphatidylethanol concentrations remained constant. Pretreatment with ethanol dose-dependently increased the potency of phenylephrine to induce vasoconstriction 4-fold (p<0.01). These effects were comparable when arteries were pre-treated with a single dose of ethanol for 30min and when ethanol concentrations were kept constant during 30min and 60min of pretreatment. While ethanol also dose-dependently increased the potency of aVP to induce vasoconstriction 1.7-fold (p<0.05), it did not affect vasoconstriction induced by endothelin-1 or KCl. Acetaldehyde pre-treatment (30 min) dose-dependently increased the potency of phenylephrine to induce vasoconstriction 2.7-fold (p<0.01) but did not affect other vasoconstrictor responses. Phosphatidylethanol did not affect any vasoconstrictor responses. Ethanol and its metabolites did not affect myogenic tone. These data suggest that ethanol and acetaldehyde selectively sensitize intrinsic constrictor responses upon activation of vascular α1-adrenergic and/or vasopressin receptors at clinically relevant concentrations. Our findings support the concept that enhanced vasoreactivity to vasoactive hormones contributes to the development of hypertension induced by ethanol consumption. Ex vivo exposure of resistance arteries to ethanol and acetaldehyde resembles effects of chronic ethanol consumption on intrinsic vascular function, and thus could serve as test platform to evaluate interventions aimed to mitigate vascular effects associated with ethanol consumption.
Highlights
Cardiovascular diseases are major health problems world-wide, affecting over 85 million people in the US alone [1]
Our findings provide new insights into pathophysiological consequences of ethanol and ethanol metabolite exposure on the vasculature, which are likely to contribute to the etiology of hypertension induced by ethanol consumption
While ethanol preexposure of the arteries did not significantly affect maximal constriction induced by PE or Hill-slopes of the dose-response curves, ethanol dose-dependently increased the potency of PE to induce vasoconstriction ~ 4-fold (Fig 1C; EC50: 0 mM ethanol - 1114 ± 207; 17.4 mM ethanol 915 ± 166; 50 mM ethanol– 383 ± 51 (p = 0.003 vs. vehicle); 100 mM ethanol– 283 ± 56 (p = 0.001 vs. vehicle))
Summary
Cardiovascular diseases are major health problems world-wide, affecting over 85 million people in the US alone [1]. While epidemiological studies suggested a U-or J-shaped dose-effect relationship between alcohol consumption and cardiovascular disease, with low-to-moderate drinking being beneficial, more recent epidemiological methodologies question this association [4]. It is well accepted, that chronic moderate-to-heavy drinking has detrimental effects on cardiovascular health [2, 4]. Chronic moderate-to-heavy drinking induces arterial hypertension in humans and animals [2,3,4,5,6,7,8,9,10,11,12,13,14] This association is of major importance as hypertension is the single most important risk factor for global burden of disease and significant percentages of hypertension can be attributed to ethanol consumption [2, 15, 16]
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