Peripheral and Cerebrovascular Actions of Ethanol, Acetaldehyde, and Acetate: Relationship to Divalent Cations

Inasmuch as ethanol is thought to exert its major effects in the autonomic and central nervous systems, it is important to determine whether acute versus chronic ingestion of this abused substance exerts any direct actions on peripheral and cerebral blood vessels. Since the chronic effects of ethanol on the cardiovascular system appear to be pivotal in the etiology of hypertension, coronary heart disease, and strokelike events, it is important to elucidate and understand the effects of chronic ethanol abuse and its mechanism(s) of action on the peripheral and cerebral blood vessels. Data are reviewed which suggest that the peripheral vasodilation and hypotension which result from acute ingestion (or administration) of ethanol may, in large part, be a consequence of its direct actions on vascular smooth muscle cells, both at the macro‐ and microcirculatory levels. At least two mechanisms appear to contribute to this vasodilator effect: 1) inhibition of the normal rhythm or vasomotion (spontaneous mechanical activity) of vascular smooth muscle, and 2) depression of the contractile responses to endogenous neurohumoral substances that play a role in maintaining vascular tone and regulation of blood flow. The data acquired so far suggest that the dilator actions are related causally to interference with movement and/or translocation of Ca 2+ across the vascular membranes. In addition, these actions appear to resemble the peripheral vascular effects of general anesthetics. Evidence is also reviewed which indicate that ethanol, in contrast to acting as a vasodilator in the splanchnic vasculature, is often a potent and concentration‐dependent constrictor of arterioles and venules in the skeletal muscle vasculature. Direct in situ observations on the rat brain, using high resolution, quantitative TV image‐intensification microscopy, indicates that administration of ethanol, irrespective of the route of administration (e.g., perivascularly, intraarterially, or systemically), produces graded concentration‐dependent spasms of arterioles and venules. Concentrations of ethanol ≅>250 mg/dl produce intense spasms resulting in rupture of these vessels. Recent in situ studies in conscious dogs, using radiolabeled microspheres, also indicate that ethanol can produce deficits in regional brain blood flow. Studies with isolated canine middle cerebral and basilar arteries clearly demonstrate that low concentrations of ethanol (e.g., <10 mM) can produce concentration‐dependent spasms by a direct vascular action. Collectively, these findings could be used to support the concept that heavy use of alcohol or binge drinking can produce stroke‐like effects. Although ethanol's major metabolites, acetaldehyde and acetate, can produce vasodilator and vasoconstrictor effects on macro‐ and microcirculatory blood vessels, their specific vascular actions, in a particular region of the microcirculation, appear to be distinctly opposite to those induced by ethanol. Thus, even though it appears that these metabolites can't in themselves explain the actions of ethanol on site‐specific vascular muscle cells, they could act to mask and/or modulate the overall hemodynamic actions of ethanol. Experiments with vascular smooth muscle obtained from rats maintained for prolonged periods of time (i.e., up to 24 weeks) on liquid ethanol diets (6.8%, v/v) indicate that arterial and venous smooth muscles develop a progressive tolerance to ethanol and become progressively hypertensive (or reactive) to contractile stimuli and neurohumoral substances. These vascular smooth muscle cells exhibit a progressive increase in exchangeable and cellular calcium concomitant with a progressive reduction in tissue magnesium content. It is suggested that these progressive, reciprocal changes in divalent cation movement observed in ethanolized vascular smooth muscle cells may provide a rational basis for etiology of hypertension in alcoholics. Preliminary experiments with rats indicate that a variety of specific Ca 2+ antagonists and the “mimic” Ca 2+ antagonist, Mg 2+ , prevent, ameliorate, or reverse alcohol‐induced cerebrovasospasms and may prove valuable in treating the hypertension, myocardial ischemia, and strokes observed in heavy users of alcohol.