Most of these studies reported a significant positive association between hypertension and ethanol consumption. Systolic pressure increased progressively with increasing ethanol consumption among 491 Caucasian males aged years. List of the main epidemiological studies describing the relationship between ethanol consumption and hypertension In this review, we will discuss the relationship between ethanol intake and hypertension and some of the possible mechanisms underlying this response. Data support the involvement of increased sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased intracellular Ca2+ in smooth muscle with a subsequent increase in vascular reactivity, oxidative stress and endothelial dysfunction.

ANIMAL MODELS OF ETHANOL-INDUCED HYPERTENSION

• The present report reviews the relationship between ethanol intake and hypertension and highlights some mechanisms underlying this response.
• Those findings suggested that regular ethanol consumption predisposes to hypertension by facilitating Ca2+ accumulation in cells involved in blood pressure regulation.
• These findings marked the beginning of a major worldwide expansion of research into the role of NO in vascular physiology and pathophysiology.
• Husain et al demonstrated that chronic ethanol consumption leads to an increased NAD(P)H oxidase activity and ROS generation that leads to membrane lipid peroxidation.
• Previously, we showed that increased blood pressure, concomitant with ethanol feeding, was observed in 2-wk ethanol-treated animals, in which the blood ethanol content was 1.67 ± 0.21 mg/mL.
• In addition to its hypertensive effect, ethanol consumption can also modulate the response to vasoactive agents in vivo.

The vascular endothelium and vascular smooth muscle cells are important targets for the effects of ethanol consumption. Similarly, ethanol consumption was also found to reduce the endothelium-dependent relaxation induced by adrenomedullin in the rat mesenteric arterial bed. In the rat carotid, the relaxation induced by IRL1620, a selective endothelin ETB receptor agonist, was reduced after treatment with ethanol; this effect was mediated by a mechanism involving the downregulation of endothelial ETB receptors. Importantly, the increased responsiveness to phenylephrine was also observed after endothelial denudation, further suggesting that the increased sensitivity to α1-adrenergic agonists was what is the catholic churchs position on ivf not dependent on the presence of the endothelium. In addition to its hypertensive effect, ethanol consumption can also modulate the response to vasoactive agents in vivo.

ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE

The second Kaiser-Permanente study reconfirmed the relationship of higher blood pressure to ethanol use. Importantly, the effect of ethanol on systolic blood pressure was independent of the effects of age, obesity, cigarette smoking and physical activity. A landmark observational study published in 1977, the Kaiser-Permanente Multiphasic Health Examination Data, reported differences in systolic blood pressure as high as 11 mmHg in individuals consuming 6 or more drinks per day compared with non-drinkers. These issues are of interest for the public health, as ethanol consumption contributes to blood pressure elevation in the population. This action is postulated to result from ethanol-induced inhibition of N-methyl-D-aspartate receptor-mediated excitotoxicity. This study was undertaken to assess the effect of varying levels of preinjury ethanol on early postinjury mortality, recovery of motor function, and degree of neural degeneration after cortical contusion injury in the rat.

Alterations in Ca2+ levels

In the Risk Factor Prevalence Study, ethanol consumption accounted for no more than 1% of hypertension in women. In these two studies, it was estimated that a maximum of 11% of hypertension in men could be attributed to the consumption of ethanol. The Australian Risk Factor Prevalence Study estimated that 7% of the prevalence of hypertension could be attributed to ethanol consumption, while the first Kaiser Permanente Study estimated a proportion of 5%. In developed countries such as the United States and England, it has been estimated that as much as 30% of hypertension may be attributed to ethanol consumption.

This review provides a description of the main studies that showed a relationship between chronic ethanol consumption and hypertension in humans. These mechanisms include an increase in sympathetic nervous system activity, stimulation of the renin-angiotensin-aldosterone system, an increase of intracellular Ca2+ in vascular smooth muscle, increased oxidative stress and endothelial dysfunction. Although the link between ethanol consumption and hypertension is well established, the mechanism through which ethanol increases blood pressure remains elusive. The loss of neuroprotection and increased mortality rates observed with high-dose ethanol may be related to ethanol-induced hemodynamic and respiratory depression. Utkan et al described that chronic ethanol consumption potentiates endothelium-dependent relaxation in aortic rings, most likely through interference with the synthesis and/or release of NO or adaptive alterations in muscarinic receptors on the endothelial cells.

Myogenic mechanism

This response could be the result of a compensatory mechanism, where increased iNOS expression could induce a substantial and sustained release of NO to compensate for the reduction of eNOS expression. In 1980, Furchgott et al, in classic study, discovered that endothelial cells produce an endothelium-derived relaxing factor (EDRF) in response to stimulation by acetylcholine. These processes may contribute directly or indirectly to increased peripheral resistance and therefore to increased blood pressure.

In vascular tissue, the enzymatic antioxidant system mainly consists of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thioredoxins and peroxiredoxins. It was also suggested that these responses were partly mediated by Mg2+ depletion and suppressed Na+ pump activity. Based on these results, it was concluded that prostanoids mediate the enhanced reactivity to phenylephrine by mechanisms that alter the mobilization of or sensitivity to extracellular Ca2+. During excitation, the intracellular Ca2+ concentration increase by either (1) Ca2+ entry through the plasma membrane through voltage- or ligand-gated ion channels, or (2) release from intracellular stores (sarcoplasmic reticulum or mitochondria). Ca2+ is a cation of critical importance for many cellular control mechanisms, including muscle contraction. These effects are complex, and the identification of biochemical/molecular mechanisms that could explain such effects is warranted.

In a previous study, we compared the effects of ethanol intake (20% v/v) for 2, 6 and 10 wk on arterial blood pressure in conscious Wistar rats. In general, the studies highlighted that the increase in systolic pressure was greater than that in diastolic pressure and that there was a trend toward a greater effect of ethanol on blood pressure in older men compared with younger men. As observed previously in the first Kaiser-Permanente study, systolic and diastolic blood pressures substantially increased at 3 to 5 and 6 or more drinks per day. Animal models of alcoholism may be relevant to understanding the mechanisms by which ethanol consumption increases blood pressure. The effects of ethanol on the cardiovascular system are complex, and attempts to evaluate the possible mechanisms underlying ethanol-induced hypertension in humans are hindered by several limitations. However, although the link between ethanol consumption and arterial hypertension is well established, the mechanism through which ethanol increases blood pressure remains elusive.

In these subjects, increased plasma Ca2+ levels were correlated with increased diastolic blood pressure. In addition to the effects observed previously, the authors observed smooth muscle cell hyperplasia in small arteries and in renal arterioles from ethanol-treated rats. These mechanisms include an increase in intracellular Ca2+ levels with a subsequent increase in vascular reactivity, oxidative stress and a reduction in NO bioavailability.

Paradoxical effects of acute ethanolism in experimental brain injury

However, increased blood pressure was observed in ethanol-treated animals after 2 wk, whereas altered responsiveness to phenylephrine was only observed in rats treated for 6 wk. Chronic ethanol consumption produced an endothelium-dependent increased responsiveness to phenylephrine in a perfused mesenteric arterial bed isolated from rats treated with ethanol for 6 wk but not from rats treated for 2 wk. Most of the experiments designed to study the relationship between alterations in vascular functionality and increases in blood pressure induced by ethanol consumption used conduit vessels, such as the aorta. In the study of Utkan et al, systolic blood pressure was recorded weekly using the tail-cuff method in Wistar rats treated with ethanol (7.2% v/v) for 4 wk. The systolic blood pressure of ethanol-fed rats was increased by 6.6 mmHg at 4 wk and by 33.8 mmHg at 22 wk compared with the controls.

The authors also found that ethanol-fed rats had a higher sympathetic activity, as beta-blockade with propranolol decreased heart rate to a greater degree in ethanol-fed rats than it did in control rats. Blood pressure was significantly higher at week 6 in Sprague-Dawley ethanol-fed rats (from 106 to 147 mmHg) and at week 8 in Wistar ethanol-fed rats (from 117 to 149 mmHg). An increase of approximately 25% in mean arterial blood pressure (from 98 to 122 mmHg) was described later by these authors using the same experimental model. Arkwright et al observed that, although blood pressure was higher among ethanol drinkers, there were no changes in plasma adrenaline, noradrenaline, cortisol and renin in these subjects. On the other hand, Potter et al did not observe changes in catecholamines levels after ethanol consumption.

Male Fisher rats orally administered 20% ethanol (4 g/kg – 12 wk) showed increased systolic and diastolic blood pressures and impaired vascular relaxation compared with controls. Increased vascular oxidative stress induced by ethanol consumption is related to the activation of the enzyme NAD(P)H oxidase, and this mechanism is involved in the increased blood pressure caused by chronic ethanol consumption. Data from our group showed that chronic ethanol consumption increased blood pressure as well as the pressor response induced by phenylephrine and endothelin-130,34. Two years later, these authors reported that verapamil, a Ca2+ channel blocker, reversed the increase in systolic blood pressure and aortic Ca2+ uptake induced by chronic ethanol consumption. In resistance arteries, Hatton et al showed an increased response of mesenteric arteries to noradrenaline in rats treated with ethanol for 18 wk.

Hypertension and chronic ethanol consumption: What do we know after a century of study?

Support for the concept of ethanol as a cause of hypertension derives from several epidemiologic studies demonstrating that in the general population, increased blood pressure is significantly correlated with ethanol consumption. After a century of study, it is established that chronic ethanol consumption leads to hypertension and that this process is a multi-mediated event involving the aforementioned mechanisms (Figure 1). The link between hypertension and chronic ethanol consumption is well established, and the mechanism by which ethanol increases blood pressure is complex.

In this review, for the purpose of standardization, the levels of ethanol consumption in humans have been expressed as the number of standard drinks per day (1 standard drink is defined here as the equivalent of 14 g of ethanol). These difficulties include differences in the duration of ethanol use, the timing and frequency of blood pressure measurements, variability in the type and frequency of ethanol intake, age, gender, ethnicity, salt use, body mass index and comorbid conditions. A link between excessive ethyl alcohol (ethanol) consumption and arterial hypertension was first suggested early last century. In this cortical contusion model, the presence of ethanol before injury appears to exert a potent neuroprotective effect when administered in low or moderate doses.

• In these subjects, increased plasma Ca2+ levels were correlated with increased diastolic blood pressure.
• Chronic ethanol consumption in rats increased the contractile response of the aorta and mesenteric arterial bed31-33.
• Male Fisher rats orally administered 20% ethanol (4 g/kg – 12 wk) showed increased systolic and diastolic blood pressures and impaired vascular relaxation compared with controls.
• Importantly, the effect of ethanol on systolic blood pressure was independent of the effects of age, obesity, cigarette smoking and physical activity.
• The causal relationship between ethanol, ROS and hypertension most likely occurs at the vascular level, where ethanol promotes oxidative stress, endothelial dysfunction, vascular inflammation, increased vascular reactivity and structural remodeling.

However, while the aorta does not offer substantial resistance to blood flow, the contribution made by vessels of smaller diameter to peripheral vascular resistance is much greater. Evidence suggests the existence of a myogenic mechanism(s) that involves alterations in the contractile/relaxant properties of vascular smooth muscle. Moreover, these authors reported that plasma renin and cortisol levels were not affected by the consumption of ethanol.

ANIMAL MODELS OF ETHANOL-INDUCED HYPERTENSION

In rats, the mesenteric circulation receives approximately one-fifth of the cardiac output, and thus, regulation of this bed provides a significant contribution to the regulation of systemic blood pressure. The potentiation of endothelin-1-induced contraction in the rat carotid was caused by reduced expression of pro-relaxation endothelial endothelin receptor type B (ETB) receptors (Table 2). The hyperactivity to endothelin-1 in the rat carotid was not different among the three periods of treatment (2, 6 and 10 wk) used in our study. Much of the research investigating the chronic effects of ethanol on the cardiovascular system has addressed vascular responsiveness to vasoconstrictor agents. A possible explanation for such a finding could be the higher blood ethanol levels found in this study (293.6 ± 5.2 mg/dL).

Acute ethanol intoxication is a frequent complicating factor in human head injury, yet its impact on neurological outcome remains poorly defined. In both setting of acute alcohol intoxication and chronic misuse, a wide range of pathologies and mechanisms of death may be encountered, particularly with regard to sudden, unexpected or violent deaths. This loss of NO that occurs in the reaction with superoxide anion deprives vascular smooth muscle cells of NO. Husain et al44,100 described down-regulation of the NO-generating system, leading to impaired vasorelaxation and hypertension. These findings marked the beginning of a major worldwide expansion of research into the role of NO in vascular physiology and pathophysiology. The inhibition of these enzymes may increase superoxide anion availability, which can react with NO to form peroxynitrite.

Alterations in Ca2+ levels

More recently, we found that chronic ethanol consumption reduced the endothelium-dependent relaxation induced by the peptide adrenomedullin in the rat aorta. Noradrenaline-induced contraction of the superior mesenteric artery was shown to be greater in rings from ethanol-treated rats. The initial studies in this field showed enhanced vascular reactivity to α1-adrenoceptor agonists in different arteries from ethanol-fed rats. In fact, the majority of studies describing the effects of ethanol on arterial blood pressure also evaluated the effects of ethanol on vascular responsiveness24,28,29,31-33.