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There was a mild but significant elevation of systolic blood pressure in the ethanol-fed rats by week 1 compared to baseline measurements, and this difference remained higher at later times. Chan and Sutter found that treatment of male Wistar rats for 12 wk with a solution of ethanol (20% v/v) resulted in mild hypertension. In this regard, increases in plasma adrenaline and noradrenaline were described in humans after ethanol ingestion, and it was suggested that activation of the adrenergic system may be responsible for the increased blood pressure. Similar results were found in a cross-sectional study in Sidney, where it was estimated that 24% of hypertension may be attributed to ethanol consumption. A French epidemiological study estimated that 24% of the prevalence of hypertension in French men could be attributed to ethanol consumption. The first Kaiser-Permanente study described a threshold relationship at 3 to 5 drinks a day for men, with a substantial increase in systolic blood pressure at 6 drinks a day.

• Moreover, the experiments designed to study the vascular effects of chronic ethanol consumption on α1-induced contraction used only one period of treatment21,28,29.
• Increased Ca2+ influx results in increased vascular contractility and reactivity, and those responses increase vascular tone and peripheral vascular resistance, thereby elevating blood pressure.
• The vascular endothelium and vascular smooth muscle cells are important targets for the effects of ethanol consumption.
• The second Kaiser-Permanente study reconfirmed the relationship of higher blood pressure to ethanol use.

Alterations in Ca2+ levels

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.

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).

The role of oxidative stress in ethanol-induced hypertension is complex and may involve increases in ROS generation or reductions in antioxidant systems. Husain et al demonstrated that chronic ethanol consumption by rats significantly depressed both cytosolic CuZn-SOD and mitochondrial Mn-SOD activities in the plasma, indicating an inability of the cells to scavenge superoxide anion. In clinical studies, increased plasma activity of SOD and GPx was observed in subjects who regularly consume ethanol85,86.

Additionally, Abdel-Rahman et al (1985), who did not detect blood pressure changes after ethanol treatment, reported a blood ethanol concentration of 0.34 ± 0.04 mg/mL in rats treated with ethanol for 30 d. Additionally, there is evidence that blood ethanol concentration contributes to the increase in blood pressure in animal models of alcoholism, where higher blood ethanol concentrations may account for the earlier development of hypertension. Brown et al showed that ethanol-consuming Sprague-Dawley rats exhibited elevated systolic blood pressures compared with the control group (151.6 ± 0.6 vs 132.9 ± 2.7 mmHg).

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.

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

In rats, chronic ethanol treatment led to increased CAT activity and impaired the maintenance of the glutathione redox cycle in renal tissue, with an increase in GPx activity and a decrease in GSH (reduced glutathione) levels. Das and Vasudevan showed that ethanol consumption increased SOD activity and decreased CAT activity in a time- and dose-dependent manner. The antioxidant mechanisms antagonizing the consequences of chronic ethanol consumption have particularities related mainly to the type of tissue studied, the duration of treatment and the concentration of ethanol used. NAD(P)H oxidase is the main source of ROS in endothelial and smooth muscle vascular cells, and it is considered a key factor in the vascular dysfunctions induced by ethanol. Together, these responses lead to increased peripheral resistance and therefore to increased blood pressure65,66.

• Husain et al44,100 described down-regulation of the NO-generating system, leading to impaired vasorelaxation and hypertension.
• The initial studies in this field showed enhanced vascular reactivity to α1-adrenoceptor agonists in different arteries from ethanol-fed rats.
• 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 resistance arteries, Hatton et al showed an increased response of mesenteric arteries to noradrenaline in rats treated with ethanol for 18 wk.
• The reason for the inconsistencies among these results is uncertain, and further studies on the mechanisms underlying the pressor effects of ethanol in humans would be of value.

Paradoxical effects of acute ethanolism in experimental brain injury

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.

ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE

Those findings suggested that regular ethanol consumption predisposes to hypertension by facilitating Ca2+ accumulation in cells involved in blood pressure regulation. whippits 10 facts to know about inhaling nitrous oxide In a clinical study, it was demonstrated that both systolic and diastolic blood pressures were significantly higher in individuals drinking 275 g ethanol per week. Because KCl-induced contraction depends almost exclusively on Ca2+ influx through the activation of voltage-sensitive channels, it was suggested that ethanol consumption increases the Ca2+ influx through these channels. The effect of chronic ethanol administration on blood pressure and its relation to Ca2+ were also investigated by Hsieh et al in 7-wk-old Wistar rats that had received 15% ethanol in their drinking water. SQ29548, a potent and selective thromboxane A2 receptor antagonist, reduced the maximal CaCl2 response of aortic rings from ethanol-treated rats, suggesting that the enhanced response to extracellular Ca2+ was modulated by PGH2/TXA2. Some studies have provided evidence that ethanol consumption increases the intracellular Ca2+ concentration.

Myogenic mechanism

Using this same model of ethanol feeding, we investigated the effects of ethanol treatment for 2 and 6 wk on both blood pressure and vessel reactivity. This finding contrasted those of previous studies, which have reported that blood pressure elevation occurred late during chronic ethanol treatment23,24,28. In light of the need for careful investigation of the mechanisms underlying the effects of ethanol on blood pressure, experimental models were created and are used for this purpose. The results of these studies raise a number of possibilities concerning the involvement of humoral mechanisms in the pressor effects of ethanol. The reason for the inconsistencies among these results is uncertain, and further studies on the mechanisms underlying the pressor effects of ethanol in humans would be of value.

These results suggest that increased intracellular Ca2+ and augmented body fluid volume contributed to the development of ethanol-induced hypertension. Increased Ca2+ influx results in increased vascular contractility and reactivity, and those responses increase vascular tone and peripheral vascular resistance, thereby elevating blood pressure. One of the mechanisms by which chronic ethanol consumption leads to alterations in vascular responsiveness is by increasing the intracellular Ca2+ levels in vascular smooth muscle cells. In fact, while studying the effect of ethanol consumption on the reactivity of rat carotids to endothelin-1, we found an increase in endothelin-1-induced contraction in this artery with no change in the contraction induced by phenylephrine41,42. Later, Ladipo et al demonstrated that chronic ethanol consumption increased the sensitivity of rat aortic rings to noradrenaline. Pinardi et al found that chronic ethanol consumption significantly enhanced the contractile response induced by phenylephrine of endothelium-intact aortic rings.

Significantly higher systolic pressures were found in Caucasian males who consumed 2 or fewer drinks a day. However, the threshold was found to be at a much lower drinking level than that described in the first Kaiser-Permanente study. In 1915, the French army physician Camille Lian studied approximately 150 French career soldiers (42 and 43 years old), relating their drinking to high blood pressure.

Conversely, iNOS expression in arteries from ethanol-treated rats was significantly increased compared with control tissues. Tirapelli et al demonstrated that chronic ethanol consumption reduced the vascular expression of eNOS in female rats. 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. In 2008, Tirapelli et al reported an increased responsiveness to KCl of arteries from female rats chronically treated with ethanol.

Moreover, chronic ethanol treatment reduced the eNOS-dependent relaxation of cerebral arterioles in rats. The endothelium plays a pivotal role as a sensor, transducer, and integrator of signaling processes regulating vascular homeostasis, and it is known that vascular diseases, including hypertension, are characterized by impaired endothelium-derived NO bioactivity. It is known that SOD activity is modulated by increased ROS generation and by lipid peroxidation83,84. ROS generation by ethanol is important to its pathophysiology in the cardiovascular system, as ethanol is extensively metabolized into acetaldehyde in the liver, mainly by the enzyme alcohol dehydrogenase.

Long-term ethanol consumption significantly reduced acetylcholine-induced relaxation in the aortic rings from rats treated with ethanol for 12 wk and 8 wk. Chronic ethanol consumption produced an increased responsiveness to phenylephrine in aortas, although there was no relationship between the period of treatment (2, 6 and 10 wk) and the magnitude of the enhancement of α1-induced contraction. Moreover, the experiments designed to study the vascular effects of chronic ethanol consumption on α1-induced contraction used only one period of treatment21,28,29. At this point, although it was well established that chronic ethanol consumption enhanced α1-induced contraction, the mechanisms underlying this response were poorly understood. 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. The studies using animal models established a positive correlation between the duration of ethanol consumption and the increase in blood pressure, showing that the period of exposure to ethanol is an important factor in the development of hypertension23,24.