by 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.
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 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.
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).
Alterations in Ca2+ levels
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.
Hypertension and chronic ethanol consumption: What do we know after a century of study?
Acute ethanol intoxication is a frequent complicating factor what to do if you relapse 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.
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.
ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE
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.
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.
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.
Myogenic mechanism
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.
- 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.
- These effects are complex, and the identification of biochemical/molecular mechanisms that could explain such effects is warranted.
- In the Risk Factor Prevalence Study, ethanol consumption accounted for no more than 1% of hypertension in women.
- Although the link between ethanol consumption and hypertension is well established, the mechanism through which ethanol increases blood pressure remains elusive.
- At this point, although it was well established that chronic ethanol consumption enhanced α1-induced contraction, the mechanisms underlying this response were poorly understood.
- A slight increase in blood pressure was found in men reporting as few as 1 to 2 drinks per day in that survey.
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.
ANIMAL MODELS OF ETHANOL-INDUCED HYPERTENSION
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.
Those findings suggested that regular ethanol consumption predisposes to hypertension by facilitating Ca2+ accumulation in cells involved in blood pressure regulation. 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.
- More recently, we found that chronic ethanol consumption reduced the endothelium-dependent relaxation induced by the peptide adrenomedullin in the rat aorta.
- 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.
- A French epidemiological study estimated that 24% of the prevalence of hypertension in French men could be attributed to ethanol consumption.
- 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.
- It was also suggested that these responses were partly mediated by Mg2+ depletion and suppressed Na+ pump activity.
- 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.
Myogenic mechanism
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.
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.
Paradoxical effects of acute ethanolism in experimental brain injury
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 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.
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.
