In the last century, numerous epidemiologic studies have found an association between ethanol consumption and arterial hypertension2-6. In ethanol-consuming populations, the amount of ethanol consumed has a significant impact on blood pressure values, the prevalence of hypertension, and cardiovascular and all-cause mortality. The present report reviews the relationship between ethanol intake and hypertension and highlights some mechanisms underlying this response. Possible mechanisms underlying ethanol-induced hypertension were proposed based on clinical and experimental observations. Forty minutes after intraperitoneal injection of ethanol or saline, the rats received a pneumatic piston-induced contusion injury of the left primary motor cortex. While low concentrations of ethanol are described to increase endothelial NO production, the chronic consumption of high doses of ethanol impairs endothelial function in association with reduced NO bioavailability.
ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE
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.
Hypertension and chronic ethanol consumption: What do we know after a century of study?
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.
Appreciating the importance of NO in the maintenance of vascular tone, some studies have examined the mechanisms underlying the impairment of NO-mediated vasodilatation by chronic ethanol consumption. The authors also observed increased phenylephrine-induced contraction and reduced acetylcholine-induced relaxation in aortas from ethanol-treated rats. 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. The extracellular fluid volume was increased in ethanol-treated rats, and the blood pressure significantly correlated with increases in the intracellular Ca2+ concentration. Tirapelli et al described an increased phenylephrine-induced contractility of arteries from ethanol-treated rats.
- Some studies have provided evidence that ethanol consumption increases the intracellular Ca2+ concentration.
- A number of mechanisms have been postulated to explain the pathogenesis of high-dose ethanol toxicity in the vasculature.
- 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.
- 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.
Paradoxical effects of acute ethanolism in experimental brain injury
The influences of life habits on the cardiovascular system may have important implications for public health, as cardiovascular diseases are among the leading causes of shorter life expectancy worldwide.
Myogenic mechanism
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.
Alterations in Ca2+ levels
- The influences of life habits on the cardiovascular system may have important implications for public health, as cardiovascular diseases are among the leading causes of shorter life expectancy worldwide.
- The authors also observed increased phenylephrine-induced contraction and reduced acetylcholine-induced relaxation in aortas from ethanol-treated rats.
- Das and Vasudevan showed that ethanol consumption increased SOD activity and decreased CAT activity in a time- and dose-dependent manner.
- 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.
- Finally, the studies showed that at 3 to 4 drinks per day, the prevalence of hypertension was approximately 50% greater than that in non-drinkers, and at 6 to 7 drinks per day, the prevalence was 100% greater.
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, 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.
ANIMAL MODELS OF ETHANOL-INDUCED HYPERTENSION
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.
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.
Paradoxical effects of acute ethanolism in experimental brain injury
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 difference in diastolic blood pressure between the control and ethanol-fed rats was 5.8 mmHg at 4 wk, and this difference increased to 47 mmHg by 22 wk of ethanol feeding. Strickland and Wooles showed that the systolic and diastolic pressures of ethanol-fed (ethanol 20% v/v) Sprague-Dawley rats became significantly greater at 4 wk and continued to increase throughout the remainder the study. Similarly, Abdel-Rahman et al observed an increase in systolic blood pressure after 12 wk of ethanol feeding (20% v/v) in Wistar and Sprague-Dawley rats. We also discuss studies using animal models of ethanol-induced hypertension, describing the main mechanisms by which ethanol consumption leads to hypertension. In this sense, it was shown that low concentrations of ethanol induced an increased release of endothelial NO due to the activation and expression of NOS98,99. Krecsmarik et al demonstrated that chronic ethanol consumption what is salvia use, effects, risks, and more induced an increase in iNOS activity and a decrease in nNOS expression in the rat gastrointestinal tract.
ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE
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).
