The contribution of ethanol consumption to the prevalence of hypertension is dependent upon the population studied and varies widely in different populations. The second Kaiser-Permanente study described that at 1-2 drinks per day, there was a slight but significant increase in blood pressure. One important finding of this study was that at 1 to 2 drinks per day, there was a slight but significant increase in blood pressure, indicating that the threshold was lower than that reported in the first Kaiser-Permanente study.
ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE
Chronic ethanol consumption in rats increased the contractile response of the aorta and mesenteric arterial bed31-33. Mild hypertension was observed in chronically ethanol-treated rats, which was due to increases in both systolic and diastolic pressures. The baseline systolic, diastolic and mean arterial pressure values of ethanol-treated rats were increased (approximately 20%) after the 3 different periods of treatment. Interestingly, the discontinuation of ethanol treatment for 7 wk did not reverse the hypertension or the adverse renal vascular changes in ethanol-induced hypertensive rats. The rats were given 5% ethanol in their drinking water for 7 wk, and the systolic blood pressure in the ethanol-treated rats was found to be significantly higher than that in the controls after 1 wk or longer25-27. Vasdev et al25-27 described an increase in systolic blood pressure in male Wistar rats after 1 wk of treatment with ethanol.
Paradoxical effects of acute ethanolism in experimental brain injury
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.
Alterations in Ca2+ levels
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.
In this sense, increased ADMA levels could also contribute to the reduced bioavailability of NO in alcoholics. In 2004, Kuhlmann et al reported that high concentrations of ethanol decreased NO synthesis in and proliferation of endothelial cells from human umbilical veins. The expression of eNOS in the thoracic aorta isolated from ethanol-fed rats was down-regulated, leading to a depletion of aortic NO.
ANIMAL MODELS OF ETHANOL-INDUCED HYPERTENSION
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.
Most of these studies reported a significant positive association between hypertension and ethanol consumption. Systolic pressure what’s the difference between ecstasy and molly 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.
Myogenic mechanism
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.
The role of catecholamines in mediating the effects of ethanol on blood pressure has been investigated in humans. A slight increase in blood pressure was found in men reporting as few as 1 to 2 drinks per day in that survey. While several studies have suggested little or no effect of up to 1 or 2 drinks per day on blood pressure2-4,12, others have shown a progressive linear association6,7,13. In fact, the threshold question is controversial, as epidemiologic studies could not resolve the question of a possible threshold for the apparent risk of hypertension.
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 induced an increase in iNOS activity and a decrease in nNOS expression in the rat gastrointestinal tract.
Hypertension and chronic ethanol consumption: What do we know after a century of study?
- 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.
- Together, these responses lead to increased peripheral resistance and therefore to increased blood pressure65,66.
- 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).
- Moreover, chronic ethanol treatment reduced the eNOS-dependent relaxation of cerebral arterioles in rats.
- This action is postulated to result from ethanol-induced inhibition of N-methyl-D-aspartate receptor-mediated excitotoxicity.
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.
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. The change in the threshold values between the two studies was the result of the division of lighter drinkers into several categories in the second study. For example, among Danish men aged years, the differences in blood pressure between those consuming 6 or more drinks per day and those consuming fewer drinks per day were 8 mmHg (systolic) and 4.5 mmHg (diastolic). This study was based on self-administered questionnaires from more than men and women and showed that a threshold of 3 or more drinks per day was a risk factor for hypertension across races and in both sexes.
Oxidative stress is a common mediator of pathogenicity in cardiovascular diseases, such as hypertension56,57. This response may result from a direct effect of ethanol on plasma membrane permeability, Na+ transport and Na+-Ca2+ exchange, and/or impaired Ca2+ transport due to a secondary abnormality, such as Mg2+ depletion, which is described in alcoholics. A number of mechanisms have been postulated to explain the pathogenesis of high-dose ethanol toxicity in the vasculature. The vascular relaxation induced by adrenomedullin in the rat mesenteric arterial bed is endothelium-dependent and involves the activation of the NO-cyclic guanosine monophosphate pathway.
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.
Hypertension and chronic ethanol consumption: What do we know after a century of study?
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.
ETHANOL CONSUMPTION AND HYPERTENSION IN HUMANS (TABLE
- 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.
- 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.
- 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.
- 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.
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.
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.
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.