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World J Cardiol. May 26, 2014; 6(5): 245-252
Published online May 26, 2014. doi: 10.4330/wjc.v6.i5.245
Alcohol-induced hypertension: Mechanism and prevention
Kazim Husain, Rais A Ansari, Leon Ferder
Kazim Husain, Leon Ferder, Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine and Health Sciences, Ponce, PR 00732, United States
Rais A Ansari, Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, United States
Author contributions: Husain K designed, performed the research and wrote the review article; Ansari RA contributed the new tools for writing the review article; Ferder L contributed the guidance and suggestions for writing the review article.
Correspondence to: Kazim Husain, PhD, DABT, Professor, Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine and Health Sciences, PO Box 7004, Ponce, PR 00732, United States. khusain@psm.edu
Telephone: +1-787-8402575 Fax: +1-787-8413736
Received: December 28, 2013
Revised: February 16, 2014
Accepted: April 16, 2014
Published online: May 26, 2014

Abstract

Epidemiological, preclinical and clinical studies established the association between high alcohol consumption and hypertension. However the mechanism through which alcohol raises blood pressure remains elusive. Several possible mechanisms have been proposed such as an imbalance of the central nervous system, impairment of the baroreceptors, enhanced sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased cortisol levels, increased vascular reactivity due to increase in intracellular calcium levels, stimulation of the endothelium to release vasoconstrictors and loss of relaxation due to inflammation and oxidative injury of the endothelium leading to inhibition of endothelium-dependent nitric oxide production. Loss of relaxation due to inflammation and oxidative injury of the endothelium by angiotensin II leading to inhibition of endothelium-dependent nitric oxide production is the major contributors of the alcohol-induced hypertension. For the prevention of alcohol-induced hypertension is to reduce the amount of alcohol intake. Physical conditioning/exercise training is one of the most important strategies to prevent/treat chronic alcohol-induced hypertension on physiological basis. The efficacious pharmacologic treatment includes the angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs) which have antioxidant activity and calcium channel blockers. The most effective prevention and treatment of alcohol-induced hypertension is physical exercise and the use of ACE inhibitors or ARBs in the clinic

Key Words: Alcohol, Hypertension, Mechanisms, Prevention/treatment, Vascular endothelium

Core tip: This is a comprehensive review of the current mechanisms of alcohol-induced hypertension and strategies for prevention and treatment of alcohol-related hypertension. This updated review will be imperative to basic scientist in the area of cardiovascular physiology/pharmacology and clinicians in the academic, industry as well as clinics and hospitals.



INTRODUCTION

Alcohol (ethyl alcohol or ethanol, C2H5OH) from fermented grain, fruit juice and honey have been used for thousands of years. Fermented beverages existed and alcoholic drinks used in early Egyptian civilization, in China around 7000 BC, in India, between 3000 and 2000 BC, in Babylon as early as 2700 BC, in Greece, and in South America[1]. In the sixteenth century, alcohol (called “spirits”) was used largely for medicinal purposes[2]. At the beginning and mid of the eighteenth century, spirits was used heavily in Britain. The nineteenth century brought a change in attitudes and the temperance movement began promoting the moderate use of alcohol. In 1920 the United States passed a law prohibiting the manufacture, sale, import and export of intoxicating liquors. Current research suggests that the moderate consumption of alcohol is beneficial to the cardiovascular system and lowers the blood pressure[3-5]. A preclinical study also showed a decrease in systolic blood pressure in rats fed ethanol (1.0 g/kg) for 12 wk[6]. Moderate drinking is generally considered to be: Two drinks a day for men younger than age 65, one drink a day for men age 65 and older and one drink a day for women of any age. A drink is 12 ounces (355 milliliters) of beer, 5 ounces (148 milliliters) of wine or 1.5 ounces (44 milliliters) of 80-proof distilled spirits. Low to moderate drinking has been shown to reduce the incidence of coronary heart disease[3-5] and to increase longevity. It has clearly been a major analgesic, and one widely available to people in pain[1,2,7].

Today, alcoholic beverages are consumed regularly by most of the human societies in the world. However its abuse is a major public health problem in the world. In United States alcohol abuse affects more than 20 million individuals leading to loss of 100000 lives annually[8,9].Chronic high dose ethanol consumption most commonly causes hepatic, gastrointestinal, nervous and cardiovascular injuries leading to physiological dysfunctions[10]. A cause and effect relationship between regular alcohol consumption and blood pressure elevation (hypertension) was first suggested in 1915 by Lian et al[11]. Recent epidemiological and clinical studies have demonstrated that chronic ethanol consumption (more than three drinks per day, 30 g ethanol) is associated with an increased incidence of hypertension and an increased risk of cardiovascular diseases[12-17]. The magnitude of the increase in blood pressure in heavy drinkers averages about 5 to 10 mmHg, with systolic increases nearly always greater than diastolic increases[18]. Similar changes in blood pressure were also reported in preclinical studies[19-22]. In the Framingham cohort[23,24], there was an increase of 7 mmHg in mean arterial pressure when heavy alcohol users were compared with all others. In some epidemiological studies a linear dose-response relationship has been established, sometimes starting with a consumption threshold of 3 drinks per day (30 g of ethanol)[25-33]. In others, the relationship has been nonlinear, especially in women, and some authors have speculated that ingestion of smaller quantities of alcohol may reduce blood pressure[34-38]. Only a few studies have addressed the relationship between alcohol and hypertension in the elderly, and most of them have shown a strong association between hypertension prevalence and alcohol intake[39,40]. However preclinical studies have also shown a linear relationship between blood pressure and ingestion of alcohol[6]. The molecular mechanisms and possible mediators through which alcohol causes vascular injury and raises blood pressure remain elusive. This review focuses the mechanisms implicated with alcohol-induced hypertension and the strategies to control, prevent or to treat alcohol-induced elevation of blood pressure.

MECHANISMS OF ALCOHOL-INDUCED HYPERTENSION

There are several possible mechanisms through which alcohol can raise the blood pressure as shown in Figure 1.

Figure 1
Figure 1 Mechanisms of alcohol-induced hypertension. CNS: Central nervous system; SNS: Sympathetic nervous system; RASAS: Renin-angiotensin system and aldosterone system.
Central nervous system in alcohol-induced hypertension

The World hypertension League speculated that the relatively greater effect alcohol on systolic blood pressure compared with diastolic blood pressure may indicate an imbalance between central nervous system factors influencing cardiac output and the peripheral vascular effects of alcohol[41,42]. There is increasing evidence that alcohol initiates central as well as peripheral reactions which in a synergistic manner have a hypertensive action. In addition, alcohol induces an increased sympathetic outflow, most probably linked to secretion of corticotropin-releasing hormone[43]. Some investigators have suggested that the association between alcohol and hypertension is related to the temporal sequence of alcohol use and blood pressure measurement[24,44]. Since many community programs require an overnight or twelve-hour fasting period, alcohol withdrawal, albeit subclinical, may be occurring. Similarly, patients may abstain or diminish alcohol intake before visiting a clinic or physician. Thus, the observed elevations in blood pressure could be due to excessive central-nervous-system excitability and adrenergic discharge associated with the withdrawal period.

Baroreceptors in alcohol-induced hypertension

Alcohol diminishes the baro (presso) reflex by interacting with receptors in the brain stem, i.e. nucleus tractus solitarii and rostral ventrolateral medulla[43]. Other investigators reported that baroreceptor reflex curves, which indicate the gain in baroreceptor reflex sensitivity, were shifted up and reduced slope in ethanol fed rats when challenged with vasoconstrictors (phenylephrine and angiotensin II) compared with controls[45]. This findings and others[42,46,47] suggest the impairment of baroreceptor control and sympathetic system. A greater decrease in heart rate in ethanol treated rats compared with control rats during β-adrenoreceptor blockade with propranolol indicates that the ethanol treated rats had an increased sympathetic activity. An increase in sympathetic activity is consistent with impairment of the baroreceptors that, when activated, inhibit the sympathetic nervous system[45,47]. However this mechanism is implicated more likely in acute alcohol-induced hypertension.

Sympathetic nervous system in alcohol-induced hypertension

Several studies reported increased sympathetic nervous system activation and discharge of sympathetic amines after alcohol consumption[43,48,49]. Alcohol may cause hypertension by affecting the autonomic nervous system[50]. However, alterations in the sympatho-adrenal function that occur during ageing may cause older people to have a different reaction to factors triggering their autonomic system than do younger individuals[51]. The increased sympathetic outflow is expected not only to induce adrenoreceptor-mediated reactions (vasoconstriction, heart rate increase) but to stimulate oxidation reactions[43]. Direct recordings of sympathetic-nerve activity suggest that short-term alcohol ingestion in humans and both short and long-term administration of ethanol in rats stimulates sympathetic-nerve discharge[47,49,50]. Moreover, in rats the alcohol-induced increases in blood pressure and sympathetic activity is centrally mediated[47]. It is possible that alcohol may stimulate adrenals to release adrenaline, resulting in increased heart rate cardiac output and systolic blood pressure[52]. Randin et al[53] have also reported that alcohol induces hypertension in rats by sympathetic activation that appears to be centrally mediated. This mechanism is also likely being implicated in alcohol-induced hypertension.

Renin-angiotensin-aldosterone system in alcohol-induced hypertension

The serum levels of vasoactive substances such as renin-aldosterone have been reported to be affected by alcohol ingestion in vivo or ethanol in vitro[54-56]. Antihypertensive drugs are shown to offer protection against alcohol induced responses in cultured human endothelial cells suggesting the possible involvement of renin-angiotensin system (RAS)[56]. It has been reported that a significant increase in plasma renin activity in patients consuming heavy alcohol compared to mild or moderate alcohol consumption[55,57,58]. However other reports showed no significant in plasma renin activity after alcohol consumption[48,59]. Other studies reported an expansion of the extracellular fluid after alcohol consumption which has been shown to elevate the systolic blood pressure in rats[60,61]. Chan et al[60] have proposed that expansion of the extracellular fluid is the result of elevated plasma vasopressin levels and plasma renin activity, indicating increased sympathetic stimulation. Recent studies have shown a significant increased in blood and aortic angiotensin II levels after alcohol ingestion in rats[62,63]. Okuno et al[64] have reported prolonged elevation of serum angiotensin converting enzyme (ACE) activity in alcoholics suggests that angiotensin II levels are elevated due to activation of ACE activity. Alcohol ingestion in dogs caused sustained RAS activation with progressive increases in plasma levels of Angiotensin II, renin activity, left ventricular ACE enzyme activity, and left ventricular myocyte Ang II AT1 receptor expression[65]. This mechanism is more likely implicated in alcohol-induced hypertension.

Cortisol in alcohol-induced hypertension

Certain studies have implicated the role of cortisol in alcohol-induced rise in blood pressure[66-68]. Potter et al[66] have reported a significant rise in plasma cortisol levels following alcohol consumption and a drop in plasma cortisol levels when alcohol intake was discontinued. Increased cortisol levels in regular alcohol drinkers may be due to direct stimulation of adrenocorticotropin hormone or potentiation of corticotropin releasing hormones by arginine vasopressin[67]. The effect of blood pressure may be due to the mineralocorticoid activity of cortisol or catecholamine hypersensitivity[68]. Alcohol stimulates the secretion of corticotrophin releasing hormone in rats[69,70] leading to stimulation of cortisol secretion[71], sympathetic stimulation and hypertension in rats. However this mechanism is implicated more likely in acute alcohol-induced hypertension.

Increased intracellular calcium and vascular reactivity in alcohol-induced hypertension

Rats treated with ethanol showed constriction of blood vessels[72] due to greater shifts in the binding of the calcium ion (Ca2+) in arterial and arteriolar smooth muscle cells causes increased sensitivity to endogenous vasoconstrictors. This finding is consistent with other reports showing the shifts of the extracellular Ca2+ to intracellular space increase the vascular sensitivity to vasoconstrictor norepinephrine[50,61]. It is proposed that alcohol increases intracellular Ca2+ by (1) direct upregulation of voltage-gated Ca2+ channels; (2) inhibition of Ca2+-adenosine triphosphatase (Ca2+-ATPase) that extrudes Ca2+ from the cells; and (3) magnesium ion (Mg2+) depletion that inhibits the sodium ion (Na+)-potassium ion (K+) pump (Na+/K+-ATPase), causing a build up of intracellular Na+ . This reaction in turn inhibits the Na+/Ca2+ exchanger, thereby increasing the intracellular calcium ion[50,61,72,73]. Chronic alcohol ingestion has been reported to induce a deficiency of blood and intracellular magnesium, which influences cellular Ca2+ homeostasis through attenuation of plasmalemmal ATPase activity[74]. Vasdev et al[75] have shown that increases in cytosolic free calcium and calcium uptake are associated with ethanol-induced hypertension in rats. Intra-arterial infusion of ethanol has been shown to reduce hand and forearm blood flow in humans[76]. This effect could be the result of a direct vasoconstriction or of a loss of endothelium dependent vasorelaxation[77]. However earlier studies in rats demonstrated no significant response of alpha-adrenergic receptor-mediated constriction of aorta after chronic ethanol ingestion in rats[45,78-80]. On the other hand, the endothelium-dependent relaxation elicited by acetylcholine was diminished in chronic alcohol-induced hypertension[77]. Our earlier study also demonstrated the role of endothelium-independent responses in the aorta of chronic alcohol treated hypertensive rats[79,80]. Inconsistencies among several reports render this mechanism of alcohol-induced hypertension less implicated.

Endothelium and oxidative stress in alcohol-induced hypertension

Imbalance of specific endogenous vasoconstrictor such as angiotensin II, endothelin-1 and nor-epinephrine and vasodilator nitric oxide (NO) may also play an important role in alcohol-induced hypertension. Alcohol stimulates the release of endothelin 1 and 2 from vascular endothelium in a dose dependent manner[81]. Alcohol also increases the angiotensin II levels in the blood and vessels[62,63]. Endothelin 1 and 2 as well as angiotensin II are known to be potent vasoconstrictors of the blood vessels[63,81]. Angiotensin II stimulates superoxide production via AT1 receptor, by activating NADPH oxidase in the vascular wall[82,83]. Superoxide productions through NADPH oxidase activation (p22phox expression) has been demonstrated in rats made hypertensive with angiotensin II infusion[84]. Chronic ethanol ingestion induces hypertension which is correlated with elevated tissue angiotensin II levels, and activation of NADPH oxidase activity causing endothelial injury in rats[62,79,80]. It is possible that alcohol ingestion raises the blood pressure by decreasing the vasodilators such as NO in the vascular endothelium either due to inhibition of endothelial nitric oxide synthase (eNOS) or inflammatory/oxidative injury to the endothelium. Earlier studies have also shown that chronic ethanol consumption either interferes with NO production or release of NO from endothelial cells[80,85-87]. The diminished NO bioavailability may either be related to reaction with superoxide anion to form peroxynitrite radicals[88] or oxidative inactivation/uncoupling of eNOS by ethanol-induced free radicals[80,89,90]. The production of NO in the endothelium is critically dependent on the function of eNOS which is regulated by vascular endothelial growth factor[91,92]. Alcohol inhibits the enzyme that converts arginine into NO[93] as well as eNOS protein expression[80]. In the endothelium, depletion of NO production or NO reaction with superoxide anion to form toxic peroxynitrite radical which causes endothelial injury, impairment and hypertension in alcohol treated rats[20-22,62,80,94]. Recent studies have shown that chronic ethanol ingestion induces hypertension which was related to increased aortic inflammation, elevated angiotensin II levels, induction of NADPH oxidase causing endothelial injury, depletion of antioxidants, down-regulation of endothelial NO generating system and impaired vascular relaxation in rats[6,19-22,62,80]. This mechanism is most likely implicated in chronic alcohol-induced hypertension.

PREVENTION AND TREATMENT OF ALCOHOL-INDUCED HYPERTENSION

There are few strategies for the control, prevention and treatment of alcohol-induced hypertension as shown in Figure 2.

Figure 2
Figure 2 Prevention and treatment of alcohol-induced hypertension. ACEi/ARBs: Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers;

Studies have shown that a reduction in alcohol intake is effective in lowering the blood pressure both in hypertensives and normotensives and may help to prevent the development of hypertension[12,41,95,96]. Heavy drinkers who cut back to moderate drinking can lower their systolic blood pressure by 2 to 4 mm of mercury (mm Hg) and their diastolic blood pressure by 1 to 2 mmHg. Heavy drinkers who want to lower blood pressure should slowly reduce how much they drink over one to two weeks.

Another non-pharmacological prevention and treatment of alcohol-induced hypertension is physical conditioning or exercise training. There is a physiological basis for effect of physical conditioning on chronic alcohol-induced hypertension in a rat model. Exercise increases the utilization of oxygen in the body and up-regulate the antioxidant defense system in the cardiovascular system[97-100]. Exercise training also generates NO in the cardiovascular system by induction of nitric oxide synthase[19,79,90,101]. Recent studies have shown the beneficial role of physical training in the control of blood pressure in humans[97,98,102,103] and experimental animals[79,90,104,105]. Physical inactivity and overweight trigger hypertension[106,107] whereas; regular physical activity has been shown to decrease the BP and body weight[102,103]. Studies have shown that physical conditioning is beneficial in lowering the BP through suppression of weight gain in chronic ethanol treated hypertensive rats[19,79]. Physical conditioning attenuates the chronic ethanol-induced hypertension by augmenting the NO bioavailability and reducing the oxidative stress response in rats[19,79,108].

PHARMACOLOGICAL TREATMENT OF ALCOHOL-INDUCED HYPERTENSION

There are no definite clinical data available on the efficacy of specific drugs in the treatment of alcohol-induced hypertension. Randin et al[53] have reported that dexamethasone (2 mg per day) in human suppresses the acute alcohol-induced hypertension. It is suggested that ACE inhibitors/angiotensin II receptor type 1 (AT1) blockers, because of their ability to increase the cardiac output in patients with alcohol-induced cardiomyopathy will be useful in the treatment of alcohol-induced hypertension. Cheng et al[65] have shown that angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy in dogs. The calcium channel blockers, because of the probability of the involvement of calcium in the development of alcohol-induced hypertension, may also likely be the drug of choice for the treatment of alcohol-induced hypertension.

Footnotes

P- Reviewers: Cheng TH, Wong M, Zhao D S- Editor: Gou SX L- Editor: A E- Editor: Wu HL

References
1.  McGovern PE Ancient Wine: The Search for the Origins of Viniculture. Princeton: Princeton University Press 2003; 314-315.  [PubMed]  [DOI]
2.  Dietler M. Alcohol: Archaeological/Anthropological Perspectives. Ann Rev Anthropol. 2006;35:229-249.  [PubMed]  [DOI]
3.  Worm N, Belz GG, Stein-Hammer C. Moderate wine consumption and prevention of coronary heart disease. Dtsch Med Wochenschr. 2013;138:2653-2657.  [PubMed]  [DOI]
4.  Bos S, Grobbee DE, Boer JM, Verschuren WM, Beulens JW. Alcohol consumption and risk of cardiovascular disease among hypertensive women. Eur J Cardiovasc Prev Rehabil. 2010;17:119-126.  [PubMed]  [DOI]
5.  Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits. BMJ. 1996;312:731-736.  [PubMed]  [DOI]
6.  Husain K, Mejia J, Lalla J, Kazim S. Dose response of alcohol-induced changes in BP, nitric oxide and antioxidants in rat plasma. Pharmacol Res. 2005;51:337-343.  [PubMed]  [DOI]
7.  Hanson DJ Preventing Alcohol Abuse: Alcohol, Culture and Control. Westport, CT: Praeger 1995; .  [PubMed]  [DOI]
8.  Li TK, Hewitt BG, Grant BF. Alcohol use disorders and mood disorders: a National Institute on Alcohol Abuse and Alcoholism perspective. Biol Psychiatry. 2004;56:718-720.  [PubMed]  [DOI]
9.  McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270:2207-2212.  [PubMed]  [DOI]
10.  Lieber CS. Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment. J Stud Alcohol. 1998;59:9-25.  [PubMed]  [DOI]
11.  Lian C. L'alcoholisme, cause d'hypertension arterielle. Bulletin de l'Academie de Medicine. 1915;74:525-528.  [PubMed]  [DOI]
12.  Skliros EA, Papadodima SA, Sotiropoulos A, Xipnitos C, Kollias A, Spiliopoulou CA. Relationship between alcohol consumption and control of hypertension among elderly Greeks. The Nemea primary care study. Hellenic J Cardiol. 2012;53:26-32.  [PubMed]  [DOI]
13.  Sesso HD, Cook NR, Buring JE, Manson JE, Gaziano JM. Alcohol consumption and the risk of hypertension in women and men. Hypertension. 2008;51:1080-1087.  [PubMed]  [DOI]
14.  Beilin LJ, Puddey IB. Alcohol and hypertension: an update. Hypertension. 2006;47:1035-1038.  [PubMed]  [DOI]
15.  Estruch R, Coca A, Rodicio JL. High blood pressure, alcohol and cardiovascular risk. J Hypertens. 2005;23:226-229.  [PubMed]  [DOI]
16.  Klatsky AL. Alcohol-associated hypertension: when one drinks makes a difference. Hypertension. 2004;44:805-806.  [PubMed]  [DOI]
17.  Kaplan NM. Alcohol and hypertension. Lancet. 1995;345:1588-1589.  [PubMed]  [DOI]
18.  Clark LT. Alcohol-induced hypertension: mechanisms, complications, and clinical implications. J Natl Med Assoc. 1985;77:385-389.  [PubMed]  [DOI]
19.  Husain K, Mejia J, Lalla J. Physiological basis for effect of physical conditioning on chronic ethanol-induced hypertension in a rat model. Mol Cell Biochem. 2006;289:175-183.  [PubMed]  [DOI]
20.  Husain K, Vazquez-Ortiz M, Lalla J. Down-regulation of ventricular nitric oxide generating system in chronic alcohol-treated hypertensive rats. Cell Mol Biol (Noisy-le-grand). 2007;53:32-37.  [PubMed]  [DOI]
21.  Husain K. Vascular endothelial oxidative stress in alcohol-induced hypertension. Cell Mol Biol (Noisy-le-grand). 2007;53:70-77.  [PubMed]  [DOI]
22.  Husain K, Vazquez-Ortiz M, Lalla J. Down regulation of aortic nitric oxide and antioxidant systems in chronic alcohol-induced hypertension in rats. Hum Exp Toxicol. 2007;26:427-434.  [PubMed]  [DOI]
23.  Gordon T, Kannel WB. Drinking and its relation to smoking, BP, blood lipids, and uric acid. The Framingham study. Arch Intern Med. 1983;143:1366-1374.  [PubMed]  [DOI]
24.  MacMahon S. Alcohol consumption and hypertension. Hypertension. 1987;9:111-121.  [PubMed]  [DOI]
25.  Moreira LB, Fuchs FD, Moraes RS, Bredemeier M, Duncan BB. Alcohol intake and blood pressure: the importance of time elapsed since last drink. J Hypertens. 1998;16:175-180.  [PubMed]  [DOI]
26.  Klag MJ, He J, Whelton PK, Chen JY, Qian MC, He GQ. Alcohol use and blood pressure in an unacculturated society. Hypertension. 1993;22:365-370.  [PubMed]  [DOI]
27.  Keil U, Chambless L, Filipiak B, Härtel U. Alcohol and blood pressure and its interaction with smoking and other behavioural variables: results from the MONICA Augsburg Survey 1984-1985. J Hypertens. 1991;9:491-498.  [PubMed]  [DOI]
28.  Dyer AR, Cutter GR, Liu KQ, Armstrong MA, Friedman GD, Hughes GH, Dolce JJ, Raczynski J, Burke G, Manolio T. Alcohol intake and blood pressure in young adults: the CARDIA Study. J Clin Epidemiol. 1990;43:1-13.  [PubMed]  [DOI]
29.  Lang T, Degoulet P, Aime F, Devries C, Jacquinet-Salord MC, Fouriaud C. Relationship between alcohol consumption and hypertension prevalence and control in a French population. J Chronic Dis. 1987;40:713-720.  [PubMed]  [DOI]
30.  Trevisan M, Krogh V, Farinaro E, Panico S, Mancini M. Alcohol consumption, drinking pattern and blood pressure: analysis of data from the Italian National Research Council Study. Int J Epidemiol. 1987;16:520-527.  [PubMed]  [DOI]
31.  Klatsky AL, Friedman GD, Armstrong MA. The relationships between alcoholic beverage use and other traits to blood pressure: a new Kaiser Permanente study. Circulation. 1986;73:628-636.  [PubMed]  [DOI]
32.  MacMahon SW, Blacket RB, Macdonald GJ, Hall W. Obesity, alcohol consumption and blood pressure in Australian men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. J Hypertens. 1984;2:85-91.  [PubMed]  [DOI]
33.  Fortmann SP, Haskell WL, Vranizan K, Brown BW, Farquhar JW. The association of blood pressure and dietary alcohol: differences by age, sex, and estrogen use. Am J Epidemiol. 1983;118:497-507.  [PubMed]  [DOI]
34.  Okubo Y, Suwazono Y, Kobayashi E, Nogawa K. Alcohol consumption and blood pressure change: 5-year follow-up study of the association in normotensive workers. J Hum Hypertens. 2001;15:367-372.  [PubMed]  [DOI]
35.  Gillman MW, Cook NR, Evans DA, Rosner B, Hennekens CH. Relationship of alcohol intake with blood pressure in young adults. Hypertension. 1995;25:1106-1110.  [PubMed]  [DOI]
36.  Maheswaran R, Gill JS, Davies P, Beevers DG. High blood pressure due to alcohol. A rapidly reversible effect. Hypertension. 1991;17:787-792.  [PubMed]  [DOI]
37.  Jackson R, Stewart A, Beaglehole R, Scragg R. Alcohol consumption and blood pressure. Am J Epidemiol. 1985;122:1037-1044.  [PubMed]  [DOI]
38.  Harburg E, Ozgoren F, Hawthorne VM, Schork MA. Community norms of alcohol usage and blood pressure: Tecumseh, Michigan. Am J Public Health. 1980;70:813-820.  [PubMed]  [DOI]
39.  Burke V, Beilin LJ, German R, Grosskopf S, Ritchie J, Puddey IB, Rogers P. Association of lifestyle and personality characteristics with blood pressure and hypertension: a cross-sectional study in the elderly. J Clin Epidemiol. 1992;45:1061-1070.  [PubMed]  [DOI]
40.  MacMahon SW, Norton RN. Alcohol and hypertension: implications for prevention and treatment. Ann Intern Med. 1986;105:124-126.  [PubMed]  [DOI]
41.  Alcohol and hypertension--implications for management. A consensus statement by the World Hypertension League. J Hum Hypertens. 1991;5:227-232.  [PubMed]  [DOI]
42.  Howes LG, Reid JL. The effects of alcohol on local, neural and humoral cardiovascular regulation. Clin Sci (Lond). 1986;71:9-15.  [PubMed]  [DOI]
43.  Rupp H, Brilla CG, Maisch B. Hypertension and alcohol: central and peripheral mechanisms. Herz. 1996;21:258-264.  [PubMed]  [DOI]
44.  Fuchs FD, Chambless LE, Whelton PK, Nieto FJ, Heiss G. Alcohol consumption and the incidence of hypertension: The Atherosclerosis Risk in Communities Study. Hypertension. 2001;37:1242-1250.  [PubMed]  [DOI]
45.  Abdel-Rahman AA, Wooles WR. Ethanol-induced hypertension involves impairment of baroreceptors. Hypertension. 1987;10:67-73.  [PubMed]  [DOI]
46.  Grassi G. Sympathetic and baroreflex function in hypertension: implications for current and new drugs. Curr Pharm Des. 2004;10:3579-3589.  [PubMed]  [DOI]
47.  Zhang X, Abdel-Rahman AA, Wooles WR. Impairment of baroreceptor reflex control of heart rate but not sympathetic efferent discharge by central neuroadministration of ethanol. Hypertension. 1989;14:282-292.  [PubMed]  [DOI]
48.  Arkwright PD, Beilin LJ, Vandongen R, Rouse IA, Lalor C. The pressor effect of moderate alcohol consumption in man: a search for mechanisms. Circulation. 1982;66:515-519.  [PubMed]  [DOI]
49.  Russ R, Abdel-Rahman AR, Wooles WR. Role of the sympathetic nervous system in ethanol-induced hypertension in rats. Alcohol. 1991;8:301-307.  [PubMed]  [DOI]
50.  Grassi GM, Somers VK, Renk WS, Abboud FM, Mark AL. Effects of alcohol intake on blood pressure and sympathetic nerve activity in normotensive humans: a preliminary report. J Hypertens Suppl. 1989;7:S20-S21.  [PubMed]  [DOI]
51.  Seals DR, Esler MD. Human ageing and the sympathoadrenal system. J Physiol. 2000;528:407-417.  [PubMed]  [DOI]
52.  Ireland MA, Vandongen R, Davidson L, Beilin LJ, Rouse IL. Acute effects of moderate alcohol consumption on blood pressure and plasma catecholamines. Clin Sci (Lond). 1984;66:643-648.  [PubMed]  [DOI]
53.  Randin D, Vollenweider P, Tappy L, Jéquier E, Nicod P, Scherrer U. Suppression of alcohol-induced hypertension by dexamethasone. N Engl J Med. 1995;332:1733-1737.  [PubMed]  [DOI]
54.  Jing L, Li WM, Zhou LJ, Li S, Kou JJ, Song J. Expression of renin-angiotensin system and peroxisome proliferator-activated receptors in alcoholic cardiomyopathy. Alcohol Clin Exp Res. 2008;32:1999-2007.  [PubMed]  [DOI]
55.  Ibsen H, Christensen NJ, Rasmussen S, Hollnagel H, Damkjaer Nielsen M, Giese J. The influence of chronic high alcohol intake on blood pressure, plasma noradrenaline concentration and plasma renin concentration. Clin Sci (Lond). 1981;61 Suppl 7:377s-379s.  [PubMed]  [DOI]
56.  Soardo G, Donnini D, Moretti M, Milocco C, Catena C, Sechi LA. Effects of antihypertensive drugs on alcohol-induced functional responses of cultured human endothelial cells. Hypertens Res. 2008;31:345-351.  [PubMed]  [DOI]
57.  Puddey IB, Vandongen R, Beilin LJ, Rouse IL. Alcohol stimulation of renin release in man: its relation to the hemodynamic, electrolyte, and sympatho-adrenal responses to drinking. J Clin Endocrinol Metab. 1985;61:37-42.  [PubMed]  [DOI]
58.  Nieminen MM. Renin-aldosterone axis in ethanol intoxication during sodium and fluid repletion versus depletion. Int J Clin Pharmacol Ther Toxicol. 1983;21:552-557.  [PubMed]  [DOI]
59.  Potter JF, Beevers DG. Pressor effect of alcohol in hypertension. Lancet. 1984;1:119-122.  [PubMed]  [DOI]
60.  Chan TC, Sutter MC. Ethanol consumption and blood pressure. Life Sci. 1983;33:1965-1973.  [PubMed]  [DOI]
61.  Hussa RO. Immunologic and physical characterization of human chorionic gonadotropin and its subunits in cultures of human malignant trophoblast. J Clin Endocrinol Metab. 1977;44:1154-1162.  [PubMed]  [DOI]
62.  Husain K, Vazquez M, Ansari RA, Malafa MP, Lalla J. Chronic alcohol-induced oxidative endothelial injury relates to angiotensin II levels in the rat. Mol Cell Biochem. 2008;307:51-58.  [PubMed]  [DOI]
63.  Wright JW, Morseth SL, Abhold RH, Harding JW. Elevations in plasma angiotensin II with prolonged ethanol treatment in rats. Pharmacol Biochem Behav. 1986;24:813-818.  [PubMed]  [DOI]
64.  Okuno F, Arai M, Ishii H, Shigeta Y, Ebihara Y, Takagi S, Tsuchiya M. Mild but prolonged elevation of serum angiotensin converting enzyme (ACE) activity in alcoholics. Alcohol. 1986;3:357-359.  [PubMed]  [DOI]
65.  Cheng CP, Cheng HJ, Cunningham C, Shihabi ZK, Sane DC, Wannenburg T, Little WC. Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy. Circulation. 2006;114:226-236.  [PubMed]  [DOI]
66.  Potter JF, Watson RD, Skan W, Beevers DG. The pressor and metabolic effects of alcohol in normotensive subjects. Hypertension. 1986;8:625-631.  [PubMed]  [DOI]
67.  Yates FE, Russell SM, Dallman MF, Hodge GA, McCann SM, Dhariwal AP. Potentiation by vasopressin of corticotropin release induced by corticotropin-releasing factor. Endocrinology. 1971;88:3-15.  [PubMed]  [DOI]
68.  Bannan LT, Potter JF, Beevers DG, Saunders JB, Walters JR, Ingram MC. Effect of alcohol withdrawal on blood pressure, plasma renin activity, aldosterone, cortisol and dopamine beta-hydroxylase. Clin Sci (Lond). 1984;66:659-663.  [PubMed]  [DOI]
69.  Rivier C, Bruhn T, Vale W. Effect of ethanol on the hypothalamic-pituitary-adrenal axis in the rat: role of corticotropin-releasing factor (CRF). J Pharmacol Exp Ther. 1984;229:127-131.  [PubMed]  [DOI]
70.  Rivier C, Imaki T, Vale W. Prolonged exposure to alcohol: effect on CRF mRNA levels, and CRF- and stress-induced ACTH secretion in the rat. Brain Res. 1990;520:1-5.  [PubMed]  [DOI]
71.  Jenkins JS, Connolly J. Adrenocortical response to ethanol in man. Br Med J. 1968;2:804-805.  [PubMed]  [DOI]
72.  Altura BM, Altura BT. Microvascular and vascular smooth muscle actions of ethanol, acetaldehyde, and acetate. Fed Proc. 1982;41:2447-2451.  [PubMed]  [DOI]
73.  Altura BM, Altura BT. Role of magnesium and calcium in alcohol-induced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR, spectroscopy and a unique magnesium ion-selective electrode. Alcohol Clin Exp Res. 1994;18:1057-1068.  [PubMed]  [DOI]
74.  Wakabayashi I, Hatake K, Hishida S. Ethanol inhibits intra- and extracellular Ca(2+)-dependent contraction of rat aorta by different mechanisms. Nihon Arukoru Yakubutsu Igakkai Zasshi. 1998;33:273-286.  [PubMed]  [DOI]
75.  Vasdev S, Sampson CA, Prabhakaran VM. Platelet-free calcium and vascular calcium uptake in ethanol-induced hypertensive rats. Hypertension. 1991;18:116-122.  [PubMed]  [DOI]
76.  Fewings JD, Hanna MJ, Walsh JA, Whelan RF. The effects of ethyl alcohol on the blood vessels of the hand and forearm in man. Br J Pharmacol Chemother. 1966;27:93-106.  [PubMed]  [DOI]
77.  Criscione L, Powell JR, Burdet R, Engesser S, Schlager F, Schoepfer A. Alcohol suppresses endothelium-dependent relaxation in rat mesenteric vascular beds. Hypertension. 1989;13:964-967.  [PubMed]  [DOI]
78.  Williams SP, Adams RD, Mustafa SJ. The effects of chronic ethanol treatment on endothelium-dependent responses in rat thoracic aorta. Alcohol. 1990;7:121-127.  [PubMed]  [DOI]
79.  Husain K, Vazquez Ortiz M, Lalla J. Physical training ameliorates chronic alcohol-induced hypertension and aortic reactivity in rats. Alcohol Alcohol. 2006;41:247-253.  [PubMed]  [DOI]
80.  Husain K, Ferder L, Ansari RA, Lalla J. Chronic ethanol ingestion induces aortic inflammation/oxidative endothelial injury and hypertension in rats. Hum Exp Toxicol. 2011;30:930-939.  [PubMed]  [DOI]
81.  Tsuji S, Kawano S, Michida T, Masuda E, Nagano K, Takei Y, Fusamoto H, Kamada T. Ethanol stimulates immunoreactive endothelin-1 and -2 release from cultured human umbilical vein endothelial cells. Alcohol Clin Exp Res. 1992;16:347-349.  [PubMed]  [DOI]
82.  Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000;86:494-501.  [PubMed]  [DOI]
83.  Fukui T, Ishizaka N, Rajagopalan S, Laursen JB, Capers Q, Taylor WR, Harrison DG, de Leon H, Wilcox JN, Griendling KK. p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res. 1997;80:45-51.  [PubMed]  [DOI]
84.  van der Zee R, Murohara T, Luo Z, Zollmann F, Passeri J, Lekutat C, Isner JM. Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation. 1997;95:1030-1037.  [PubMed]  [DOI]
85.  Pinardi G, Brieva C, Vinet R, Penna M. Effects of chronic ethanol consumption on alpha-adrenergic-induced contractions in rat thoracic aorta. Gen Pharmacol. 1992;23:245-248.  [PubMed]  [DOI]
86.  Puddey IB, Zilkens RR, Croft KD, Beilin LJ. Alcohol and endothelial function: a brief review. Clin Exp Pharmacol Physiol. 2001;28:1020-1024.  [PubMed]  [DOI]
87.  Slomiany BL, Piotrowski J, Slomiany A. Alterations in buccal mucosal endothelin-1 and nitric oxide synthase with chronic alcohol ingestion. Biochem Mol Biol Int. 1998;45:681-688.  [PubMed]  [DOI]
88.  Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990;87:1620-1624.  [PubMed]  [DOI]
89.  Johnson RA, Freeman RH. Sustained hypertension in the rat induced by chronic blockade of nitric oxide production. Am J Hypertens. 1992;5:919-922.  [PubMed]  [DOI]
90.  Husain K. Physical conditioning modulates rat cardiac vascular endothelial growth factor gene expression in nitric oxide-deficient hypertension. Biochem Biophys Res Commun. 2004;320:1169-1174.  [PubMed]  [DOI]
91.  Bouloumié A, Schini-Kerth VB, Busse R. Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells. Cardiovasc Res. 1999;41:773-780.  [PubMed]  [DOI]
92.  Isner JM. Myocardial gene therapy. Nature. 2002;415:234-239.  [PubMed]  [DOI]
93.  Persson MG, Gustafsson LE. Ethanol can inhibit nitric oxide production. Eur J Pharmacol. 1992;224:99-100.  [PubMed]  [DOI]
94.  Wakabayashi I, Hatake K. Effects of ethanol on the nervous and vascular systems: the mechanisms of alcohol-induced hypertension. Nihon Eiseigaku Zasshi. 2001;55:607-617.  [PubMed]  [DOI]
95.  Ueshima H, Mikawa K, Baba S, Sasaki S, Ozawa H, Tsushima M, Kawaguchi A, Omae T, Katayama Y, Kayamori Y. Effect of reduced alcohol consumption on blood pressure in untreated hypertensive men. Hypertension. 1993;21:248-252.  [PubMed]  [DOI]
96.  Grogan JR, Kochar MS. Alcohol and hypertension. Arch Fam Med. 1994;3:150-154.  [PubMed]  [DOI]
97.  Rengo G, Parisi V, Femminella GD, Pagano G, de Lucia C, Cannavo A, Liccardo D, Giallauria F, Scala O, Zincarelli C. Molecular aspects of the cardioprotective effect of exercise in the elderly. Aging Clin Exp Res. 2013;25:487-497.  [PubMed]  [DOI]
98.  Beck DT, Casey DP, Martin JS, Emerson BD, Braith RW. Exercise training improves endothelial function in young prehypertensives. Exp Biol Med (Maywood). 2013;238:433-441.  [PubMed]  [DOI]
99.  Meilhac O, Ramachandran S, Chiang K, Santanam N, Parthasarathy S. Role of arterial wall antioxidant defense in beneficial effects of exercise on atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2001;21:1681-1688.  [PubMed]  [DOI]
100.  Somani SM, Husain K. Exercise training alters kinetics of antioxidant enzymes in rat tissues. Biochem Mol Biol Int. 1996;38:587-595.  [PubMed]  [DOI]
101.  Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res. 1994;74:349-353.  [PubMed]  [DOI]
102.  McCarthy WJ, Arpawong TE, Dietsch BJ, Yancey AK. Effects of exercise and weight loss on hypertension. JAMA. 2003;290:885; author reply 886-887.  [PubMed]  [DOI]
103.  Tsai JC, Yang HY, Wang WH, Hsieh MH, Chen PT, Kao CC, Kao PF, Wang CH, Chan P. The beneficial effect of regular endurance exercise training on blood pressure and quality of life in patients with hypertension. Clin Exp Hypertens. 2004;26:255-265.  [PubMed]  [DOI]
104.  Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res. 1993;73:829-838.  [PubMed]  [DOI]
105.  Graham DA, Rush JW. Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. J Appl Physiol (1985). 2004;96:2088-2096.  [PubMed]  [DOI]
106.  Joshi AV, Day D, Lubowski TJ, Ambegaonkar A. Relationship between obesity and cardiovascular risk factors: findings from a multi-state screening project in the United States. Curr Med Res Opin. 2005;21:1755-1761.  [PubMed]  [DOI]
107.  Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000;133:92-103.  [PubMed]  [DOI]
108.  Husain K, Somani SM. Response of cardiac antioxidant system to alcohol and exercise training in the rat. Alcohol. 1997;14:301-307.  [PubMed]  [DOI]