Alcohol and hypertension: Implications from Research for clinical practice

Journal of Substance Abuse Treatment, Vol. 3, pp. 121-129, 1986 Printed in the USA. All rights reserved.

0740-5472/86 $3.00 + .00 Copyright © 1986 Pergamon Journals Ltd

TECHNICAL REPORT

Alcohol and Hypertension: Implications from Research for Clinical Practice STANLEY E . GITLOW, MD, LAURA BERTANI DZIEDZIC, PhD AND STANLEY W . DZIEDZIC, PhD, MD Department of Medicine of the Mount Sinai School of Medicine of the City University of New York, New York, NY

Abstract-Despite the fact that recent epidemiological and laboratory studies appear to confirm that alcohol has an effect upon blood pressure, its impact has largely been ignored in clinical practice. This study was undertaken in an effort to answer f o u r basic questions (a) Is there an association between blood pressure and ethanol ingestion and i f so is it causal or related to common genetic and~or environmental factors?; (b) I f an association exists, what is its likely physiological mechanism?; (c) What additional studies are needed in order to further elucidate the relationship between alcohol and blood pressure?; (d) What clinical recommendations, i f any, are justified with our present state o f knowledge?

Keywords-Alcohol, hypertension, catecholamines, withdrawal, norepinephrine SINCE THE EARLY 1950S, the medical means for interrupting the course o f one of the major determinants of cardiovascular mortality has been available for clinical use. Hypertension, a critical precursor o f arteriosclerotic disease, could then be relieved by the appropriate use of a host of therapeutic agents. Of more recent concern has been the determination of the relative advantages between the reduction of blood pressure by drugs as opposed to changes in lifestyle. To this end, weight reduction, dietary sodium, and exercise have received considerable scrutiny. Despite sporadic clinical observations and some epidemiologic data as early as 1915 (Lian, 1915), the influence of alcohol ingestion upon the incidence of hypertension has been largely ignored in clinical practice. Worse, a publication of the American Heart Association aimed toward the care of the hypertensive patient denied a relationship between alcohol and blood pressure, and recent data supporting a potential beneficial effect of alcohol upon the incidence of coronary heart disease was heralded in the lay press without critical attention to the possibility of adverse effects of ethanol upon blood pressure. Within the past 15 years, however, epidemiologic evidence of a relationship between ethanol and blood

pressure has mounted. Present investigators have turned their attention to four basic questions. 1. Is there an association between blood pressure and ethanol ingestion, and if so is it causal or related to common genetic a n d / o r environmental factors? 2. If an association exists, what is its likely physiological mechanism? 3. What additional studies are needed in order to further elucidate questions [1] and [2]? 4. What clinical recommendations, if any, are justified with our present state of knowledge?

IS THERE AN ASSOCIATION BETWEEN BLOOD PRESSURE AND ETHANOL INGESTION? The clinical observation by those physicians treating large numbers of alcoholic patients undergoing detoxification supported the notion that the incidence of hypertension early in treatment was extremely high and that the majority of subjects were normotensive a week later (Gitlow, S.E., personal observation). Various series have described elevations in blood pressure in from 33 to 100°70 of such patients (D'Alonzo & Pell, 1968; Saunders, Beevers and Paton, 1979; Saunders, Beevers and Paton, 1981; Criqui, Wallace, Mishkel, Barret-Connor & Heiss, 1981). Although the incidence of residual hypertension might be elevated among the abstemious subjects after detoxifi-

Requests for reprints should be sent to Stanley E. Gitlow, Clinical Professor of Medicine, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029.

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cation (D'Alonzo & Pell, 1968), the fall in blood pressure concomitant with a decrease in ethanol ingestion among alcoholic subjects represents convincing evidence that alcohol can in some way elicit hypertension when ingested by this particular patient population. Potter and Beevers studied hypertensive patients whose daily habits included the ingestion of up to 80 grams of ethanol (moderate-heavy drinkers). The discontinuation of antihypertensive drugs 2 weeks prior to hospitalization permitted the evaluation of the relationship between ethanol and blood pressure. Most simply put, their blood pressure values fell shortly after discontinuing ethanol, only to rise again 48 hours after it was resumed (Potter & Beevers, 1984). Hospitalization in and of itself failed to lower blood pressure in the presence of continued ethanol ingestion. Although stress has been cited as the underlying etiologic factor in this relationship, these circumstances hardly support such a notion. Certainly, detoxification of alcoholic subjects rarely leads to such resolution of stressful circumstances that one would expect the commonly observed fall in blood pressure by the 5th day of abstinence. It should also be noted that hypertensive patients who are fully or partially controlled with medication may develop increases in blood pressure during episodes of ethanol ingestion making their blood pressure difficult to contrel (Gitlow & Dziedzic, personal observation). This observation, confirmed by Wilkinson and his co-workers (Wilkinson, Kornaczewski, Rankin & Santamaria, 1971), could conceivably result from either the pharmacologic effect of ethanol upon the hypertensive patient or inadequate compliance with the use of antihypertensive medications (Ramsay, 1982). Although many patients with clinically active alcoholism suffer from hypertension, some clearly fail to experience blood pressure elevation. The authors have studied some alcoholic patients who had ingested a fifth or more of distilled spirits daily for as long as 10 years, but whose blood pressure values remained consistently below 150/90 (Gitlow and Dziedzic, personal observations). It is therefore apparent that among patients with alcoholism, alcohol ingestion is not the sole determinant of hypertension. In an effort to eliminate the potential import of some genetic predisposition, Myrhed studied both monozygotic and dizygotic twins (Myrhed, 1974). In the dyzygotic twins who were discordant for alcohol use, the mean levels of systolic and diastolic blood pressure were significantly higher in the co-twins with higher alcohol consumption. Unfortunately, because of the high degree of concordance of monozygotic twins for alcohol consumption only a small number of pairs discordant for alcohol use could be studied and statistical significance in blood pressure data could not be achieved. It is apparent that since alcohol ingestion can elevate

S.E. Gitlow, L.B. Dziedzic and S. IV. Dziedzic

blood pressure of only certain individuals, there must be some predisposition to this pharmacologic result. One clue regarding the nature of such a tendency is the frequency with which alcohol can elicit such a response among hypertensive subjects per se. It must be remembered that patients with essential hypertension possess increased vascular reactivity to pressor substances such as catecholamines and angiotensin (Mendlowitz, Naftchi, Wolf, & Gitlow, 1968). Such vascular hyperactivity has even been demonstrated in the normotensive children of hypertensive subjects (Doyle & Fraser, 1961). The enormous incidence of such a hypertensive diathesis, largely genetically predisposed, could offer a rich harvest for the elevation of blood pressure following the use of drugs capable of stimulating natural pressor mechanisms. Epidemiologic studies appear to confirm these largely anecdotal observations. Mathews observed that those socioeconomic and occupational groups with high death rates from cirrhosis (presumably largely alcoholic) also had high death rates from hypertension and stroke (Mathews, 1976). Kozarevic and his associates observed a relationship between death rate from cerebrovascular disease and heavy drinking (Kozarevic, McGee & Vojvodic, 1980). Studies of alcoholics left unanswered the issue as to whether or not alcohol ingestion resulted in an adverse effect upon blood pressure, morbidity, a n d / o r mortality among patients other than those with alcoholism. Major epidemiologic studies in the United States (Klatsky, Friedman, Siegelaub & Gerard, 1967; McQueen, & Celentano, 1982; Gruchow, Sobocinski & Barbariak, 1985), Australia (Arkwright, Berlin, Vandongen, Rouse and Lalor, 1982), Denmark (Gyntelberg & Meyer, 1974), and Yugoslavia (Kozarevic, McGee & Vojvodic, 1980) demonstrated a relationship between blood pressure and ethanol ingestion within large population groups. Some of these studies were retrospective and suffered from methods for data accumulation which were barely adequate for the investigative purpose. Others utilized naive instruments for the estimations of ethanol ingestion. Some excluded that sub-population receiving treatment for hypertension despite the fact that the compliance of a heavily drinking group was known to be low and one would be artificially loading the data with heavily drinking untreated hypertensive subjects (Ramsay, 1982). Others failed to evaluated for alternate independent variables, although a few employed multiple linear regression analyses in order to separate the impact of ethanol ingestion from that of age, sex, weight, sodium intake, family history of hypertension, smoking, coffee consumption, serum cholesterol levels, social class, educational achievement, and personality profile. The unreliability of questionnaires for quantitation of ingestion of socially disapproved quantities of various substances can be estimated from

Alcohol and Hypertension

two observations: (a) obese subjects are more apt to offer food ingestion histories with low caloric value (Gruchow, Sobocinski & Barbariak, 1985), and (b) self-estimates of alcohol ingestion rarely exceed 50°7o of alcohol consumption as mirrored by beverage sales data (Pernanen, 1974). Nonetheless, an underestimation of ethanol ingestion would serve only to minimize the true impact of ethanol upon blood pressure. An occasional study failed to take into account the clinical observation that institutionalization per se will commonly result in reduction of elevated blood pressure. Some historical instruments fail to recognize that as many as two-thirds of the alcoholic community use drugs other than alcohol in a dependent manner (Gitlow, personal observations). Many of these substances are strongly sympathomimetic (cocaine, amphetamines, etc.). Many diet pills and cold remedies contain enough adrenergic material to elicit an elevation of blood pressure in patients with essential hypertension. The validity of the questionnaire in eliciting reliable data about the use of not only over-the-counter drugs but illicit substances as well must be considered in the design of an epidemiologic study. Perhaps, the most difficult problem of all resulted from the inability to correlate the specific substance, amount and timing of ingestion of the alcohol containing beverage with the blood pressure measurements. As will be noted later, the pharmacologic effect of alcohol varies markedly ¥ith the dose of the drug and the timing of the observations. Although some investigators noted a continuous increase of blood pressure with increasing alcohol ingestion, others observed a theshold-like effect at three or more drinks per day. Such a threshold effect, occasionally leading to a J- or U-shaped curve relating blood pressure and alcohol ingestion, might stem from inadequate validity of the instrument used for determining ethanol ingestion. It is even conceivable that a sub-group possessing some reason or anxiety over their cardiovascular status might tend toward low alcohol use or abstinence but reveal minimal elevations in their blood pressure values. The accentuation of the J curve effect among female patients gives this concept greater credence (Klatsky, Friedman, Siegelaub & Gerard, 1967). In sum, an association between ethanol ingestion and blood pressure would seem undeniable. IF AN ASSOCIATION EXISTS, WHAT IS ITS LIKELY PHYSIOLOGICAL MECHANISM? The administration of ethanol to animals has resulted in a somewhat confusing literature since Grollman first observed its ability to elevate blood pressure (GroUman, 1930; Stein, Lieber, Leevey, Cherrick & Abelman, 1963; Webb & Degerli, 1965; Maines & Aldinger, 1967; Conway, 1968). It must be clearly understood that there is no precise animal model for

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human hypertension. If we accept the likelihood that some peculiar human predisposition enables alcohol to elicit the hypertensive response, the diversity found with animal experimentation would not be unexpected. Moreover, the pharmacologic effects of ethanol are complex and appear to vary especially on the basis of whether its concentration is increasing or decreasing. The tendency for general anesthetics to increase sensitivity to catecholamines might also explain why certain experiments resulted in greater ethanol-induced pressor effects than others (Price & Dripps, 1970). Human subjects ingesting large amounts of ethanol have long been observed to present a clinical state suggestive of hyperadrenergia (tachycardia, sweating, tremulousness, etc.), not dissimilar to that which might be seen in the presence of a pheochromocytoma or thyrotoxicosis. Some of the acute effects of ethanol, such as mobilization of free fatty acids, may be blocked by administration of alpha and/or beta adrenergic blockers. Beta blockade has been used in the treatment of some of these ethanol-induced effects during detoxification of alcoholics (Potter, Bannan, & Beevers, 1984). Other investigators have also observed evidence of hyperadrenergia in human subjects given ethanol. Ireland, Vandongen, Davidson, Beilin and Rouse found elevated catecholamines and increased blood sugar in such subjects (Ireland, Vandongen, Davidson, Beilin and Rouse, 1984). They also found elevated plasma cortisol, a circumstance that requires particular attention since glucocorticoids can induce an increase in vascular reactivity to norepinephrine (Mendlowitz, Gitlow & Naftchi, 1958). These investigators (Ireland, Vandongen, Davidson, Beilen & Rouse, 1984) noted the consistency with which ethanol could induce elevated plasma catecholamines and cortisol among human subjects. This observation would posit the presence of a further variable to explain why some individuals become hypertensive after ethanol and others do not. Other investigators confirmed the ability of ethanol to modify those human mechanisms commonly believed to be related to blood pressure control (catecholamines, renin, aldosterone, cortisol, and vasopressin among others) (Ibsen, Christensen & Rasmussen, 1981; Arkwright, Beilin, Vandongen, Rouse & Lalor, 1982; Banden, Potter, Beevers, Saunders, Walters & Ingram, 1984; Potter & Beevers, 1984). Only the catecholamines and cortisol have demonstrated a fairly consistent correlation with the level of blood pressure, however (Potter, Bannen& Beevers, 1984). Late in the 1950s it became apparent that ethanol would induce a change in human catecholamine metabolism such as to result in a shift in the excretion of oxidized to reduced catecholamine metabolites (Smith, Gitlow, Gall, Wortis & Mendlowitz, 1960). Unfortunately, quantitative assay of such catecholamine catabolites as vanillylmandelic acid (VMA) and

124

S.E. Oitlow, L.B. Dziedzic and S. I41".Dziedzic

3-methoxy-4-hydroxyphenylethyleneglycol (G) are often performed by techniques lacking reliability and specificity. The interpretation of such studies makes the evaluation of the state of adrenergic function difficult (Ischeidt, Issekutz & Himievick, 1961; Mendelson, 1970; Hawkens & Kalant, 1972, Gitlow, Dziedzic, S., Dziedzic, L. & Wong, 1976). By the end of the 1970s the obvious hyperadrenergia associated with alcoholism as well as the withdrawal syndrome demanded the evaluation of the metabolism of catecholamines during chronic alcohol ingestion and the withdrawal syndrome. To this end, the development of biochemical methods that used tritium-labeled norepinephrine (3H-NE) whereby catecholamine metabolism of the intact human subject would be more precisely evaluated, led to the detailed study of two volunteer subjects during and after ingestion of more than 22 ounces of whiskey per day (Gitlow, Mendlowitz, Bertani, Wilk, S. & Wilk, E. 1971, Gitlow, Bertani, Dziedzic, & Wong, 1971, Gitlow, Dziedic, L., Dziedzic, S., & Wong, 1976). The administration of 3H-NE followed by 20 urine collections over a 7 day period and assay of radioactive and endogenous NE, VMA, homovanillic acid (HVA), G, 3-methoxytyramine (MT), epinephrine (E), metanephrine (M) and normetanephrine (NM) permitted evaluation of the relative size of the labeled pool and the internal distribution of the label. As little as one ounce of ethanol elicited a shift in the catabolic pathways of NE favoring the formation of G as opposed to VMA (Figure 1) (Smith & Gitlow, 1966; Davis, Brown, Huff & Cashaw, 1967). Endogenous catecholamine catabolites in the subjects receiving alcohol were compared to 15 control subjects who abstained from all drugs including alcohol (Table 1). Studies of the subjects ingesting specific amounts of alcohol were performed while they were hospitalized in a clinical research unit during control, ethanol ingestion, and withdrawal phases. Patient 1 was a normal subject while Patient 2 satisfied the clinical criteria for the diagnosis of alcoholism (Seixas, 1972). During ethanol ingestion, the total endogenous NE metabolites increased by 5007o in Patient 1 (Table 1) and 77070 in Patient 2 (Table 2), a

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change predominantly accounted for by the deaminated catabolite, G. During the withdrawal period the total excretion of endogenous NE catabolites fell, although this level still remained above normal. The shift in catabolic pathways present during ethanol ingestion disappeared promptly after drug discontinuation. It should be noted that the excretion of endogenous NE and NM increased most noticeably during ethanol ingestion, whereas elevation of E and M excretion characterized withdrawal (Figures 2 and 3). The second patient, having ingested in excess of 22

TABLE 1 Changes In Catecholamlne metabolltes excretion* resulting from ethanol Ingestion (Patient 1)

Control Alcohol t (p) Normal (n = 150)

VMA

G

Total Deaminates**

1.03 ± 0.72 0.33 ± 0.13 4. (<0.01) 1.23 ± 0.39

0.66 ± 0.25 2.38 ± 0.52 6.72 (<0.01) 1.05 ± 0.38

1.69 ± 0.32 2.71 ± 0.26 8.69 (<0.01) 2.29 ± 0.70

NM 0.15 0.09 1.94 0.094

± 0.06 ± 0.03 (<0.1) ± 0.026

NE 0.033 0.035 0.28 0.021

± 0.018 ± 0.005 (<0.5) ± 0.011

*Each value is the mean ± SD of 10 sequential urine specimens expressed as ug/mg creatinine. **VMA + G. Reproduced from the Annals New York A c a d e m y of Sciences 273: 263, 1976, with permission of the authors.

HVA 2.25 2.75 1.18 1.54

± 0.80 ± 0.88 (<0.3) ± 0.54

G 1.84 ± 0.20 3.39 ± 0.75 2.64 ± 0.51 5.36 (<0.01) 5.97 (<0.01) 2.44 (<0.05) 2.29 ± 0.70

Total Deaminates** 0.16 ± 0.06 0.24 ± 0.05 0.23 ± 0.07 2.68 (<0.05) 1.20 (<0.30) 1.33 (<0.20) 0.094 ± 0.03

NM 0.14 ± 0.02 0.17 ± 0.04 0.22 ± 0.05 1.64 (<0.2) 4.86 (<0.01) 2.71 (<0.05) 0.087 ± 0.03

M 0.027 ± 0.009 0.054 ± 0.030 0.039 ± 0.010 3.95 (<0.01) 2.12 (<0.01) 1.54 (<0.20) 0.021 ± 0.011

NE

*Each value is the mean ±SD of 10 sequential urine specimens expressed as ug/mg creatinine. **VMA = G. Reproduced from the Annals New York Academy of Sciences 273:263, 1976, with permission of the authors.

a) Control 0.86 ± 0.21 1.03 ± 0.13 b) Alcohol 0.48 ± 0.24 2.91 ± 0.71 c) Withdrawal 1.41 ± 0.32 1.23 ± 0.30 t (p)ab 2.92 (<0.01) 7.32 (<0.01) t (p)ac 4.52 (<0.01) 1.70 (<0.20) 6.61 (<0.01) 6.64 (<0.01) t (p)bc Normal 1.23 ± 0.39 1.05 ± 0.38 (n = 150)

VMA

E 0.006 ± 0.004 0.007 ± 0.004 0.011 ± 0.007 1.14 (<0.30) 2.09 (<0.05) 2.47 (<0.05) 0.003 ± 0.002

TABLE 2 Changes In Catecholamlne metabollte excreUon* resulting from ethanol Ingestion (Patient 2)

2.07 ± 1.0 2.88 ± 0.3 3.18 ± 0.9 2.31 (<0.0) 3.24 (<0.0) 1.28 (<0.3) 1.54 ± 0.5

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126

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ounces of whiskey per day for over 10 years, not only demonstrated an elevation in the excretion of endogenous NE metabolites in excess of Patient 1 (whose ethanol ingestion was of much shorter duration), but also revealed a significant increase in the 3H-NE turnover rate (t-l/2) during ethanol ingestion. The

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FIGURE 3. Mean and ranges of total deaminates (VMA & G) and HVA in 30 urine samples from Subject 2 during control, ethanol ingestion and withdrawal periods.

anomalous t - l / 2 was substantively slowed during the withdrawal period. The excretion of HVA and MT suggested that not only E but dopamine synthesis a n d / o r release also achieved maximal levels during withdrawal. Endogenous E and M excretion reached peak levels approximately 48 hours after cessation of ethanol ingestion. The rapid fall in NE synthesis and rise in the excretion of E and its metabolites following discontinuation of ethanol ingestion failed to support the hypothesis that stress alone could account for the change in catecholamine metabolism during and following ethanol administration. Ogata and his associates also observed such differences between NE and E metabolism during and following ethanol ingestion (Ogata, Mendelson, Mello & Majchrowicz, 1971). It must be realized that either NE or E is capable of eliciting an increase in blood pressure, especially in an individual with increased vascular reactivity. Although the ability of ethanol to increase adrenal medullary secretions in man was described almost 30 years ago (Perman, 1958), more recent sophisticated studies demonstrated not only evidence of increased catecholamine turnover (Pohorecky, 1982) and biosynthetic enzymes (Pohorecky, 1982; Altura & Altura, 1983), but changes in vascular responsivity following chronic ethanol administration to animals (Altura, Pohoecky & Altura, 1980). These investigators found that chronic "in vivo" ethanol administration to animals could produce tolerance in the reactivity of blood vessels to "in vitro" testing with ethanol. They suggested that the mechanism for such tolerance was similar to that observed in neural tissue and probably related to the permeability of divalent calcium ions across membranes. As noted previously, not only ethanol but general anesthetics, barbiturates and morphine may induce such changes as to modify the reactivity of blood vessels to various pressor stimuli (Altura & Altura, 1979; Altura, Pohorecky & Altura, 1980; Weinberg & Altura, 1980). In essence, the contractile concentration effect curves following application of catecholamines or angiotensin to blood vessels from animals maintained on ethanol differed from those obtained from normal controls. The interaction of such an effect with those human subjects inheriting greater vascular reactivity to adrenergic stimuli can only be imagined. The ability of ethanol administered to rats to induce cerebrovascular spasm which could be abrogated by administration of a calcium antagonist (Verapamil) was recently noted (Altura, Altura & Gebrewold, 1983). These observations offered some insight into those epidemiological studies that revealed a relationship between the incidence of cerebrovascular accidents in humans and their alcohol intake (Kozarevic, McGee & Vojvodic, 1980). Just as cation flux across red-cell membranes have

Alcohol and Hypertension

undergone considerable evaluation in patients with elevated blood pressures (Poston, Sewell, Wilkinson, Richardson, et al., 1981; Woods, Beevers & West, 1981), there is evidence of changes in this mechanism as a result of ethanol administration (Israel, Kalant, LeBlanc, Bernstein & Salazar, 1970; Stokes, 1982). On the other hand, the role played by hypervolemia resulting from ethanol ingestion is difficult to evaluate as a cause of blood pressure variation. Changes in the renin-angiotensin-aldosterone system have been noted as a result of ethanol administration to human subjects (Linkola, J., Fyrquist, F. & Ylikahri, 1979). The changes varied with time after drug administration, plasma renin activity increasing last (Ibsen, Christensen, Rasmussen, et al., 1981). Although this may correlate with the 48 hour delay between restarting alcohol ingestion and a rise in blood pressure as observed by one group of investigators (Potter & Beevers, 1984), others failed to observe a correlation between plasma renin activity and blood pressure in chronic heavy drinkers (Ibsen, Christensen, Rasmussen et al., 1981). It is also possible that some of these variations might be secondary to increased adrenergic activity. Sodium balance has also been suggested as a factor of potential significance in the correlation of ethanol and blood pressure, but there are few data available and none of a particularly convincing nature to suggest that such a mechanism is paramount (Arkwright, Berlin, Vandongen, Rouse & Lalor, 1982; Mitchell, Morgan, & Boddle, 1980). Changes in the excretion or distribution of various divalent cations (other than calcium) and other electrolytes following the administration of ethanol were reviewed (Kayser & Noth, 1984). These investigators failed to conclude that these represented a critical factor in the ability of ethanol to elicit an increase in blood pressure.

WHAT ADDITIONAL STUDIES ARE NEEDED IN ORDER TO FURTHER ELUCIDATE QUESTIONS 1) AND 2)? It has been suggested that those patients with hypertension aggravated by alcohol ingestion suffer the same morbidity and mortality as do patients whose hypertension is unrelated to their alcohol ingestion. In this sense, the alcohol "induced" hypertension may not be considered to represent a clinically unimportant or "pseudohypertension" (Potter, Banna & Beevers, 1984). It is therefore critical to achieve convincing data regarding the role played by ethanol in clinical hypertension. Unfortunately, few details and longitudinal studies are available by which one may estimate whether or not a group of young normotensive adults would suffer later untoward blood pressure variations

12 7

as a result of their drinking habits. In regard to the issue of the potential import of an as yet only hypothesized hypertensive diathesis, a study of pre-hypertensive young adults from families with and without a strong genetic history of hypertension might demonstrate a differing response to alcohol exposure. The clinician, actively involved in the medical management of his hypertensive patients, must know whether or not alcohol ingestion modifies blood pressure control, whether such a response is specific to certain ethanol-containing beverages, at what dosage it is likely to do so, and what role specific antihypertensive drugs play? Such studies among well-controlled hypertensive subjects should be capable of being achieved with the cooperation of a relatively modest number of volunteers. Since a defensive attitude regarding the use of appetite-relieving substances such as food or drugs appears to result in diminution of historical reliability, it might be critical to perform some longitudinal studies upon patients who would volunteer to increase their minimal substance use to an arbitrary elevated level for the purpose of study rather than to rely solely upon patients suffering from some substance dependency. A recent investigation presented evidence for a direct effect of alcohol consumption upon the blood pressure of normotensive male volunteers who underwent longitudinal variations in alcohol ingestion (Puddey, Beilin, Vandongen, Rouse & Rogers, 1985). Unfortunately, these subjects should not have been classified initially as moderate drinkers. In addition, sodium intake was not controlled and no physiological measurements were made in order to elucidate the mechanism of these observations. In any longitudinal study, simultaneous physiological, metabolic and biochemical mensuration might permit adequate evaluation of underlying mechanisms. Inherently, such studies might yield information concerning a "safe" ethanol dose, a conclusion which might be of some import to those interested in the use of this drug for prevention of other cardiovascular problems. Future epidemiological studies should possess carefully detailed information concerning the ethanol dose and duration as well as the interval between its administration and blood pressure measurement. Similarly, a detailed history of other licit and illicit drug ingestion must be obtained simultaneously. Upon achieving reliable information concerning both the nature of the patient and the ethanol dosage beyond which a counterproductive effect ensues, the medical practitioner must then learn whether or not the advisable limitations in lifestyle are likely to be achieved. Such changes in lifestyle as consistently restricted caloric intake or ethanol ingestion are difficult to attain without the use of special therapeutic techniques with which the general physician has historically had too little experience.

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S.E. Gitlow, L.B. Dziedzic and S. W. Dziedzic

Some o f the studies might yield to the new techniques for ambulatory blood pressure monitoring.

WHAT CLINICAL RECOMMENDATIONS, IF ANY, ARE JUSTIFIED WITH OUR PRESENT STATE OF KNOWLEDGE? There is little question but that ethanol can induce an increase in blood pressure in certain individuals. Such a circumstance represents in and of itself a relatively modest reason for the reduction of ethanol ingestion by a patient with alcoholism. On the other hand, all hypertensive subjects would do well to abstain from ethanol until it becomes clear whether or not the drug plays a significant role in the cause of their hypertension. Similarly, those patients whose hypertension resists control by the usual medical therapy deserve evaluation of the level of their alcohol intake as well as the possibility that ethanol ingestion might be interfering with their compliance. It is difficult to make a recommendation for those subjects who are neither alcoholic nor hypertensive, but at this moment epidemiologic data suggests that it might be wise to limit ethanol ingestion to three drinks per day. It is unlikely that current information permits a dogmatic attitude concerning the potential cardiovascular benefit to drinking one or two drinks per day. To answer this question, further information is not only required about the relationship of alcohol to hypertension, but to coronary disease and cardiac dysrhythmias as well.

CONCLUSION It is probably more likely to represent the result of societal attitudes than medical knowledge that the classic textbooks on hypertension have failed to draw attention to the importance of ethanol ingestion to blood pressure (Pickering, 1969; Genest & Koiw, 1972; Laragh, 1973). A society in which some 20% of the population suffers from essential hypertension and the majority of adults ingest a drug capable of increasing excretion of pressor substances must ultimately lead to a possible elevation of morbidity and mortality resulting from the coincidence of these factors. The clinical appreciation of the relationship of these circumstances has been achieved and what remains for future investigation is the precise and detailed delineation of their interaction.

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