- Email: [email protected]
Effects of ethanol and acetaldehyde on the heart
E#ects
of ethanol
and
ac~~a~~~~
Thomas N. James, M.D.” Edward S. Bear, X.D. Detroit, Mirh.
en have drunk alcohol in joy and in grief, alone and in groups, to celebrate and to forget, with hesitation and with compulsive habituation, throughout recorded history. For many years, physicians have known that patients consummg large amcunts of alcohol frequentiy have heart disease. A resurgence of interest in this form of heart disease began with the recent studies of Evans1 Brigden and Robinson2 and Burch and Walsh,3 which stressed that the usual explanations blaming malnutrition and vitamin deficiency were too often incorrect or insufficient. Despite considerable recent interest in this question, however, the reason that chronic alcoholics so often develop heart disease remains unclear. A paradox exists between the old clinical knowledge that chronic alcoholism is associated with myocardial insufficiency and most of the experimental evidence accumulated in the past which indicates that alcohol has little direct effect on the cardiovascular system except in very high concentrations.” With newer methodology there is now some clinical5,6 and experimental’ evidence which suggests that alcohol may alter the metabolism of the myocardial cell. Histochemical8 and electron microscopic9 studies of myocardium from patients dying with
?I.iV’A ?Yakoholic cardiomyopdth;~ _ jlilb\V~l ‘ tensive morphologic changes. ‘JLI whether these caused the heart to iaiE 1)~ whether they were due to the cardiac f,,ilure (and its therap!. and complications) is unknown. One may- summarize piesen: concepts about the pathogenesis of alcoholic cardiomq-apathy as follows. ‘Ther:~ is little question that malnutrition and vitamin deficiency may lead to carc!iac: failure in the alcoholic patient who eats poorly, but this explains only a small portion of hose with the disease. Since some nfcoholics do not take care of themselves physically, the>‘ ma)- he more susceptible to infectious :liseases, and cardiac invob,ement b> viruses may contribute to the problem ; Sut in the absence of convincing evidence hat such is often the case, this remains speculative. Deficient dietar\Intake of certain trace metals, parlic~ilariy zinc and magnesium, may contri!~ ie to the pathogenesis of alcoholic i~irdi:,:n!-opatls~~ But the principal enigma in alcoholic cardiomyopathy concerns the i’atient who eats well. takes reasonabl>r good care of himself, is not the victim of unusual viral or bacterial illnesses, yet just because he drinks too much eventually develops progressive cardiac en.largement .~nd failure. Tf continuing studies of tlris problem
E’rom the Section on Cardiovascular Research. Henry Ford Hosplrai, L)rixoit, Mich. These studies were supported in part by grants from the Michigan IIeart dvsociation Health Service. Dr. Bear worked as a Michigan Heart Association Research Fello-ju. Received for publication Sept. 19, 1966. *Address: Henry Ford Hospital, 2799 West Grand Blvd., Detroit, Mich., 48202.
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confirm that ingested ethyl alcohol in man has a direct noxious effect on the heart, as some recent reports suggest, then the large volume of older information indicating insignificant direct cardiac effect will be refuted. However, the metabolic and pathophysiologic consequences of chronic alcoholism include more than simply the direct action of ethanol. Ingested ethanol is rapidly metabolized to acetaldehyde and then to water and acetic acid. Acetaldehyde has been shown to have significant cardiovascular effects.lO-rj In the present study, we performed experiments to examine the effect of ethanol, acetaldehyde, and acetic acid on the sinus node, and compared these with the effects of methanol, formaldehyde, and formic acid. Since the sinus node is composed of specialized myocardial cells, effects on it represent what may be anticipated (with few exceptions) in general cardiac effects. Furthermore, its function as the normal cardiac pacemaker gives it an essential role in determining how fast the heart beats. Materials
and methods
Sixty-five dogs were prepared for experiments as follows. After anesthesia with pentobarbital sodium (30 mg. per kilothe trachea was intubated for gram), mechanical ventilation with room air. The chest was opened in the midline, the heart suspended in the pericardium, and the right coronary artery dissected free in the atrioventricular sulcus to isolate the branch to the sinus node.16f1’ A small polyethylene cannula was introduced into the sinus node artery and ligated in place. Ligation of the canine sinus node artery has no significant effect on the rate of the sinus node18 because of the extensive arterial anastomoses in that region.r$ A three-way stopcock attached to the proximal end of the cannula in the sinus node artery permitted injections into the artery and, between injections, the measurement of retrograde pressure. Other pressures routinelv measured included those in the aorta (via a femoral artery) and the right atrium {via a jugular vein). Heart rate was constantly monitored by an instantaneous tachogram derived with an analog computer from successive R waves in the electrocardiogram. During constant record-
Am. Heart 1. hwst, 1967
ing of the tachogram and pressures at 0.25 mm. per second on a polygraph, the pulses and ECG were monitored on an oscilloscope with a sweep speed of 50 mm, per second. Through a slave circuit a separate ECG was recorded constantly at 25 mm. per second and collated with the master record. The right stellste ganglion was isolated within the thorax and stimulated with an electronic square-wave stimulator at 30 c.p.s., l-millisecond impulses, in 6-second trains, at submaximal voltage. Solutions for injection into the sinus node artery were prepared either in Ringer’s solution or in fresh autogenous arterial blood, as indicated. Ethanol, methanol, acetaldehyde, formaldehyde, acetic acid, and formic acid were so prepared. Of these, acetaldehyde presented a special problem because of its volatility at ordinary room temperature; for consistent preparations it was necessary to mix acetaldehyde in cold (about 6°C.) Ringer’s solution or blood. Each injection into the sinus node was preceded by a control injection of either Ringer’s solution or arterial blood. These injections were routinely of Z-ml. volume delivered from a hand syringe in 5 to 10 seconds. Any injection directly into the sinus node artery produces bradycardia, which has been determined to be due most likely to physical distention of the sinus node artery.20 After such injections there is routinely a brief postinjection acceleration which is due to local release sulfate, I of norepinephrine. 21 Atropine mg. per kilogram, was injected intravenously. Reserpine was administered intramuscularly, 0.5 mg. per kilogram, for 2 days prior to an experiment. Propranolol* and I-norepinephrine bitartrate were prepared in Ringer’s solution for intranodal injection. Chronotropic effects of test solutions were interpreted relative to preceding control injections in each animal. Negative effects are reported only as they exceeded the control-injection bradycardia in degree and duration. Positive effects are calculated as they exceeded the control degree and duration of postinjection acceleration. The effects of injections of acetaldehyde *Supplied by Dr. A. Sahagian New York, N. Y.
Edwards.
Ayerst
Laboratories,
which were ali cold were compared rouCnely x0 control injections of the same temperature. The pulse amplitude in the ligated sinus node artery is due to atria1 contractio@ and was used together with xhe intra-atria1 pulse as an indirect indicat-or of inotropic response.
The resu!cs -my Se siilii?3litr:L~ii i)j, indicating that acetaldehyde i&as the on1~ substance studied which produced an effect, except at very high concentrations. Ethanol ‘1a.d no significant chronotropic action, except at 10,000 fig per milli!itei- ;Kg. S.),
Fig. 1. This experiment demonstrates the characteristic re.,pcnse to 2 ‘brief direci peritir:ti,i :)i t;x dnx iorie with ethanol. Bradycardia during injection and postinjection acceleration are the same after the contra! (Cj injection of Ringer’s solution and after 0.1 and 1.0 mg. per milliliter of ethanol. Only with IO nip, per milliliter of ethanol was there a consistent negative chronotropic effect, here manifest by loss of the 11crma! pokxjectioc acceleration and slight prolongation of the injection bradycardia. Recordings in this and sui;scquent similar graphs are CfYonz above dow,n) right atria1 pressure (I?.A), retrograde pressure in the cannulated lisated sinus node artery (SNA), aortic pressure (Ao), tachogram (HI?), and electrocardiogram (EC@. The prekres are scaled In millimeters of mercury, and HR in number of beats per minute. Recording paper speeds are indicated by horizontal-bar time references.
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which is twice the level ever observed in man, even in deepest drunkenness. The same was true of methanol. Acetic acid had an insignificant effect below concentrations of 100 ug per milliliter, at which level the pW of the test solution was 3.7. Formic acid acted similarly. Constituting the two acids in fresh autogenous arterial blood at the same concentrations lessened the acidity of the solutions, because of
Am. Heart J. .$uglcst, 1967
normal buffering mechanisms in blood, and similarly reduced or eliminated the chronotropic effect. Formaldehyde had no significant effect below a concentration of 1,000 ,ug per milliliter (Fig. 2). The only cardiac effects observed with ethanol (16 dogs), methanol (4 dogs), acetic acid (10 dogs), formic acid (4 dogs), and formaldehyde (7 dogs) were depressive, slowing the sinus node and reducing the ampli-
Fig. 2. On brief direct perfusion of the sinus node, formaldehyde (FOLD) had no significant chronotropic action below concentrations of 1 mg. per milliliter, and only a negative action at that concentration. Here the transition from sinus rhythm to A-V nodal rhythm is demonstrated after 1 mg. per milliliter of FMLD had been injected into the sinus node artery. The point of transition is indicated by the asterisks. This effect lasted 2 minutes; recovery of sinus rhythm was attributable to the rapid removal of FMLD by flow from arterial anastomoses about the sinus node.
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tude of atria1 pulses, the latter representing a negative inotropic action. The depressive effects persisted after atropinization and reserpinization, indicating that they were not mediated by vagal stimulation and were not an antiadrenergic effect. Acetaldehyde produced increasing degrees of acceleration of the sinus node with increasing test concentrations, beginning with a significant but inconsistent effect at 10 pg per milliliter (Table I and Figs. 3 and 4). There was a concomitant increase in the amplitude of the pulse in the ligated
Fig. 4. During rhythm remains
the effect of ACLD here of sinus origin in the ECG,
sinus node artery and in the right atrium, indicating a positive inotropic action. Both the positive chronotropic and inotropic effects resembled the actions of tyramine injected directly into the sinus node.23 Serial injections of intranodal acetaldehyde, 1,000 bg per milliliter at lo-minute intervals (in 5 dogs), continued to produce maximal accelerative responses for 1 hour; longer serial periods or shorter intervals between injections were associated with sinus arrest and periodic rhythm, which most likely represented toxicity.
the recording paper speed was accelerated and the amplitude of A waves in the atria1
to demonstrate pulse is increased.
that
the
jrable I. Sinus tachycardia acetaldehyde in 16 dogs
jrom
intranodal
I ,
Concentration
1 -
of acetaldehyde (Pd~~~.) -7
10
1
100
1,000
Ivlaximum level* of acceleration
(beats/minrrte) Duration* of acceleration (seconds)
3
j! 11
Same as control
acera!d& ycie is:as of 3 dogs, prepared in a?ltogenotis lrrterix! 5’100$, and 5ltranodal injections ~xoduced the same responses as dkl acetaldeh>de prepared in Ringer’s solurion. Intravenous administration: of acetaldehyde, ? mg. r;er kilogram a:ld less, produceb :ninor IV consistent effects, but 10 mg. ixr kilngram consistently produced both aortic hypertension and sinus ta&ycardia (Fig. 5), as has been demonstrated IS>T~thers.*~-‘~ Aortic hq;pertension, increased amplitude of atria1 pulses, and sinus acceierarion were ail much diminished or &sent ai”ter res. . . . erpinlzatlon in 4 dogs (Fig. 01. ‘The acIll
thi:
case
freshly
23 A 17
81 *
51
45i
12
311 & 139
*Both the level and duration of acceleration are expressed only as they exceeded the response to control injections of Ringer’s solution in the same dog. Results for the 16 dogs are given as the arithmetic mean * 1 SD.
Fig. 5. AU injection of acetaldehyde into the central venws circ&Gon [right atriwx), c‘~ob!ip‘mb:i~ .il alw~rr 50 times the maximal volume given in the experiments u;ith intrailodal iiijection in Figs. 3 XK~ 4., pwd;~~s aurtic hypertension and slight cardiac acceleration. The brief slowing dliring intra-atria1 injecticxx was dlte to the loral effect of 10 ml. of cold test solution. Since the chronotropic action by this large volume of ACLO adminisre.rcci systemically is SOmuch less than that by the much smailer volilme perfused d’irectly throL!gh :he sintrs tx&, an extracardiac effect from recirculated ACLD is not likely to be a significant factor jn the ::osiriw cbronolropi.c response after intranodal ACLD.
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celerative response to acetaldehyde could not be restored with intranodal norepinephrine in the reserpinized dogs, although it can be with tyranline23; it may be noted that intranodal norepinephrine also fails to restore the response to stimulation of the stellate ganglia in reserpinized dogsg3 The increased pulse amplitude and the sinus tachycardia were readily reversible in 4 dogs with intranodal propranolol (Fig. 7), and blocked in immediately subsequent injections of acetaldehyde. In 3
of these 4 dogs, responses to acetaldehyde were followed at lo-minute intervals and returned to control levels of acceleration in 40 to 60 minutes, which is the duration of action of propranolol in this experimental preparation. Stimulation of the stellate ganglia in 3 dogs during the acceierative effect of various concentrations of intranodal acetaldehyde produced either normal or slightly reduced accelerative responses and increased atria1 pulse amplitudes (Fig. 8); neither the positive chrono-
Fig. 6. In this reserpinized dog (KSP), response to intranodal norepinephrine (NE) and control Ringer’s soluof ACLD has no significant chronotropic effect. The longer tion (R) is of the usual type, but 1 m,.w per milliliter duration of injection bradycardia after ACLD than after Ringer’s solution is due to a wash-in of NE from the catheter by the Ringer’s solution.
tropic nor inotropic neurogenic response was augmented by acetaldehyde. Sinus tachycardia from intranodal norepinephrine, 0.05 and 0.1 pg per milliliter, was not augmented by prior or concomitantly administered acetaldehyde. Maximal sinus acceleration from intranodal acetaldehyde was similar before and after intravenous atropinization in 3 dogs. Discussic9n -4cetaldehyde clearly has profound direct effects on the heart. Cardiac stimulstion occurred at levels which normally
Fig.
develop In man after ingestion oi eihano?, and resemble those observed ;tfter the experimental administration of :icetaldehyde intravenously in human vol~~r~~ers.“” Concentrations of acetaldchyde after drinking in man may reach 10 pg per milliliter, and with prior administration of tiisuifiram (,?ntabuse) can reach 100 yg per rniflifiter, Since both acetaldehyde and etkuroi have a number of significant concomilant extracardiac effects” SO,I5 which ma>’ secondarily influence the heart, it is not surprising that physical findings, such as rhe blood pressure and heart rate, are so variable
7. Reversal of the effects of intranodal -4CLD by intranodal piopranolol
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Am Heart I. Augast. 1967
Fig. 8. The sinus tachycardia after a submaximal stimulation of the right stellate ganglion (KS) was similar before (left panel) and during the positive chronotropic effect of intranodal ACLD. This makes it unlikely that “sensitization” to normally released (or normally present) norepinephrine is a significant factor in the positive chronotropic effect of ACLD.
in groups of alcoholic patients, as well as from one time to another in the same patient. Hypotension associated with the warm flush in acute alcoholism may counteract the hypertensive effect of acetaldehydemia. Tachycardia from acetaldehyde or secondarily from hypotension (or both) may be opposed by the direct noxious effect of ethanol on the heart or even by the toxicity of certain congeners occurring in some alcoholic beverages. In considering the mechanism of the ultimate cardiovascular effects of ethanol, one must begin with an appreciation of the complexity of the factors involved. Since recent reviews have
discussed the physiologic responses to ethanol and the many possible contributing factors in the pathogenesis of alcoholic cardiomyopathy,2~3~24-36 this discussion will concentrate on the actions of acetaldehyde. The possible role of acetaldehyde in the net effects of chronic alcoholism has been investigated by a number of workers, but primarily relative to neurologic effects and especially after disulfiram, which inhibits the degradation of acetaldehyde.4*35 When one is considering the potential role of acetaldehyde in the genesis of alcoholic it is important to indicardiomyopathy, cate that patients who are chronic alco-
holics do not lose the ability to change ethanol into acetaldehyde, and that they may even do it more rapidly and efficiently than nonalcoholic patients.36 This is true despite the fact that the aIcohol-dehydrogenase activity which transforms ethanol to acetaldehyde, as well as the aldehydeoxidase activity which breaks down acetaldehyde, both occur predominantly and almost exclusively in the liver,28 which is frequently diseased in alcoholic patients. On the basis of the present and previous nndings about the cardiovascular effects of acetaldehyde, its actions on the heart may be summarized as follows. In concennot infrequently occurring in trations acute alcoholism in man, acetaldehyde rapidly releases myocardial stores of norepinephrine. This interpretation is based on the similarity of its actions to those of tyramine or of directly administered norepinephrine, and the fact that these actions can be reversed and blocked with specific beta-receptor blocking agents and are not observed in the reserpinized animal. Acetaldehyde is also known to be capable of releasing norepinephrine and epinephrine from extracardiac stores, including the adrenal medulla, but its cardiovascular effects are nearly as prominent even after ligation of the adrenal veins.r1J3 Although circulating catecholamines released from the adrenal medulla may augment the stimulating effect of acetaldehyde on the heart, the direct cardiac action is probably more important. Since the action of acetaldehyde in these and otherI experiments could not be restored after reserpinization by the administration of norepinephrine, its norepinephrine-releasing action differs from that of tyramine and resembles that which follows adrenergic nerve stimulation. There is no vagolytic component to the sinus tachycardia from acetaldehyde, nor is there any element of sensitization to norepinephrine. Formaldehyde does not share the positive chronotropic and inotropic actions of acetaldehyde. In the present study, we performed only acute experiments, and the duration of the administration of test substances was brief (5 to 10 seconds). The actions of acetaldehyde were consistent and marked under these circumstances. The absence of significant action of ethanol and of the other
substances studied, except in ~:?~s~all>~ high concentrations, must be interpreted in view of the brief administrations, and with more prolonged administration these substances may have significant effects Since acetaldehyde acutely stimulates the heart, one can construe its actions to be beneficial. This stimulation occurs through the liberation of cardiac stores of norepinephrine, however, and it has recently been demonstrated that t-he myocardium is deficient in norepinephrine during congestive heart failure c?~e to a variety of causes. 35-3g If the heart of the chronic alcoholic is at all diseased, then further depiction of its stored cztecholamines must be deleterious, pa.rtirulariy if this occurs repeatedly a.nd for- 2~ long time. In addition to the ultimate bad effects of depletion of norepinephrine, the acute stimulation during the course of release of norepinephrine may be thought of as whipping a tired horse. This is particularly the case if substances (induding ethanol) with cardiac depressan L actions are simuitaneousiy present. Fu.rn.hermore, chronic repeated cardiac stimuiation of the heart with catecholamines (ar In pheochromocytoma) may directly damage the myocardium,40 In addition to its norepinephrine-releasing action, acetaldehyde is also capable of releasing serotonin.41 Serotonin has only a weak negative chronotropic xction on direct perfusion of the sinus node,“” but under certain circumstances may sfimdate the heartd3 Whether this contribiltes to the final effect of acetaldehyde on th.e heart in alcoholic patients is uncertai!k, but the action of acetaldehyde in releasing norepinephrine seems more likely to be the important one. One of the puzzles in alcoholic cardiomyopathy is why, among patients consuming similar amounts of ethanol and eating reasonably comparabie adequate diets, some develop heart disease an.d others do not. Undoubtedly, the presence oe’ associated problems, such as coronary atheroscIerosis or viral infections!, ma?; account for some of this discrepa.ncy. VVC may also consider possible individual differences in response to the release of norepinephrine by acetaldehyde. Those patients with generous stores of myocardial ?-orepineph-
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rine may get profound stimulation during the acute effects of acetaldehyde, whereas those with smaller stores may not. Similarly, there must be individual variation in the ability to resynthesize depleted stores of norepinephrine. Those alcoholic patients with a high level of such ability may not develop the ill effects of catecholamine depletion for a long time, or at all, whereas those with poor ability to replace norepinephrine may develop cardiac disease soon. Summary
In anesthetized dogs, direct perfusion of the sinus node with acetaldehyde produced marked stimulation in concentrations similar to those occurring in human alcoholism. Ethanol and closely related compounds had only depressant effects, which during these acute experiments were observed only with unusually high concentrations. The stimulating action of acetaldehyde resembled that of tyramine, was not altered by atropinization, could be reversed and blocked with propranolol, and was virtually absent after reserpinization, which suggests that it is due to the direct release of myocardial norepinephrine. Both the acute and chronic cardiac effects of alcoholism may be due in part to the release of myocardial norepinephrine by acetaldehyde, the principal metabolite of ethanol. REFERENCES Evans, W.: The electrocardiogram of alcoholic cardiomyopathy, Brit. Heart J. 21:445, 1959. 2. Brigden, W., and Robinson, J.: Alcoholic heart disease, Brit. M. J. 2:1283, 1964. 3. Burch, G. E., and Walsh, J. J.: Cardiac insufficiency in chronic alcoholism, Am. J. Cardiol. 6:864, 1960. 4. Goodman, L. S., and Gilman, A.: The pharmacologic basis of therapeutics, ed. 3, New York, 1965, The Macmillan Company. 5. Wendt, V. E., Wu, C., Balcon, R., Doty, G., and Bing, R. J.: Hemodynamic and metabolic effects of chronic alcoholism in man, Am. J. Cardiol. 15:175, 1965. 6. Wendt, V. E., Ajluni, R., Bruce, T. A., Prasad, A. D., and Bing, R. J.: Acute effects of alcohol on the mvocardium, Am. .I. Cardiol. 17:804, 1966. . 7. Regan, T. J,, Kcroxenidis, G., Moschos, C. B., Oldewurtel, H. A., Lehan, P. H., and Hellems, H. K.: The acute metabolic and hemodynamic responses of the left ventricle to ethanol, J. Clin. Invest. 45:270, 1966. 1.
8.
Ferrans, V. J., Hibbs, I?. G., Weilbaecher, D. G., Black, W. C., Walsh, J. J., and Burch, G. E. : Alcoholic cardiomvooathv. A histochemical study, AM. HEART J. 6$:+48, i965. 9. Hibbs, R. G., Ferrans, V. J., Black, W. C., Weilbaecher, D. G., Walsh, J. J., and Burch, G. E.: Alcholoic cardiomyopathy. An electron microscopic study, AM. HEART J. 69:766, 1965. 10. Handovsky, H. : Au sujet des proprietes biologiques et pharmacodynamiques de l’acetaldehyde, Compt. Rend. Sot. Biol. (Paris) 117: 238,1934. 11. Nelson, E. E. : Pressor response to acetaldehyde and its potentiation by cocaine, Proc. Sot. Exper. Biol. & Med. 52:23, 1943. 12. Asmussen, E., Hald, J., and Larsen, V.: The pharmacological action of acetaldehyde on the human organism, Acta Pharmacol. 4:311,1948. of sympathomimetic 13. Eade, N. R.: Mechanism action of aldehvdes. 1. Pharmacol. & Exper. Therap. 127 :29,\959. d 14. Kumar, M. A., and Sheth, U. K.: The sympathomimetic action of acetaldehyde on isolated atria, Arch. Int. Pharmacodyn. 137:188, 1962. 1.5. Toels. N.. and Neil. E.: The action of acetaldehide’ in’ the chemoreceptors of the carotid glomus, J. Physiol. 168:234, 1963. 16. James. T. N. : Anatomy of the coronary arteries, New York, 1961, Paul B. Hoeber, Inc. 17. James, T. N., and Nadeau, R. A.: Direct perfusion of the sinus node: An experimental model for pharmacologic and electrophysiolcgical studies of the heart, Henry Ford Hosp. M. Bull. 10:21, 1962. 18. James, T. N,, and Hershey, E. A., Jr.: Experimental studies on the pathogenesis of atria1 arrhythmias in myocardial infarction, AM. HEART J. 63:196, 1962. 19. James, T. N.: Anatomy of the sinus node of the dog, Anat. Rec. 143:251, 1962. 20. James, T. N., and Nadeau, R. A.: Sinus bradycardia during injections directly into the sinus node artery,-Am. J. Physiol. 204:9, 1963. 21. Tames. T. N.. and Nadeau, R. A.: The chronoGropic’and vagal-blocking ‘actions of naphthylisoproterenol studied by direct perfusion of of the sinus node, J. Pharmacol. & Exper. Therap. 143:350, 1964. 22. James, T. N., and Nadeau, R. A.: A study of retrograde pressure and pulse in the sinus node artery, AM. HEART J. 66:343, 1963. 23. James, T. N., and Nadeau, R. A.: The chronotropic action of tryamine studied by direct perfusion of the sinus node through its artery, J. Pharmacol. & Exper. Therap. i44:83, 1964. 24. Tacobsen. E.: The metabolism of ethyl alcohol, Pharmacol. Rev. 4:107, 1952. . 25. Ganz, V.: The acute effect of alcohol on the circulation and on the oxygen metabolism of the heart, AM. HEART J. 66:494, 1963. 26. Gimeno, A. L., Gimeno, M. F., and Webb, J. L.: Effects of ethanol on cellular membrane potentials and contractility of isolated rat atrium, Am. J. Physiol. 203:194, 1962. A. H.: Ethanol and urinary catechola27. Anton, mines in man, Clin. Pharmacol. Therap. 6:462, 1965.
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C. S., and Davidson, C. S.: Some metabolic effects of ethpl alcohol, Am. J. Med. 33319, 1962. Perkoff, G. T., Hardy, P., and Velez-Garcia, E.: Reversible acute muscular syndrome in chronic alcoholism, New England J. Med.
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P. W., and Horvath, S. M.: Coronary during and following ethyl alcohol Arch. Int. I’harmacodyn. 148:181,
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Perman, E. S.: The effect of ethyl alcohol on the secretion from the adrenal medulla in man, Acta Physiol. Scandinav. 4$4:241, 1958. Perman, E. S.: The effect of ethyl alcohol on the secretion from the adrenai medulla of the cat, Acta Physiol. Scandinav. 48:323, 1960. Perman, E. S.: Observations on the effect of ethanoi on the urinary excretion of histamine, j-hydroxyindole acetic acid, catecholamines and 17-hydroxvcortiscosteroids in man, Acta Physiol. Scandinav. 51:62, 1961. Perman, E. S.: Effect of ethanol and hydration on the urinary excretion of adrenaline and noradrenaiine and on the blood sugar of rats, Acta Physiol. Scandinav. 51:68, 1961. Perman, E. S.: Studies on the Antabuse-alcohol reaction in rabbits, Acta Physiol. Scandinav. S%(Suppl. 190):5, 1962. Truitt, E. B., Jr,, and Duritz, G.: Gas chrornatographically determined blood levels of ethanol and acetaldehyde in healthy and
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Chidsey, C. A., Sonnenblick, E. H., :Morrow, A. G., and Rrauawald, E.: Siorepinrphrine stores and contractiie force oi paoilinry muscle from the failing human heart, Ci-c,r!arion
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$2.
Coveil,
J. X’., Chidsey, C. X., and Br,~unwald, F,.: Reduction of the cardiac req~njr to poetganglionic sympathetic nerve Stirr.l:iatiOil in experimental heart failure, Circulation Res, 19:5:, 1966. Chidsey, C. .k, and Braunwaid; E.: Sympathetic activity and nemotransmitter dcpletiou in congestive heart failure, Pharinacol. Rev. 18:685, 1966. Van Vleit, P. D., Burchell, H. B., RW? Titus, J. L.: Focal myocarditis associates’ with pheochromocytoma, New England J. Med. 2’i4:1102, 1966. Duritz, G., and Truitt, E. R., Jr.: ‘I‘ht: role of acetaldehyde in the action of afcohoi DII brain norepinephrine and seroto::in, Fl_d, Proc. 22:272, 1963. James, T, X.: The chrcnotropic action of serotonin studied by direct perfnsron of the sinus node, J. Pharmacol. & Esper Therap.
146:209,1964. 4.3.
Schneider, J. A., and Yorkmart, F. !:‘.: Species differences in the respiratory and cardiovascular response to serotonin (5-hqdroxytr~ptarnine), J, Pharmacof. & Exper. Therap. 11j :85. 1951.
of ethanol
and
ac~~a~~~~
Thomas N. James, M.D.” Edward S. Bear, X.D. Detroit, Mirh.
en have drunk alcohol in joy and in grief, alone and in groups, to celebrate and to forget, with hesitation and with compulsive habituation, throughout recorded history. For many years, physicians have known that patients consummg large amcunts of alcohol frequentiy have heart disease. A resurgence of interest in this form of heart disease began with the recent studies of Evans1 Brigden and Robinson2 and Burch and Walsh,3 which stressed that the usual explanations blaming malnutrition and vitamin deficiency were too often incorrect or insufficient. Despite considerable recent interest in this question, however, the reason that chronic alcoholics so often develop heart disease remains unclear. A paradox exists between the old clinical knowledge that chronic alcoholism is associated with myocardial insufficiency and most of the experimental evidence accumulated in the past which indicates that alcohol has little direct effect on the cardiovascular system except in very high concentrations.” With newer methodology there is now some clinical5,6 and experimental’ evidence which suggests that alcohol may alter the metabolism of the myocardial cell. Histochemical8 and electron microscopic9 studies of myocardium from patients dying with
?I.iV’A ?Yakoholic cardiomyopdth;~ _ jlilb\V~l ‘ tensive morphologic changes. ‘JLI whether these caused the heart to iaiE 1)~ whether they were due to the cardiac f,,ilure (and its therap!. and complications) is unknown. One may- summarize piesen: concepts about the pathogenesis of alcoholic cardiomq-apathy as follows. ‘Ther:~ is little question that malnutrition and vitamin deficiency may lead to carc!iac: failure in the alcoholic patient who eats poorly, but this explains only a small portion of hose with the disease. Since some nfcoholics do not take care of themselves physically, the>‘ ma)- he more susceptible to infectious :liseases, and cardiac invob,ement b> viruses may contribute to the problem ; Sut in the absence of convincing evidence hat such is often the case, this remains speculative. Deficient dietar\Intake of certain trace metals, parlic~ilariy zinc and magnesium, may contri!~ ie to the pathogenesis of alcoholic i~irdi:,:n!-opatls~~ But the principal enigma in alcoholic cardiomyopathy concerns the i’atient who eats well. takes reasonabl>r good care of himself, is not the victim of unusual viral or bacterial illnesses, yet just because he drinks too much eventually develops progressive cardiac en.largement .~nd failure. Tf continuing studies of tlris problem
E’rom the Section on Cardiovascular Research. Henry Ford Hosplrai, L)rixoit, Mich. These studies were supported in part by grants from the Michigan IIeart dvsociation Health Service. Dr. Bear worked as a Michigan Heart Association Research Fello-ju. Received for publication Sept. 19, 1966. *Address: Henry Ford Hospital, 2799 West Grand Blvd., Detroit, Mich., 48202.
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confirm that ingested ethyl alcohol in man has a direct noxious effect on the heart, as some recent reports suggest, then the large volume of older information indicating insignificant direct cardiac effect will be refuted. However, the metabolic and pathophysiologic consequences of chronic alcoholism include more than simply the direct action of ethanol. Ingested ethanol is rapidly metabolized to acetaldehyde and then to water and acetic acid. Acetaldehyde has been shown to have significant cardiovascular effects.lO-rj In the present study, we performed experiments to examine the effect of ethanol, acetaldehyde, and acetic acid on the sinus node, and compared these with the effects of methanol, formaldehyde, and formic acid. Since the sinus node is composed of specialized myocardial cells, effects on it represent what may be anticipated (with few exceptions) in general cardiac effects. Furthermore, its function as the normal cardiac pacemaker gives it an essential role in determining how fast the heart beats. Materials
and methods
Sixty-five dogs were prepared for experiments as follows. After anesthesia with pentobarbital sodium (30 mg. per kilothe trachea was intubated for gram), mechanical ventilation with room air. The chest was opened in the midline, the heart suspended in the pericardium, and the right coronary artery dissected free in the atrioventricular sulcus to isolate the branch to the sinus node.16f1’ A small polyethylene cannula was introduced into the sinus node artery and ligated in place. Ligation of the canine sinus node artery has no significant effect on the rate of the sinus node18 because of the extensive arterial anastomoses in that region.r$ A three-way stopcock attached to the proximal end of the cannula in the sinus node artery permitted injections into the artery and, between injections, the measurement of retrograde pressure. Other pressures routinelv measured included those in the aorta (via a femoral artery) and the right atrium {via a jugular vein). Heart rate was constantly monitored by an instantaneous tachogram derived with an analog computer from successive R waves in the electrocardiogram. During constant record-
Am. Heart 1. hwst, 1967
ing of the tachogram and pressures at 0.25 mm. per second on a polygraph, the pulses and ECG were monitored on an oscilloscope with a sweep speed of 50 mm, per second. Through a slave circuit a separate ECG was recorded constantly at 25 mm. per second and collated with the master record. The right stellste ganglion was isolated within the thorax and stimulated with an electronic square-wave stimulator at 30 c.p.s., l-millisecond impulses, in 6-second trains, at submaximal voltage. Solutions for injection into the sinus node artery were prepared either in Ringer’s solution or in fresh autogenous arterial blood, as indicated. Ethanol, methanol, acetaldehyde, formaldehyde, acetic acid, and formic acid were so prepared. Of these, acetaldehyde presented a special problem because of its volatility at ordinary room temperature; for consistent preparations it was necessary to mix acetaldehyde in cold (about 6°C.) Ringer’s solution or blood. Each injection into the sinus node was preceded by a control injection of either Ringer’s solution or arterial blood. These injections were routinely of Z-ml. volume delivered from a hand syringe in 5 to 10 seconds. Any injection directly into the sinus node artery produces bradycardia, which has been determined to be due most likely to physical distention of the sinus node artery.20 After such injections there is routinely a brief postinjection acceleration which is due to local release sulfate, I of norepinephrine. 21 Atropine mg. per kilogram, was injected intravenously. Reserpine was administered intramuscularly, 0.5 mg. per kilogram, for 2 days prior to an experiment. Propranolol* and I-norepinephrine bitartrate were prepared in Ringer’s solution for intranodal injection. Chronotropic effects of test solutions were interpreted relative to preceding control injections in each animal. Negative effects are reported only as they exceeded the control-injection bradycardia in degree and duration. Positive effects are calculated as they exceeded the control degree and duration of postinjection acceleration. The effects of injections of acetaldehyde *Supplied by Dr. A. Sahagian New York, N. Y.
Edwards.
Ayerst
Laboratories,
which were ali cold were compared rouCnely x0 control injections of the same temperature. The pulse amplitude in the ligated sinus node artery is due to atria1 contractio@ and was used together with xhe intra-atria1 pulse as an indirect indicat-or of inotropic response.
The resu!cs -my Se siilii?3litr:L~ii i)j, indicating that acetaldehyde i&as the on1~ substance studied which produced an effect, except at very high concentrations. Ethanol ‘1a.d no significant chronotropic action, except at 10,000 fig per milli!itei- ;Kg. S.),
Fig. 1. This experiment demonstrates the characteristic re.,pcnse to 2 ‘brief direci peritir:ti,i :)i t;x dnx iorie with ethanol. Bradycardia during injection and postinjection acceleration are the same after the contra! (Cj injection of Ringer’s solution and after 0.1 and 1.0 mg. per milliliter of ethanol. Only with IO nip, per milliliter of ethanol was there a consistent negative chronotropic effect, here manifest by loss of the 11crma! pokxjectioc acceleration and slight prolongation of the injection bradycardia. Recordings in this and sui;scquent similar graphs are CfYonz above dow,n) right atria1 pressure (I?.A), retrograde pressure in the cannulated lisated sinus node artery (SNA), aortic pressure (Ao), tachogram (HI?), and electrocardiogram (EC@. The prekres are scaled In millimeters of mercury, and HR in number of beats per minute. Recording paper speeds are indicated by horizontal-bar time references.
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which is twice the level ever observed in man, even in deepest drunkenness. The same was true of methanol. Acetic acid had an insignificant effect below concentrations of 100 ug per milliliter, at which level the pW of the test solution was 3.7. Formic acid acted similarly. Constituting the two acids in fresh autogenous arterial blood at the same concentrations lessened the acidity of the solutions, because of
Am. Heart J. .$uglcst, 1967
normal buffering mechanisms in blood, and similarly reduced or eliminated the chronotropic effect. Formaldehyde had no significant effect below a concentration of 1,000 ,ug per milliliter (Fig. 2). The only cardiac effects observed with ethanol (16 dogs), methanol (4 dogs), acetic acid (10 dogs), formic acid (4 dogs), and formaldehyde (7 dogs) were depressive, slowing the sinus node and reducing the ampli-
Fig. 2. On brief direct perfusion of the sinus node, formaldehyde (FOLD) had no significant chronotropic action below concentrations of 1 mg. per milliliter, and only a negative action at that concentration. Here the transition from sinus rhythm to A-V nodal rhythm is demonstrated after 1 mg. per milliliter of FMLD had been injected into the sinus node artery. The point of transition is indicated by the asterisks. This effect lasted 2 minutes; recovery of sinus rhythm was attributable to the rapid removal of FMLD by flow from arterial anastomoses about the sinus node.
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tude of atria1 pulses, the latter representing a negative inotropic action. The depressive effects persisted after atropinization and reserpinization, indicating that they were not mediated by vagal stimulation and were not an antiadrenergic effect. Acetaldehyde produced increasing degrees of acceleration of the sinus node with increasing test concentrations, beginning with a significant but inconsistent effect at 10 pg per milliliter (Table I and Figs. 3 and 4). There was a concomitant increase in the amplitude of the pulse in the ligated
Fig. 4. During rhythm remains
the effect of ACLD here of sinus origin in the ECG,
sinus node artery and in the right atrium, indicating a positive inotropic action. Both the positive chronotropic and inotropic effects resembled the actions of tyramine injected directly into the sinus node.23 Serial injections of intranodal acetaldehyde, 1,000 bg per milliliter at lo-minute intervals (in 5 dogs), continued to produce maximal accelerative responses for 1 hour; longer serial periods or shorter intervals between injections were associated with sinus arrest and periodic rhythm, which most likely represented toxicity.
the recording paper speed was accelerated and the amplitude of A waves in the atria1
to demonstrate pulse is increased.
that
the
jrable I. Sinus tachycardia acetaldehyde in 16 dogs
jrom
intranodal
I ,
Concentration
1 -
of acetaldehyde (Pd~~~.) -7
10
1
100
1,000
Ivlaximum level* of acceleration
(beats/minrrte) Duration* of acceleration (seconds)
3
j! 11
Same as control
acera!d& ycie is:as of 3 dogs, prepared in a?ltogenotis lrrterix! 5’100$, and 5ltranodal injections ~xoduced the same responses as dkl acetaldeh>de prepared in Ringer’s solurion. Intravenous administration: of acetaldehyde, ? mg. r;er kilogram a:ld less, produceb :ninor IV consistent effects, but 10 mg. ixr kilngram consistently produced both aortic hypertension and sinus ta&ycardia (Fig. 5), as has been demonstrated IS>T~thers.*~-‘~ Aortic hq;pertension, increased amplitude of atria1 pulses, and sinus acceierarion were ail much diminished or &sent ai”ter res. . . . erpinlzatlon in 4 dogs (Fig. 01. ‘The acIll
thi:
case
freshly
23 A 17
81 *
51
45i
12
311 & 139
*Both the level and duration of acceleration are expressed only as they exceeded the response to control injections of Ringer’s solution in the same dog. Results for the 16 dogs are given as the arithmetic mean * 1 SD.
Fig. 5. AU injection of acetaldehyde into the central venws circ&Gon [right atriwx), c‘~ob!ip‘mb:i~ .il alw~rr 50 times the maximal volume given in the experiments u;ith intrailodal iiijection in Figs. 3 XK~ 4., pwd;~~s aurtic hypertension and slight cardiac acceleration. The brief slowing dliring intra-atria1 injecticxx was dlte to the loral effect of 10 ml. of cold test solution. Since the chronotropic action by this large volume of ACLO adminisre.rcci systemically is SOmuch less than that by the much smailer volilme perfused d’irectly throL!gh :he sintrs tx&, an extracardiac effect from recirculated ACLD is not likely to be a significant factor jn the ::osiriw cbronolropi.c response after intranodal ACLD.
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celerative response to acetaldehyde could not be restored with intranodal norepinephrine in the reserpinized dogs, although it can be with tyranline23; it may be noted that intranodal norepinephrine also fails to restore the response to stimulation of the stellate ganglia in reserpinized dogsg3 The increased pulse amplitude and the sinus tachycardia were readily reversible in 4 dogs with intranodal propranolol (Fig. 7), and blocked in immediately subsequent injections of acetaldehyde. In 3
of these 4 dogs, responses to acetaldehyde were followed at lo-minute intervals and returned to control levels of acceleration in 40 to 60 minutes, which is the duration of action of propranolol in this experimental preparation. Stimulation of the stellate ganglia in 3 dogs during the acceierative effect of various concentrations of intranodal acetaldehyde produced either normal or slightly reduced accelerative responses and increased atria1 pulse amplitudes (Fig. 8); neither the positive chrono-
Fig. 6. In this reserpinized dog (KSP), response to intranodal norepinephrine (NE) and control Ringer’s soluof ACLD has no significant chronotropic effect. The longer tion (R) is of the usual type, but 1 m,.w per milliliter duration of injection bradycardia after ACLD than after Ringer’s solution is due to a wash-in of NE from the catheter by the Ringer’s solution.
tropic nor inotropic neurogenic response was augmented by acetaldehyde. Sinus tachycardia from intranodal norepinephrine, 0.05 and 0.1 pg per milliliter, was not augmented by prior or concomitantly administered acetaldehyde. Maximal sinus acceleration from intranodal acetaldehyde was similar before and after intravenous atropinization in 3 dogs. Discussic9n -4cetaldehyde clearly has profound direct effects on the heart. Cardiac stimulstion occurred at levels which normally
Fig.
develop In man after ingestion oi eihano?, and resemble those observed ;tfter the experimental administration of :icetaldehyde intravenously in human vol~~r~~ers.“” Concentrations of acetaldchyde after drinking in man may reach 10 pg per milliliter, and with prior administration of tiisuifiram (,?ntabuse) can reach 100 yg per rniflifiter, Since both acetaldehyde and etkuroi have a number of significant concomilant extracardiac effects” SO,I5 which ma>’ secondarily influence the heart, it is not surprising that physical findings, such as rhe blood pressure and heart rate, are so variable
7. Reversal of the effects of intranodal -4CLD by intranodal piopranolol
2.52
James and Bear
Am Heart I. Augast. 1967
Fig. 8. The sinus tachycardia after a submaximal stimulation of the right stellate ganglion (KS) was similar before (left panel) and during the positive chronotropic effect of intranodal ACLD. This makes it unlikely that “sensitization” to normally released (or normally present) norepinephrine is a significant factor in the positive chronotropic effect of ACLD.
in groups of alcoholic patients, as well as from one time to another in the same patient. Hypotension associated with the warm flush in acute alcoholism may counteract the hypertensive effect of acetaldehydemia. Tachycardia from acetaldehyde or secondarily from hypotension (or both) may be opposed by the direct noxious effect of ethanol on the heart or even by the toxicity of certain congeners occurring in some alcoholic beverages. In considering the mechanism of the ultimate cardiovascular effects of ethanol, one must begin with an appreciation of the complexity of the factors involved. Since recent reviews have
discussed the physiologic responses to ethanol and the many possible contributing factors in the pathogenesis of alcoholic cardiomyopathy,2~3~24-36 this discussion will concentrate on the actions of acetaldehyde. The possible role of acetaldehyde in the net effects of chronic alcoholism has been investigated by a number of workers, but primarily relative to neurologic effects and especially after disulfiram, which inhibits the degradation of acetaldehyde.4*35 When one is considering the potential role of acetaldehyde in the genesis of alcoholic it is important to indicardiomyopathy, cate that patients who are chronic alco-
holics do not lose the ability to change ethanol into acetaldehyde, and that they may even do it more rapidly and efficiently than nonalcoholic patients.36 This is true despite the fact that the aIcohol-dehydrogenase activity which transforms ethanol to acetaldehyde, as well as the aldehydeoxidase activity which breaks down acetaldehyde, both occur predominantly and almost exclusively in the liver,28 which is frequently diseased in alcoholic patients. On the basis of the present and previous nndings about the cardiovascular effects of acetaldehyde, its actions on the heart may be summarized as follows. In concennot infrequently occurring in trations acute alcoholism in man, acetaldehyde rapidly releases myocardial stores of norepinephrine. This interpretation is based on the similarity of its actions to those of tyramine or of directly administered norepinephrine, and the fact that these actions can be reversed and blocked with specific beta-receptor blocking agents and are not observed in the reserpinized animal. Acetaldehyde is also known to be capable of releasing norepinephrine and epinephrine from extracardiac stores, including the adrenal medulla, but its cardiovascular effects are nearly as prominent even after ligation of the adrenal veins.r1J3 Although circulating catecholamines released from the adrenal medulla may augment the stimulating effect of acetaldehyde on the heart, the direct cardiac action is probably more important. Since the action of acetaldehyde in these and otherI experiments could not be restored after reserpinization by the administration of norepinephrine, its norepinephrine-releasing action differs from that of tyramine and resembles that which follows adrenergic nerve stimulation. There is no vagolytic component to the sinus tachycardia from acetaldehyde, nor is there any element of sensitization to norepinephrine. Formaldehyde does not share the positive chronotropic and inotropic actions of acetaldehyde. In the present study, we performed only acute experiments, and the duration of the administration of test substances was brief (5 to 10 seconds). The actions of acetaldehyde were consistent and marked under these circumstances. The absence of significant action of ethanol and of the other
substances studied, except in ~:?~s~all>~ high concentrations, must be interpreted in view of the brief administrations, and with more prolonged administration these substances may have significant effects Since acetaldehyde acutely stimulates the heart, one can construe its actions to be beneficial. This stimulation occurs through the liberation of cardiac stores of norepinephrine, however, and it has recently been demonstrated that t-he myocardium is deficient in norepinephrine during congestive heart failure c?~e to a variety of causes. 35-3g If the heart of the chronic alcoholic is at all diseased, then further depiction of its stored cztecholamines must be deleterious, pa.rtirulariy if this occurs repeatedly a.nd for- 2~ long time. In addition to the ultimate bad effects of depletion of norepinephrine, the acute stimulation during the course of release of norepinephrine may be thought of as whipping a tired horse. This is particularly the case if substances (induding ethanol) with cardiac depressan L actions are simuitaneousiy present. Fu.rn.hermore, chronic repeated cardiac stimuiation of the heart with catecholamines (ar In pheochromocytoma) may directly damage the myocardium,40 In addition to its norepinephrine-releasing action, acetaldehyde is also capable of releasing serotonin.41 Serotonin has only a weak negative chronotropic xction on direct perfusion of the sinus node,“” but under certain circumstances may sfimdate the heartd3 Whether this contribiltes to the final effect of acetaldehyde on th.e heart in alcoholic patients is uncertai!k, but the action of acetaldehyde in releasing norepinephrine seems more likely to be the important one. One of the puzzles in alcoholic cardiomyopathy is why, among patients consuming similar amounts of ethanol and eating reasonably comparabie adequate diets, some develop heart disease an.d others do not. Undoubtedly, the presence oe’ associated problems, such as coronary atheroscIerosis or viral infections!, ma?; account for some of this discrepa.ncy. VVC may also consider possible individual differences in response to the release of norepinephrine by acetaldehyde. Those patients with generous stores of myocardial ?-orepineph-
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rine may get profound stimulation during the acute effects of acetaldehyde, whereas those with smaller stores may not. Similarly, there must be individual variation in the ability to resynthesize depleted stores of norepinephrine. Those alcoholic patients with a high level of such ability may not develop the ill effects of catecholamine depletion for a long time, or at all, whereas those with poor ability to replace norepinephrine may develop cardiac disease soon. Summary
In anesthetized dogs, direct perfusion of the sinus node with acetaldehyde produced marked stimulation in concentrations similar to those occurring in human alcoholism. Ethanol and closely related compounds had only depressant effects, which during these acute experiments were observed only with unusually high concentrations. The stimulating action of acetaldehyde resembled that of tyramine, was not altered by atropinization, could be reversed and blocked with propranolol, and was virtually absent after reserpinization, which suggests that it is due to the direct release of myocardial norepinephrine. Both the acute and chronic cardiac effects of alcoholism may be due in part to the release of myocardial norepinephrine by acetaldehyde, the principal metabolite of ethanol. REFERENCES Evans, W.: The electrocardiogram of alcoholic cardiomyopathy, Brit. Heart J. 21:445, 1959. 2. Brigden, W., and Robinson, J.: Alcoholic heart disease, Brit. M. J. 2:1283, 1964. 3. Burch, G. E., and Walsh, J. J.: Cardiac insufficiency in chronic alcoholism, Am. J. Cardiol. 6:864, 1960. 4. Goodman, L. S., and Gilman, A.: The pharmacologic basis of therapeutics, ed. 3, New York, 1965, The Macmillan Company. 5. Wendt, V. E., Wu, C., Balcon, R., Doty, G., and Bing, R. J.: Hemodynamic and metabolic effects of chronic alcoholism in man, Am. J. Cardiol. 15:175, 1965. 6. Wendt, V. E., Ajluni, R., Bruce, T. A., Prasad, A. D., and Bing, R. J.: Acute effects of alcohol on the mvocardium, Am. .I. Cardiol. 17:804, 1966. . 7. Regan, T. J,, Kcroxenidis, G., Moschos, C. B., Oldewurtel, H. A., Lehan, P. H., and Hellems, H. K.: The acute metabolic and hemodynamic responses of the left ventricle to ethanol, J. Clin. Invest. 45:270, 1966. 1.
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Ferrans, V. J., Hibbs, I?. G., Weilbaecher, D. G., Black, W. C., Walsh, J. J., and Burch, G. E. : Alcoholic cardiomvooathv. A histochemical study, AM. HEART J. 6$:+48, i965. 9. Hibbs, R. G., Ferrans, V. J., Black, W. C., Weilbaecher, D. G., Walsh, J. J., and Burch, G. E.: Alcholoic cardiomyopathy. An electron microscopic study, AM. HEART J. 69:766, 1965. 10. Handovsky, H. : Au sujet des proprietes biologiques et pharmacodynamiques de l’acetaldehyde, Compt. Rend. Sot. Biol. (Paris) 117: 238,1934. 11. Nelson, E. E. : Pressor response to acetaldehyde and its potentiation by cocaine, Proc. Sot. Exper. Biol. & Med. 52:23, 1943. 12. Asmussen, E., Hald, J., and Larsen, V.: The pharmacological action of acetaldehyde on the human organism, Acta Pharmacol. 4:311,1948. of sympathomimetic 13. Eade, N. R.: Mechanism action of aldehvdes. 1. Pharmacol. & Exper. Therap. 127 :29,\959. d 14. Kumar, M. A., and Sheth, U. K.: The sympathomimetic action of acetaldehyde on isolated atria, Arch. Int. Pharmacodyn. 137:188, 1962. 1.5. Toels. N.. and Neil. E.: The action of acetaldehide’ in’ the chemoreceptors of the carotid glomus, J. Physiol. 168:234, 1963. 16. James. T. N. : Anatomy of the coronary arteries, New York, 1961, Paul B. Hoeber, Inc. 17. James, T. N., and Nadeau, R. A.: Direct perfusion of the sinus node: An experimental model for pharmacologic and electrophysiolcgical studies of the heart, Henry Ford Hosp. M. Bull. 10:21, 1962. 18. James, T. N,, and Hershey, E. A., Jr.: Experimental studies on the pathogenesis of atria1 arrhythmias in myocardial infarction, AM. HEART J. 63:196, 1962. 19. James, T. N.: Anatomy of the sinus node of the dog, Anat. Rec. 143:251, 1962. 20. James, T. N., and Nadeau, R. A.: Sinus bradycardia during injections directly into the sinus node artery,-Am. J. Physiol. 204:9, 1963. 21. Tames. T. N.. and Nadeau, R. A.: The chronoGropic’and vagal-blocking ‘actions of naphthylisoproterenol studied by direct perfusion of of the sinus node, J. Pharmacol. & Exper. Therap. 143:350, 1964. 22. James, T. N., and Nadeau, R. A.: A study of retrograde pressure and pulse in the sinus node artery, AM. HEART J. 66:343, 1963. 23. James, T. N., and Nadeau, R. A.: The chronotropic action of tryamine studied by direct perfusion of the sinus node through its artery, J. Pharmacol. & Exper. Therap. i44:83, 1964. 24. Tacobsen. E.: The metabolism of ethyl alcohol, Pharmacol. Rev. 4:107, 1952. . 25. Ganz, V.: The acute effect of alcohol on the circulation and on the oxygen metabolism of the heart, AM. HEART J. 66:494, 1963. 26. Gimeno, A. L., Gimeno, M. F., and Webb, J. L.: Effects of ethanol on cellular membrane potentials and contractility of isolated rat atrium, Am. J. Physiol. 203:194, 1962. A. H.: Ethanol and urinary catechola27. Anton, mines in man, Clin. Pharmacol. Therap. 6:462, 1965.
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Schneider, J. A., and Yorkmart, F. !:‘.: Species differences in the respiratory and cardiovascular response to serotonin (5-hqdroxytr~ptarnine), J, Pharmacof. & Exper. Therap. 11j :85. 1951.