STUDIES ON ALCOHOL DIURESIS. II. THE EVALUATION OF ETHYL ALCOHOL AS AN INHIBITOR OF THE NEUROHYPOPHYSIS

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1 STUDES ON ALCOHOL DURESS.. THE EVALUATON OF ETHYL ALCOHOL AS AN NHBTOR OF THE NEUROHYPOPHYSS Charles R. Kleeman,, Ezra Lamdin, Franklin H. Epstein J Clin nvest. 1955;3(3): Research Article Find the latest version:

2 STUDES ON ALCOHOL DURESS.. THE EVALUATON OF ETHYL ALCOHOL AS AN NHBTOR OF THE NEUROHYPOPHYSS 1, 2 BY CHARLES R. KLEEMAN, MLTON E. RUBN,3 EZRA LAMDN, AND FRANKLN H. EPSTEN (From the Department of nternal Medicine, Yale University School of Medicine, New Haven, Conn.) (Sbmitted for pblication September 7, 195; accepted November 2, 195) n the normally hydrated semirecmbent individal, alcohol cases a rise in rine flow that is characterized by an increase of free water clearance (CH2O) and a decreased excretion of sodim, potassim and chloride (1). The evidence to date strongly sggests that the rise of CH2O is cased by inhibition of the release of antidiretic hormone. The present stdy was ndertaken to evalate the effect of alcohol on the excretion of water and soltes in physiologic states in which alterations in the activity of antidiretic hormone have been demonstrated or sggested. The following states were stdied: 1) Minimal antidiretic hormones (ADH) activity prodced by sstained positive loads of water; 2) ncreased ADH activity prodced by infsions of hypertonic sodim chloride soltions, a) dring water diresis with high rine flows (1 to 15 cc. per min.), and b) in sbjects with low rine flows (1 to 2 cc. per min.); 3) ncreased antidiretic activity prodced by venos congestion of the limbs. MATERALS, METHODS AND RESULTS Sbjects were normal males, aged 25 to 32. No control of diet prior to the day of stdy was attempted. One to one and a half hors after a light breakfast the sbjects voided and reclined in a semirecmbent position. All stdies were begn at 8:3 to 9: A.M.; dirnal variations in rinary flow and composition (2) were therefore presmably similar in all experiments. Alcohol was given as 12 cc. of 1 proof borbon whisky imbibed over a 1minte period. Techniqes for collection of blood and rine and chemical methods have been described in the previos paper (1). n all stdies insensible water loss was assmed to be approximately 5 cc. per hor. Changes in extracelllar 1 Spported in part by a Grant from the U. S. Pblic Health Service. 2 Presented in abstract form at the meeting of the American Society for Clinical nvestigation, Atlantic City, May 25, Major, MC, USA. 'Postdoctorate Research Fellow of the U. S. Pblic Health Service. space were calclated approximately from changes in the chloride space (3), assming an initial extracelllar volme of 2 per cent of body weight Changes in plasma volme were calclated from changes in hemoglobin and hematocrit (1). Urine flow was divided into two fractions: Osmolar clearance (C.,,) milliosmols per kilo of rine milliosmols per kilo of plasma X rine flow (cc. per min.) Free water clearance (CH2) = rine flow C, Grop. Effect of alcohol dring water diresis (Table, Figre 1C) A positive water balance was indced in two semirecmbent sbjects by drinking one liter of water, and was maintained by infsing per cent frctose soltion intravenosly and administering spplemental water by moth. The accracy of this techniqe was checked by weighing the sbject at the beginning and the end of each experiment. Frctose soltion was chosen becase of its minimal effect on the total hexose in the blood. By limiting the rate of infsion to 8 cc. per minte or less, no redcing sbstances cold be detected in the rine by qalitative test with Benedict's soltion. After a maximal steady rine flow had been maintained for at least two 3minte periods, alcohol was imbibed. Urine was collected at 15 to 3minte intervals dring the next three hors. Under these circmstances, alcohol did not indce a frther increase in rine flow or CH,o (Figre 1C). f large positive loads of water (1 cc.) completely inhibit ADH release ("physiologic diabetes insipids"), this reslt wold be expected.5 The rates of excretion 5 The statement that maximm water diresis is associated with complete inhibition of ADH release or socalled "physiologic diabetes insipids" probably is tre for the recmbent and semirecmbent positions only. n npblished experiments the athors have demonstrated that when a positive water load of 1 cc. is maintained, the maximm rinary flow and free water clearance (CH2) attained in the standing or 5 position were frther increased by lying down. This sggests a continal "tonic" release of ADH in the pright positions in spite of the sstained water load or nonhormonal factors blocking the maximm rise in rinary flow. 8

3 m t P C., ~. N ; 1; C. ; i ' X ~ E Ei d oc E CE U2 Ė a 3. H N 2 6 z Z CO 3.. o el. axo ' ++ _ 2 et~, o eqqo o o CC CCC 2i * 8 (on')' C o,~~~~~~~~f C~~~~~c." e~~ o e'o C. c it; o. c ETHANOL NHBTON OF THE NEUROHYPOPHYSS o e C, vzoe^q ( No o o O o o'o 2 oo oc c:1 oo Ca C CS Go ', W 2 : on e br( 2! c! * r'.a C,,' 'AP.'C.fCeo. oc.j*' o.)nw. aotoo% oe *csowoww wolotl CV%totorOee a looooo N \o\ t. q',. choaot'.o. ooa.en t' 9o a Z.U) C t,* O bt~m c mv 1o ooo vo+ebao_* in _ ok ok _ ao N, _o_ Cc1Ol r o esc eebb o o co t 8..OC'..r'.oOOo. U) MC'),GqoaqC NONO ) CO1v6C ** va ( Cst t oob"tno. *te N _ N +>o_ F) z A.. 2 '1.. m to a C t 9 of Na and Cl did not decrease after alcohol ingestion and althogh the rine became more acid, excretion of ammonim was not enhanced. These reslts contrast sharply with the findings when alcohol is administered to sbjects with low or moderate rinary flows (1). Grop a. Effect of the simltaneos administration of alcohol and hypertonic saline to waterloaded sbjects (Table A, Figre 1A and 1B) Positive water balances were achieved in for experiments in a manner similar to that described for Grop. n two control tests (No. 1 and No. 2 Table A) 5 cc. of hypertonic saline (5 to 6 per cent) was infsed withot alcohol. n two frther experiments (No. 3 and No., Table A), alcohol was imbibed simltaneosly with the beginning of the hypertonic infsion. The administration of hypertonic saline withot alcohol, at the height of a water diresis, was followed by a prompt decrease in rine flow and free water clearance (Figre 1A). n contrast, the sbjects receiving alcohol not only failed to show an antidiresis, bt actally increased their flow of rine above the levels reached dring maximal water diresis (Figre 1B). Free water clearance (CH2o) increased in spite of a to 5 per cent rise in the osmolarity of the serm. t is apparent that alcohol effectively blocked the antidiretic response to hypertonic saline. Grop b. Effect of alcohol on the antidiresis following hypertonic saline in sbjects with low rine flows (Table B, Figre 2) n two sbjects, 3 cc. of 5 to 6 per cent saline were 2 infsed intravenosly after a sitable control period. Approximately 3 mintes after starting the infsion alcohol was imbibed. c n neither sbject did a water diresis occr after al " cohol. Prior administration of hypertonic saline, with a, conseqent increase in the effective osmotic pressre of f extracelllar flid, presmably indced the release of increased amonts of ADH from the posterior pititary (). Since alcohol affects neither exogenos ADH nor ' the ability of the tbles to respond to this hormone (5) an excess of circlation ADH probably masked the inm hibitory effect of alcohol pon the spraopticohypophyseal system in these experiments. 8.1 Grop. Effect of alcohol on the antidiresis of venos 1. congestion (Table, Figre 3) The effect of alcohol on the antidiresis prodced by venos congestion of the limbs was tested in three sbjects in whom sphygmomanometer cffs were inflated i.a c abot the thighs to a pressre of 7 to 8 mm. Hg. (n all, a positive water load of 5 cc. was established and maintained throghot the experiment.) n two stdies (No. 1 and No. 2, Table ) a control period of venos congestion for 3 mintes, institted after maximal rine flow had been attained, prodced a prompt fall in rine flow, CH2o, and Co.m, as well as in the rates of excretion of sodim, potassim, chloride, and creatinine. These

4 5 g C. R. KLEEMAN, M. E. RUBN, E. LAMDN, AND F. H. EPSTEN A WATE R S ALT S U r Cosm O~ CH,sO URNE FLFW 2 r WHSKEY o2 ec) v i%,saine U U M ALCOHOL B WATER 1 SALT 11 S1m121 WLi ill md,~~~~~m ar~~~~~~~~ t.:,il~~ ; ALCOHOL O/ C + ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1 WATER 7 : it 12 8 so _..f POO MNUTES FGURE 1 Alcohol prodced no increase in an established water diresis (Figre C). n contrast, when alcohol was given with an intravenos load of hypertonic saline, rine flow and CH2o increased (Figre 1B), and the characteristic antidiretic effect of hypertonic saline (Figre A) was blocked. A ALCOHOL (B a ~ WN"X :*lw /\ t \ Cosm~~~~% a" G < o / fl& L gl E o~~~~~~~~~ 19 B ALCOHOL SALT C (c) 2 MN UTES so no FGURE 2 Prior administration of hypertonic saline (Figres 2B and 2C) blocked the characteristic diresis following alcohol (Figre 2A).

5 . *; *g 9 3.) A qb.1 Slb la S *. i a; U5 CO 9 o t _~~~~. ETHANOL NHBTON OF THE NEUROHYPOPHYSS W) 3N if)1s 3 q 3 wv)s ' 33 U) o % U) if U) 's 'd ' ' W W G V1) ( if G '..oe ef) eq t, ' 1'_ Go eq % % e. eq eq e ' eqeqeq C eq if %a N a NO...all eq N No o ' eq N eq e. eq eq emm e if) eq 3 i i) if if if) if if) 'o N i o o 3 *.. *.. coeqc N% eq U) N % ' N v3) t U) _ ) U) fif 3 U) Nz if%eq_; eq S eq eq N eq C eq N CS eq _ ( 3 if) eq if eq C. O N C O. O. *3 ~ U)... U)*U eq U) No eq coo eq e e q N % U) if if U) U) % W) % G ' Coo) U) if) U) if)c ' eq eq _ i '* _.if 1 V) 1* % c.. O i)eq U CO. if._ q, C6'i m m t ON " V ) 1.7 m) $ if)if) m m m % U) U) "i if " 1 i) 3 3 t N M N.o S 1U) Ḵ i en t " NOo 1, tn M. Obe_ ; b * ' if%. )..o%if) Ni 51 (O. *2 3..' * Oa. 9 i 1 N fz U.2 ( s z Q " %O i ) W)133 3tt.N 2 O : 6 "oev>o Ne"Noreq eq N if if N '3.U) t' % fnk:a!nu)ncou)qnq % ' ct" if3q'eeq!eq ' eq eq'%i)omr81ceqe b q q% U) % e 3% q ) '3 'l3a a'% an ' 39 c3 if)if)neqeq 3 33W)W eqq eeif) if) aif if) %'~! Oleq33 ' "1U)...%.%%NN en M. O V N3eq 33 "vn""""eeya NN 3 N' U)N%if%3 eqeq_ i) if if "".e i ) ". ), r_ r_ o k t "WM _; o _;c o ii f% ~!~U~f%.N.3 n qcj.3.3* %.* teqef)u 'U, % eqn _ '. t q 3%'if)U)% W3 U)' eqnt U) V) 'U) N %'W33 ) NNU)o'%' if ^ eq eq e i if) ifi) if)eqif U>^>^_8X U) WNN_ eq N3i) ~ e i)i)e N. V). U) if) N.) 'q W) in.n O W eqif)e qq eq if3.i) ' )U U) ' U)No e Y) U) 3 if e eq i f) N UW). i) ifn Ne if ON i 3 e eqeqqee eq eqeqeqeq if)e Wqe 33r1)... S.W L Oif)3eq'U)%% W 'eq)'sns3eq3e U)eqNifif)''UNe inf)e).uwl)ooo) W)) '''''^'^d NvN'''''' N'U)U)U)U)U)U)U)''U)U)U)U)U. :3 en * m~~~~~~~)m ll~ ~~. ~~ P ; xlc + ++)" K,Q.> U*. * 11

6 52 C. R. KLEEMAN, M. E. RUBN, E. LAMDN, AND F. H. EPSTEN x, v.x. t :s, l.b a at m o "., O * Ca' '. is * e m o. X ' *S ) 65 co S CEl ce o i_n el! _ C ' " co S A.. Nq O oo r e a o, C) C C C.] CCCCC s! ")Ove m"m.o rv ffc!cmv C ( C~ 1 m " " 1 C go8 OO "c" Ot.OOtOO (ZoWO, *+ ec) o, 7 ~C 3. C C ""cā ma. CCC C~ Ce e) Cc MO ow) W ~~..~~~. R a.*.! *o 'o CiU a E1 F fnctions retrned to or toward control levels after the congestion was released. After a sitable period of recovery, dring which the rine flow stabilized, alcohol was administered 3 mintes prior to the application of congesting cffs for the second time, this time for 6 mintes. Despite a more prolonged period of venos congestion, only slight falls in rine flow and free water clearance were prodced, althogh the decrease in solte excretion and C..m was comparable to that dring the control period of cffing. Under these circmstances, therefore, prior ingestion of alcohol minimized the antidiretic effect of venos congestion (Figre 3A). n a third sbject (No. 3, Table ), alcohol was imbibed 1 mintes after the cffs had been inflated. Urine flow and CH,o, which had diminished after the cffs had been, applied, did not increase after alcohol was administered, and started to rise only after the cffs were released (Figre 3B). DSSSON n the present stdy, alcohol prevented or minimized the fall of rine flow and free water clearance (CH2o) that characteristically follows the administration of hypertonic soltions of sodim chloride or venos congestion of the extremities. Alcohol will also prevent the antidiresis of dehydration (6) or the administration of acetylcholine (7) and nicotine (6), and it has no effect on rine flow when it is given at the height of water diresis or to dogs with diabetes insipids (7). These observations constitte overwhelming evidence that it has an inhibitory action on the spraopticohypophyseal system. The antidiresis that reglarly follows venos congestion of the lower extremities or stationary standing has been ascribed in part to increased activity of the nerohypophysis as a reslt of diminished effective blood volme (8, 9). Facts in favor of this interpretation are: 1) a diminished or absent response in sbjects with diabetes insipids or in hydropenic sbjects with maximal ADH activity who are ndergoing a mannitol diresis (1); 2) a fall in rine flow ot of proportion to the changes in electrolyte excretion and glomerlar filtration (8, 9); 3) the appearance of an antidiretic sbstance in the blood of normal sbjects after circlatory collapse indced by motionless standing (11). The ability of alcohol to inhibit the antidiresis of venos congestion lends added weight to the concept that changes in rine flow following alterations in the volme and distribtion of body flids are to an important degree

7 S.; 1:;. ETHANOL NHBTON OF THE NEUROHYPOPHYSS,,, if) o '%~t 1) i) 53 )b R..b No N o oet eqeq N M eq eq Ce W o S " " " " N 11) l G eq G eq eq eq if 8" s.f S,i W) N 11E eqt.o r ~ G a.b *s CqeN ( C C1 Eq Ce t O N Cl C o eq eqif G c ' if e* _ "? "? t c o N d GoN so v o _ ow CZ 65 %. * '.: ~ eq eq (q pe em eq ~ 7%V ) % % %CS *. *. t; dqeq1 e e " f) 11) )) if %a co z G $, Z.. Sq t C _ % f) ) i mm w i eq),i) d _..1) co ) 1.) a) 1O ) 8 $ t %;~c "cc )tcmvt,)q % q)qi)q eq. V " ' el!oa Ot Y) V l q dli tci,, ~ ) c ) ) Q 1O. '. z)eq mv1)1w)w*11)*%"nn*%*' * 11)qOV bdv)c!q % %D~~~~~~~~~~~~~~ *)eqteqififeq ) X eqv)eqi) s>v) V e1)f)feqeqeqeqeqeqeqeqeqeqs dd t * C.oee 'eq W.) Ot%if%% ' a t~q! d eq" aora iftl ' t etq')11) OR e~lq V)11) 3 c ~s x OD z: z w c) 1% % co qnav A i)eifcl meq V)qqqq)%oeq C C Xqfi)%e ZL eq.t)v,w eqe1c%c.e% e ta a a% 11Go)G (.. N if)% 1) CW)( e oeq% meq11)^' CKN%'( Go(eqeqeqao co ) if)eq") if eq eqe eq eqe eq. %C1)eq in 1)if fe) q %W)NO Cl11)(N'' if) S _ 1 ' ml) ic) ).W) in.. eqt N)taVOUi M s _VN ^_ro eq eqeeen q q q ot oo ' rreq V)eqQ%11)if)eeqO td'yodqeeqi co to" C %1)e % C.qf)e ~ e W) co eq c% v,s eq eq _" 1W)q z C' eq eq % %aeqeq_f) eq " M q eq t eq O9OddUZ+_ed eqif) Weq.. )m d )'' G tv % C'*'%*Cl"..Cl* 1)' ' " 'cc'''''' _ steqnq N 3 qc vn,)v " q" 1) * ec. o q...a eclclee so * 1 Q :3 q) 3 a

8 5 A B a a U 2a 15 lot 8 C. R. KLEEMAN, M. E. RUBN, E. LADN, AND F. H. EPSTEN LL cffs H.lM aol.~~~~~~~~~~~ 2 _cf fs S5lHS VENOUS CONGESTON. xt3 cffs KrLt p (Chao) (h.. URNE FLOW 1J MNUTES FGRz 3 Alcohol minimized the antidiretic effect of venos congestion when given prior to the latter (Figre 3A). n contrast, alcohol had little effect when given dring the period of venos congestion (Figre 3B). secondary to variations in the activity of the nerohypophysis.6 Alcohol had little effect on rine flow and free water clearance in those experiments in which it was given after an infsion of hypertonic saline or venos congestion had been initiated. Once the nerohypophysis has been stimlated the resltant excess of circlating antidiretic hormones might, ntil it is inactivated or destroyed, mask the temporary inhibition of the posterior pititary by alcohol. These experiments sggest that alcohol diresis may be blocked by a prior rise in circlating endogenos ADH as well as by the administration of exogenos Pitressin (5, 6). n the experiments of Grop, when the release of ADH was presmably completely inhibited by a positive water load in the semirecmbent position, administration of alcohol cased no frther rise in rine flow and free water clearance. fn a stdy pblished since completion of this paper Newman (12) demonstrated that alcohol cold effectively block the antidiresis of qiet standing. The increase in CH2o which occrred in the waterloaded sbjects of Grop b, to whom alcohol was given simltaneosly with an infsion of hypertonic saline, was therefore nexpected. The sitation in these experiments is probably comparable to the rapid administration of large solte loads to patients with diabetes insipids, in whom an increased volme of isosmotic flid is sddenly delivered to a distal tblar segment in which water reabsorption is blocked bt where frther reabsorption of solte does occr. n this case an increase in the calclated vale of free water clearance (CH2o) might be prodced, not by diminished reabsorption of water in the distal tble (Smith, 13), bt by an increased distal reabsorption of solte. An increase in CH2o dring mannitol or solte diresis in sbjects with diabetes insipids can in fact be demonstrated by recalclating the data of Brodsky and Rapoport (1). Similar increases in CH2o, CO8m, and rine flow were shown by Welt, Yong, Thorp, and Brnett (15) to follow the adminis

9 . ETHANOL NHBTON OF THE NEUROHYPOPHYSS 55 tration of a carbonic anhydrase inhibitor to waterloaded sbjects who were in a state of "physiological diabetes insipids." Althogh tblar secretion of water (1) cold explain sch changes, there seems little reason to invoke sch a concept. A relative or absolte increase in antidiretic hormone has been implicated in the abnormal water metabolism of sch clinical states as hyponatremia, cirrhosis of the liver, congestive heart failre, adrenal insfficiency, and panhypopititarism. The reslts of the present and previos stdies (1, 5) sggest that the effects of alcohol in states of abnormal water metabolism might be of vale in interpreting their pathophysiology. Sch investigations are now in progress. SUMMARY 1. Alcohol had no effect pon rine flow or solte excretion when given at the height of a water diresis. 2. Alcohol blocked the antidiretic response to hypertonic saline when both were simltaneosly administered to waterloaded sbjects. 3. Alcohol minimized the antidiretic effect of venos congestion of the legs in waterloaded sbjects, when imbibed before the legs were congested.. The characteristic diretic response to alcohol was blocked by prior infsion of hypertonic saline or cff congestion of the limbs. 5. When administered prior to the stimls, alcohol will effectively block stimlation of the release of ADH. ACKNOWLEDGMENT The athors wish to thank Dr. John P. Peters for his advice and criticism and Drs. D. Lester and L. J. Greenberg of the Department of Applied Physiology, Yale University for their sggestions and assistance in setting p the techniqe for alcohol determination in the blood. The technical assistance of Mrs. M. Browning and Mrs. M. Kompare is grateflly acknowledged. REFERENCES 1. Rbini, M. E., Kleeman, C. R., and Lamdin, E., Stdies on alcohol diresis.. The effect of ethyl alcohol ingestion on water, electrolyte and acidbase metabolism. J. Clin. nvest, 1955, 3, Stanbry, S. W., and Thomson, A. E., Dirnal variation in electrolyte excretion. Clin. Sc., 1951, 1, Elkinton, J. R., and Taffel, M., Prolonged water deprivation in the dog. J. Clin. nvest., 192, 21, Verney, E. B., The antidiretic hormone and the factors which determine its release. Proc. Roy. Soc., London, s. B., 197, 135, Strass, M. B., Rosenbam, J. D., and Nelson, W. P.,, The effect of alcohol on the renal excretion of water and electrolyte. J. Gin. nvest, 195, 29, Eggleton, M. G., The diretic action of alcohol in man. J. Physiol., 192, 11, van Dyke, H. B., and Ames, R. G., Alcohol diresis. Acta Endocrinol., 1951, 7, Wilkins, R. W., Tinsley, C. M., Clbertson, J. W., Brrows, B. A., Jdson, W. E., and Brnett, C. H., The effects of venos congestion of the limbs pon renal clearances and the excretion of water and salt.. Stdies in normal sbjects and in hypertensive patients before and after splanchnicectomy. J. Clin. nvest, 1953, 32, Fitzhgh, F. W., Jr., McWhorter, R. L., Jr., Estes, E. H., Jr., Warren, J. V., and Merrill, A. J., The effect of application of torniqets to the legs on cardiac otpt and renal fnction in normal hman sbjects. J. Clin. nvest, 1953, 32, Jdson, W. E., Epstein, F. H., Tinsley, C. M., Brrows, B. A., and Wilkins, R. W., The hemodynamics and renal fnctional effects of venos congestion of the limbs in patients with diabetes insipids. J. Cin. nvest, 195, 29, Brn, C., Kndsen, E.. E., and Raascho, F., On the case of postsyncopal oligria. Acta med. Scandinav., 195, 122, Newman, E. V., Metabolic adjstments to normal and distrbed circlation in man. New England J. Med., 195, 25, Smith, H. W., The Kidney, Strctre and Fnction in Health and Disease. New York, Oxford University Press, Brodsky, W. A., and Rapoport, S., The mechanism of polyria of diabetes insipids in man. The effect of osmotic loading. J. ain. nvest, 1951, 3, Welt, L. G., Yong, D. T., Thorp,. A., Jr., and Brnett, C. H., Renal tblar phenomena nder the inflence of a carbonic anhydrase inhibitor. Am. J. Med., 195,16, 612.