Effects of systemic hypoxemia and catecholamines on arterial potassium ion concentrations before and after β-adrenergic blockade

EUROPEAN JOURNAL OF PHARMACOLOGY 16 (1971) 142 147 NORTH-HOLLANDPUBLISHING COMPANY

EFFECTS OF SYSTEMIC HYPOXEMIA AND CATECHOLAMINES ON ARTERIAL

POTASSIUM ION CONCENTRATIONS

AND AFTER 3-ADRENERGIC

BEFORE

BLOCKADE *

Jimmy C COSTIN and N Sheldon SKINNER, Jr ** Department (9] Medtcme, Dtvtston of Chntcal PhyTlology, Emory Umverszty School oJ Medtcme, Atlanta, Georgta 30303, USA

Received 13 April 1971

Accepted 3 August 1971

J C COSTIN and N S SKINNER, Jr, E]Jects o] systemic hypoxemta and catecholammes on artertal potassmm ton concentrattons before and after 3-adrenergw blockade, European J Pharmacol 16 ( 1971) 142-147 Arterial blood potassmm concentrations were measured in dogs before, during and following adrenahne and noradrenallne lnfusmn and systemic hypoxemm Adrenahne infusion produced marked but transient hyperkalemm that was followed by slgmficant hypokalemm Systemic hypoxemm resulted in a large increase m the arterial blood concentratmn of potassium that was not followed by hypokalemm Noradrenahne infusion resulted m a small increase m arterml potassium but no sigmficant hypokalemla Beta-adrenerglc blockade diminished and delayed the maximum lncrease~ m arterial potassmm concentratmn assocmted with hypoxemla and adrenahne and blocked completely the marked hypokalemia that followed adrenaline mfusion The absence of hypokalemm following hypoxemm and the presence of it with adrenahne infusmn offers suggestiveevidence that the potassium changes assocmted with systemm hypoxemia may not be mediated solely through adrenahne release Potassium

~3-Adrenerglc receptors

1 INTRODUCTION Systemic hypoxemla causes a substantml but transient increase m the arterial blood concentration of potassium (Houssay et a l , 1936, Cattell and Clvm, 1938) as does the intravenous infusion of adrenaline (D'Sdva, 1934) Since systemic hypoxemm is a potent stimulus for the release of catecholammes from the adrenal medulla (Cannon and Hoskins, 1911, McQuame et a l , 1939, Feldman et a l , 1940, Becker, 1968, Stemsland et a l , 1970), it would appear that humoral stimulation of beta-adrenergm receptors is an event common to both systemm hypoxemla and adrenaline infusion With prolonged stimulation of beta-adrenergm re* Supported by National Institutes of Health Grant HE 12566-03. ** Reclpmnt of USPHS Career Development Award 1 KO4 HE 46346.

Adrenaline

Noradrenahne

Hypoxemla

ceptors produced by adrenahne mfusxon, the transient hyperkalemla is converted into hypokalemla (D'Sdva, 1934, Brewer et a l , 1939, Robertson and Peyser, 1951, Craig and Homg, 1963, Todd et a l , 1969) Stimulation of beta-adrenerglc receptors m skeletal muscle with rather adrenaline or lsoproterenol produces consistently an uptake of potassmm (Powell and Skinner, 1966) Hence evidence is available which suggests that both the mltlal hyperkalemxa and the more sustained hypokalemla associated with adrenahne infusion may relate to stimulation of betaadrenerglc receptors No reformation is available that compares the potassmm changes that occur with reflex release of catecholammes with those induced by infusion of adrenaline and noradrenahne, both before and following beta-adrenergm blockade The present studies, therefore, were undertaken to examine the effects of betaadrenerglc receptor blockade on potassium ion changes in arterial blood d u n n g reflex release of cate-

J C Costm, N S Skmner, Jr, Systemtc hypoxta and catecholammes

cholammes by systemic hypoxemla and by adrenahne and noradrenallne infusions

2 MATERIALS AND METHODS Mongrel dogs of both sexes (12 0 to 21 0 kg) were anesthetized with sodium pentobarbital (25 mg/kg) injected intravenously A tracheostomy was routinely performed, the animals were ventdated with a Harvard respirator (Model 607) A femoral artery and vein were cannulated for measurement of systemic arterial pressure and for intravenous infusions A carohd artery was also cannulated for collecting arterial blood samples for determination of plasma potassium, pH, pO2 and arterial oxygen saturation Sodium heparm (5000-10,000 units) was used for antlcoagulaUon Plasma potassium determinations were made with an Instrumentation Laboratories Flame Photometer Analysis of whole blood pH and pO2 were made with a Beckmann Physiological Gas Analyzer (Model 160), and arterial oxygen saturation was determined with an Instrumentation Laboratories CO-Oximeter Systemic arterial pressure was measured with a Statham P23Db transducer and continuously recorded on a Sanborn direct-writing oscillograph A Harvard infusion-withdrawal pump was used for intravenous infusion of pharmacological agents Noradrenallne (Levaphed Bltartrate @, 0 1% base) and adrenaline injection (1 1000) were both diluted 1 200 in Ringer's soluhon and used for infusions Beta-adrenergIc receptor blockade was accomphshed by intravenous infusion of 2 mg/kg propranolol (Inderal @) *, a dose whlch has been shown to competitively block beta-adrenergic receptors (Marshall et al, 1965, Flacke et al, 1966, Nakano and Kusakarl, 1966, Shanks, 1966, Lacrolx et al, 1968, Warner, 1968, Vlck et al, 1970) The raw powder was dissolved in Ringer's solution and infused intravenously at a rate of 5 - 8 mg per mm The procedures used in these studies is described briefly Two periods of systemic hypoxemia each lasting 3 min were produced by ventilating the animals with two gas mLxtures 5 5% O2 in N2, and * Kindly supphed by Dr R O Davies, Ayerst Laboratories

143

100% N2 Arterial pH, pO2 and 02 saturation were determined before hypoxemaa and 5 sec before cessation of it Similarly, noradrenahne and adrenahne were Infused Intravenously at two rates 0 97 ml/mln for 3rain (total = 14 55 7) and 3 8 8 m l / m l n for 1 mm (total = 19 4 ~/) In every instance, arterial blood was obtained for determination of plasma potassium concentrations before any Interventions were begun and then at 1 mm Intervals for 6 mm following the onset of either systemic hypoxemla or catecholamine Infusion

3 RESULTS Eleven animals were studied Two degrees of systemic hypoxemla were employed as well as two infusion rates of both adrenahne and noradrenahne These studies were made before and following betaadrenerglc blockade All p values refer to the paired Student's t-test 3 1

Systemic hypoxemta

Sixteen experiments were performed in eleven animals in which these dogs were ventilated with 100% N2 for three man Table 1 shows the values for arterial pH, pO2 and 02 saturation, for control and inter. vention samples Although no arterial blood samples were routinely taken for determination of these parameters after reoxygenatlon was begun, it is emphasized that the animals' ventilation was controlled and that previous use of the same technique for inducing systemic hypoxemla has resulted in the restoration of arterial pH, pO2 and 02 saturation to control levels within 1 - 2 min after reoxygenatlon was begun (Costm and Skinner, 1970, 1971) The changes that occurred in the concentrations of arterial potassium are shown in the upper part of fig 1 Before the beta-adrenergic block (open circles) the arterial potassium concentration increased from a control of 411+005 (SEM) to 744 +O19meq/1 (p< 0 001) This procedure was repeated after betaadrenergic blockade The closed circles in the upper part of fig 1 show that this level of systemic hypoxemla now increased the arterial potassium concentration from a control of 4 3 0 + 0 16 to 5.66 -+ 0 28 meq/1 (p
144

J C Costm, N S Skmner, Jr, Svstemtc hypo~:m and catecholammes

Table 1 Results from 11 animals m which 2 levels ot systemic hypoxemla were induced (5 5% O2 and 0 0% O2), showing pH, pO 2 and oxygen saturatmn for control (no hypoxemla) and 5 sec before cessatmn of the hypoxemm All values are mean -+S E M Control

5 sec before cessatmn of hypoxemla

Gas mixture 55%oxygen 00%oxygen

pH

PO2

O2 sat

pH

pO2

O2 sat

741+_008 7 39-+007

792± 1 92 74 2-+ 1 99

948-+ 1 17 91 1 -+ 201

739-+003 7 37---005

28 1-+ 1 04 92+166

51 8± 1 84 104+_297

clated with not only an attenuation of the hyperkalemla but also a slower rate of production of the hyperkalemla, l e , the peak response was approximately 1 rain later with the beta-adrenerglc block As shown m fig 1, the arterial potassmm concentrations returned to control values following cessation of the hypoxemlc stimulus but did not, during the time period studied, fall below control concentrations When a less severe hypoxemlc stlnmlus was used (5 5% 02 in N2), the changes m potassium concentrations wexe considerably smaller The lower part of

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Fig 1 Arterial potassmm concentrations (meq/l) are plotted against time (ram) for 2 levels of systemic hypoxemm upper panel, hypoxemxa reduced with 0 0% O~, lower panel, 5 5% O~ Periods of systemic hypoxemia reduction (3 rain) are shown by arrows Open circles, sohd hnes are before betaadrenerglc blockade, closed circles, dashed hnes, after blockade All values are mean +-S E M

fig 1 shows the results before (open circles) and after (closed circles) beta-adrenergic blockade Similar to the experiments with 100% N2, there was a statistically significant increase ( p < 0 001) in the potassium concentration before the beta-block However, the statistically significant increase in arterial potassium following beta-block found in the experiments with 100% N2 was not present in the experiments with 5 5% O2 3 2 Adrenahne mfusion

The upper portion of fig 2 shows the effect of adrenahne infusion (3 88 ml/mln × 1 man) on arterial potassium concentrations before (open circles) and following (closed circles) beta-adrenerglc blockade Adrenahne infusion before beta-block resulted In an increase in potassium from a control of 4 14 + 0 05 to 7 60 + 0 14 meq/l ( p < 0 001) After beta-block the increase an potassmm was from 4 12 + 0 10 (control) to 5 61 + 0 12 meq/1 ( p < 0 001) The lower portion of fig 2 shows the effect of adrenaline infusion (0 97 ml/mln × 3 rain) on arterial potassium concentrations before and following beta-adrenergic blockade The potassmm increases were highly significant ( p < 0 001) both before and after beta-block A finding common to both Infusion rates of adrenaline was that of statistically significant ( p < 0 001) hypokalemxa following the hyperkalemxa m the non beta-blocked animals but not after a beta-adrenerglc blocking agent was administered The greatest degree of hypokalemla occurred at 6 rain and in each instance control (pre-anterventlon) values for potassium were approximated at seven rain Of note, as shown in the lower portion of fig 2, the potassium concentration had begun to fall while adrenahne was still being infused Also common to both Infusion rates of adrenaline was the finding that the beta-adrenerg~c

J C Costm, N S Skmner, Jr, Systemtc hypoxta and catecholammes

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Fig 2 Arterial potassmm concentrations (meq/1) are plotted against time (mln) for adrenaline infusions (between arrows) at 2 rates upper panel at 0 97 ml/min (total dose = 14 553,), lower panel, 3 88 ml/min (total dose = 19 43,) Open circles, solid hnes are before beta-adrenerglc blockade, closed circles, dashed hnes, after blockade All values are mean -+ S E M

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Fig 3 Arterial potassium concentrations (meq/l) are plotted against time (mm) for noradrenahne infusions (between arrows) at 2 rates upper panel at 0 97 ml/mm (total dose = 14 553'), lower panel 3 88 ml/mln (total dose = 19 47)

145

blockade not only attenuated and prolonged the hyperkalemic response but abolished the hypokalemlc response as well 3 3. Noradrenahne mfuston Fig 3 shows the response o f arterial potassium concentrations to Intravenous infusion of noradrenahne at 3 88 ml/mln for 1 mln (upper panel) and at 0 97 ml/mm for 3 min (lower panel) Thirteen observations were made with each infusion m eleven ammals With the more rapid infusion of noradrenahne arterial potassium concentrations increased from a control of 4 0 9 + - 0 0 3 to 4 6 3 + 0 0 7 meq/l ( p < 0 001) Following beta-adrenergic blockade these values were 4 13 + 0 09 and 4 39 +- 0 12 meq/1 respectively The change was not statistically s~gnificant With the slower infusion, the arterial potassium concentration increased to 4 37 -+ 0 11 (control 4 14 -+ 0 12) meq/1 before beta-blockade and to 4 34 + 0 10 (control 4 18 + 0 11) after beta-adrenergic blockade None of these changes were statistically significant Control mean arterial pressure for the eleven animals ranged between 98 and 140 mm Hg, arterial pressure increased with each type of intervention and was 1 8 3 - 2 4 8 mm Hg No data were included unless arterial pressure had returned to within -+ 10% of control values after the intervention was completed

4 DISCUSSION These data have demonstrated the striking hyperkalemia associated with severe degrees of hypoxemlc stress and infusions of large amounts of adrenaline The potassium response to both was shown to be related to the degree of hypoxemla achieved and to the amount of adrenahne infused In contrast, the infusion of noradrenallne in comparable doses resulted in only minimal hyperkalemla In all instances beta-adrenerglc blockade diminished and delayed the maximum increases in arterial potassium concentrations In addition, these data revealed that betaadrenerglc blockade prevented the highly slgmflcant hypokalemm that occurred following a short per=od of adrenahne infusion o~ that occurred during and following more prolonged infusions of adrenahne Previous studies have demonstrated the b=phaslc

146

J C Covtm, N S Skmner, Jr, Svstermc h),povta and catecholarnme,

response of arterial potassium COllcentratlons during adrenaline infusion (D'SIIva, 1934, Brewer et a l , 1930, Robertson and Peysel, 1951, Craig and [tonlg, 1963, Todd et al , 1969)The source of potassium fol the lmtlal hyperkalemlc response appears 1o be primarily the liver (D'SIIva, 1936) In hne with thJs conclusion are the results of Houssay et al (1937) and those of Marenzl and Gersham (1937) in which it was demonstrated that the hyperkalemla induced by adrenahne was reduced substantially following hepatectomy Fenn (1940) upon reviewing the potassium changes associated with systemic hypoxemla concluded that the hypoxemlc stress caused release of adret~allne flora the adrenal glands which tn turn 1esuited in the release of potassium from the liver The evidence for such release of adrenahne with hypoxemta seeins conclusive (Houssay et al , 1926, Nahas et a l , 1954, Fowler et a l , 1961) The present data, by delnonstrallng that beta-adrenerglc blockade leduces and delays the increase in arterial potassluln concentration associated with hypoxenrla and adrenahne infusion, indicate that the beta-adrenerglc receptor, at least in palt, contributes to tire transient hyperkalemla accompanying these interventions The telatlonshlp between beta-adrenerglc receptols and blood potassium concentrations has received solne support The present data (fig 2) demonstrate, as have others (Brewer et a l , 1939, Robertson and Peyser, 1951, Crmg and Homg, 1963, Todd el a l , 1969), a rather marked hypokalemla associated with adlenahne Infusion In addmon, the plesent data llltlstrate the ability of proplanolol to not only block this hypokalemm, but also prolong the initial hyperkalemla (fig 2) Thus, the beta-adrenerglc receptors appear to be unpoltant in the productmn of the well documented hypokalemm-assocmted adrenahne infusion Since D'SIIva (1936) found that hepatectomy not only reduced the hyperkalemlc response to infused adrenahne but also decreased tire subsequent hypokalemla, it would appear that liver tissue participates in the le-uptake of potassmm Skeletal muscle thlough beta-adrenerglc stimulation may be involved in the re-uptake of potassium as well It is known (Powell and Skinner, 1966) that infusion of either adrenahne or asoproterenol into a reservoir-perfused skeletal muscle causes a striking uptake of potassium in this tissue that can be blocked readily by beta-adrenerglc blockade with propranolol In addl-

tlon, Vlck et al (1970) tound that the hypokalemla that follows muscular exercise is largely prevented by beta-adrenerglc blockade Hence, it appears that the beta-adrenerglc leceptor is a major mechanism by which these types of hypokalemla occur When the upper panels of fig 1 (hypoxemla) and hg 2 (adrenaline infusion) are compared, it is apparent that the hyperkalemlc response to hypoxemla and adrenahtae is virtually identical before betaadrenerglc blockade However, while striking hypokalenua followed adrenaline infusion, there was no evidence lot post-hypoxennc hypokalemla Although it is possible that tire hypoxenr~a studies were not calrled out for pellOds sufficient to detect a reduction of potassium concentration to below control levels, the data shown Ul the Iowel panel of fig 2 (open circles) would tend to negate this possibility As shown, lntuslon ol adrenaline tor the salne time period that was used for hypoxelnla (1 e 3 nrln) resulted in d decrease in potassium during the actual Infusion period Hence, these data indicate that potasSIUUl changes associated with adlenahne infusion are quahtatlvely different from those produced by hypoxelrrla As such, these data suggest thal hypoxemla does not produce changes in potassium ion movelnent solely through the effect of adrenahne release froln the adrenal lnedulla These data do not offer any lnlorlnatlon that would help explain these dlffelences In summary, these data offer additional evidence that potassium ion movement Is influenced by reflex ielease of catecholalmnes or by lntUslon o[ them As well, these data indicate that the effect o! catechof alrrlnes on the release or uptake of potassium ions is mediated lit part via beta-adrelrerglc receptors and that these effects can be modified by beta-adrenerglc blockade Finally, these data indicate that the potassiunr changes associated with vmylng degrees of hypoxemla cannot be explained solely on the basis of endogenous catecholamlne release

REFERENCES Becker, E J, 1968, Sympathoadrenal response to hypoxla, Pflugers Arch 304, 1 Brewer, G , P S Larson, A R Schroeder, 1939, On the effect of epinephrine on blood potassium, Amer J Physlol 126,708 Cannon, WB and RG Hosklns, 1911, The effects of as-

J C Costtn, N S Skinner, Jr, Systemic hypoxta and catecholammes phyxla, hypernoea, and sensory stimulation on adrenal secretion, Amer J Physlol 29, 274 Cattel, McK and H Clvm, 1938, Influence of asphyxm and other factors on serum potassium of cats, J B~ol Chem 126,633 Costln, J C and N S Skinner, J r , 1970, Effects of systemic hypoxemla on vascular resistance m dog skeletal muscle, Amer J Physlol 218,886 Costln, J C and N S Skinner, J r , 1971, Competition between vasoconstrictor and vasoddator mechanisms m skeletal muscle, Amer J Physlol 220, 462 Craig, A B and C R Honlg, 1963, Hepatic metabolic and vascular response to epinephrine A unifying hypothesis, Amer J Physlol 205, 1132 D'Sdva, J L , 1934, The action of adrenaline on serum potassium, J Physlol 82, 393 D'Sllva, J L , 1936, The action of adrenahne on serum potassium, J Physlol 86, 219 Feldman, J , R Cartell and E Gellhorn, 1940, On the vagomsuhn and sympathetlco-adrenal system and their mutual relationship under conditions of control excitation Induced by anoxm and convulsant drugs, Amer J Physlol 131,281 Fenn, W O , 1940, The role of potassmm in physiological processes, Physlol Rev 20, 377 Flacke, J W , P F Osgood and H H Bendlxen, 1966, Actions of propranolol and lsoproterenol in blocked dogs, Federation Proc 25,471 Fowler, N O , R Shabetal and J C Halmes, 1961, Adrenal medullary secretion during hypoxla, bleeding and rapid intravenous infusion, Circulation Res 9,427 Houssay, B A , A D Marenzl and R Gerschman, 1936, Mecamsmo slmp~tlco-adrenahno-hep~itlco y potaslo sangtlmeo, 1936, Rev Soc Arg Blol 12, 434 Houssay, B A , A D Marenzl and R Gerschman, 1937, Potassium sanguln et me'camsme sympathlque-adr~nahno h6patlque, Compt Rend Soc Blol 124, 383 Houssay, B A and E A Mahnelh, 1926, Adrenal secretion produced by asphyxia, Amer J Physlol 76, 538 Lacrolx, E , G Demeester and I Leusen, 1968, Effects of

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beta-adrenerglc blockade on the hemodynamlc response to carotid sinus reflexes, Arch Int Pharmacodyn 175, 447 Marenzl, A D and R Gerschman, 1937, Adrenaline et potassium sangum, Compt Rend Soc Blol 124, 382 Marshall, R J , W E Barnes, J E Beane, J A Matlo and L T Schwab, 1965, Blockade by propranolol (1 C I 45,520) of the hemodynamlc and metabolic responses to refused catecholammes, Federation Proc 24, 713 McQuarne, J , M F Zlegler, W E Stone and O H Wangensteen, 1939, Mechanism of insulin convulsion Effects of varying partml pressures of atmospheric gases after adrenalectomy, Proc Soc Exptl Blol (N Y) 42, 513 Nahas, G G , GW Mather, J D M Wargo and WL Adams, 1954, Influence of acute hypoxla on sympathectomxzed and adrenalectomlzed dogs, Amer J Physlol 177, 13 Nakano, J and T Kusakarl, 1966, Effect of beta-adrenerglc blockade on the cardiovascular dynamics, Amer J Physlol 210, 833 Powell, W J , Jr and N S Skinner, Jr, 1966, Effect of the catecholammes on ionic balance and vascular resistance in skeletal muscle Amer J Cardlol 18, 73 Robertson, W van B , and P Peyser, 1951, Changes m water and electrolytes of cardiac muscle following epinephrine, Amer J Physlol 166, 277 Shanks, R G , 1966, The effect of propranolol on the cardiovascular responses to lsoprenahne, adrenaline and noradrenahne in the anaesthetized dog, Brlt J Pharmacol 26, 322 Stemsland, O S, S S Passo and G G Nahas, 1970, Blphaslc effect of hypoxla on adrenal catecholamme content, Amer J Physlol 218,995 Todd, E P , R L VIck, F M B o n n e r a n d D W Luedke, 1969, The influence of the rate of Infusion on the kalemotroplc effect of epinephrine, Arch Intern Physlol Btochem 77, 33 Vlck, R L , D W Luedke and E P Todd, 1970, Changes in arterial plasma (K) during exercise Effect of propranolol, Federation Proc 29,477 Warner, W A , 1968, Beta-adrenerglc blocking agents and anaesthesia A review, Can Anaes Soc J 15, 42