Epinephrine-induced hypokalemia: The role of beta adrenoceptors

Epinephrine-induced Hypokalemia: TheRoleof BetaAdrenoceptors JOHN L. REID, DM, KENNETH F. WHYTE, MB, and ALAN D. STRUTHERS,

or timolol. The serum potassium decreased from 4.06 to 3.22 mmol/liter after epinephrine. Serum potassium decreased to a lesser extent to 3.67 mmol/ liter after atenolol and actually increased to 4.25 mmol/liter after timolol. In a further study wit ilar design another nonselective @blocker pr lol also increased potassium after epinephrine. While atenolol also prevented hypokalemia in this study, it did not block the &-receptor mediated decrease in diastolic BP. Epinephrine-induced hypokalemia results from stimulation of a P-adrenoceptor linked to membrane sodium/potassium adenosine triphosphatase causing potassium influx. This appears to be predominantly mediated by p2 receptors although receptors may also play a part. (Am J Cardiol 1986;57:23P-27F)

Epinephrine was infused intravenously in 9 normal volunteers to plasma concentrations similar to those found after acute myocardial infarction. This study was undertaken on 3 occasions after 5 days of treatment with placebo or the fl-adrenoceptor antagonist, atenolol, which is relatively PI selective, or timolol, which blocks both fll and & receptors. Epinephrine increased the systolic blood pressure (BP), decreased the diastolic BP and increased the heart rate modestly. These changes were prevented by atenolol. However, after timolol the diastolic BP rose by +19 mm Hg and heart rate fell by -8 beats/ min. Epinephrine caused the corrected QT interval to lengthen (0.38 f 0.02 to 0.41 f 0.08 second). No significant changes were found in the corrected QT interval when subjects were pretreated with atenolol

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that in skeletal muscle as in heart, there is a mixed population of & and p2 receptors. Epinephrine-induced hypokalemia may have important implications for patients with acute myocardial infarction. These patients have increased circulating levels of catecholamines,lOJ1 especially of epinephrine, which may act directly on pacemaker cells and indirectly by the just described mechanism of hypokalemia to provoke arrhythmias. In the indirect mechanism, increased plasma epinephrine may stimulate potassium influx into cells causing systemic hy pokalemia. Hypokalemia after myocardial infarction is associated with anincreased incidence of ventricular arrhythmias and mortality.12-15 Epinephrine given in pharmacologic doses lowers serum potassium in man .16 We have reported that when the circulating epinephrine levels are increased to those levels observed after myocardial infarction, potassium influx is stimulated and significant hypokalemia results in normal volunteers.17 We have investigated the effect of cardioselective and nonselective /3

eta adrenoceptors appear to be associated with a membrane-bound sodium/potassium adenosine triphosphatase in skeletal muscle. In animals this has been demonstrated in rat soleus muscle in vitr0.l In man, P-receptor agonists increase the intracellular concentration of potassium in erythrocytes and decrease intracellular sodium.2 Epinephrine released from the adrenal medulla is the likely endogenous ligand for these receptors because hypokalemia results from changes in plasma * epinephrine within the range observed in physiologic and pathologic states.3-6Most of the studies suggest that the subtype of adrenoceptormediating potassium influx is the Pz subtype.3-8 However, &-selective antagonists do in part modify epinephrine-induced hypokalemia.g It is thus possible From the Department of Materia Medica, University of Glasgow, Scotland, United Kingdom. Address for reprints: John L. Reid, DM, Department of Materia Medica, Stobhill General Hospital, Glasgow GZl 3UW, Scotland, United Kingdom. 23F

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blockers on potassium changes and hemodynamic effects after intravenous infusions of epinephrine. These studies have been previously reported in fu11.gJ7-20

each treatment. On each study day, intravenous cannula were inserted into the antecubital veins of both arms. Subjects then received three go-minute infusions of 5% glucose solution containing ascorbic acid Methods (1 mg/ml] and 0, 0.01 and 0.06 pg/kg/min, respectively, Normal healthy volunteers, aged 20 to 32 years, of epinephrine (L-adrenaline) (Antigen Ltd.], which was infused at 55 ml/hour by a Braun Perfusor were studied. They had normal electrocardiograms, chest x-rays, serum biochemistry and hematology. Epi- VI pump. Blood pressure (BP), heart rate, serum elecnephrine was infused intravenously to plasma levels trolytes and plasma catecholamines were followed similar to those found after myocardial infarction.lO for 1.5 hours before, during and 2 hours after the Informed written consent was obtained from each infusions. subject. In each case the study protocol was approved BP was measured by a semiautomatic sphygmoby the Research and Ethical Committee of the North- manometer. The electrocardiogram was continuously ern District of the Greater Glasgow Health Board. displayed on an oscilloscope and also recorded at inEach subject was studied on 8 occasions on the fifth tervals on a polygraph (Grass model 7D). Serum elecday of treatment with 6 blocker or placebo. Timolol, 10 trolyte samples were centrifuged within 80 minutes mg 2 times a day (Blocadren@ Merck Sharp & Dohme), to prevent hemolysis and subsequently analyzed on atenolol, 50 mg 2 times a day (Tenormin@ Stuart), a Technicon SMA 6/60 (Technical Instrument Corp.) using standard methods. Plasma epinephrine samples or placebo were given in a randomized single-blind were collected into heparinized tubes kept on ice, cenfashion. The heart rate response to submaximal exercise trifuged at 4OCand stored at -7OOC until assayed. The was measured on days 2 and 4 preceding each study epinephrine levels were measured by the sensitive day. The doses of p blocker were then adjusted in each radioenzymatic method of Da Prada and Zurcher.21 individual to produce the same degree of p1 blockade The QT interval was measured from the onset of the Q (20% reduction in exercise-induced tachycardia) with wave to the point where a tangent to the descending limb of the T wave crossed the baseline. The QT interval was corrected for heart rate by the Bazett formu; la.22 Statistical analysis was performed by repeated measures analysis of variance and paired t tests where blood ~rersue 140appropriate. All results are presented as mean f stan(mmHg) lx)dard deviation. T In further studies in similar subjects using a ranlcodomized, single-blind, placebo-controlled protocol, we have examined the influence of pretreatment for 5 days with labetalol,lg propranolol, oxprenolol and atenolo120or single doses of ICI 118,5511*on epinephrine-induced hypokalemia and other hemodynamic Heart Rate 90 effects. In these later studies the epinephrine infusion fbeotr/minl protocol was modified slightly. Because the low dose 70 (0.01 pg/kg/min) had little effect on potassium, epinephrine was given in a stepwise manner at 0.01, 0.02 and 0.04 pg/kg/min for 10 minutes each. If no adverse effects were noted then the infusion rate was inSerum K 1 ImmoVL I creased to 0.06 pg/kg/min and maintained for 90 minAoutes. After this 5% glucose was’infused for a further 120 minutes. Thus these studies were undertaken with the ‘same maximum dose of epinephrine (0.06 pg/ 36kg/min) for a similar time as the studies described earlier in detail. 32-

Results

FIGURE 1. Hemodynamic effects and changes in serum potassium (K) during infusion of epinephrine at 0.06’ pg mind1 kg-’ in the absence of any pretreatment with p blockers. Results are shown as mean X!Cstandard deviation (n = 6).

The effects of epinephrine (0.06 pg/kg/min) on BP and serum potassium in healthy subjects are shown in Figure 1. In the ,&blocker study during placebo treatment, the baseline BP was 103 f 9/61 f 7 mm Hg and the heart rate was 60 f 6 beats/min. After atenolol pretreatment the BP was 95 f 7/58 f 6 mm Hg and the heart rate 51 f 6 beats/min. The dose of atenolol was 50 mg 2 times a day in 7 volunteers but in 2 other volunteers this was required to be increased to 100 mg

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FIGURE 2. Summary of changes in blood pressure (BP) and heart rate after go-minute intravenous infusions of epinephrine 0.06 yg/kg/min. Results are shown as mean f standard deviation (n = 9). q = placebo; f5 = atenolol; H = timolol; * = p <0.65; ** = p <0.605. Reproduced with permission from Clin Sci.g

2 times a day to produce the same degree of pi blockade as timolol. After timolol pretreatment, the BP was 98 f 7/55 f 6 mm Hg and the heart rate was 52 f 7 beats/min. The dose of timolol was 10 mg 2 times a day in all subjects. The plasma levels measured during the epinephrine infusions at 0.06 pg/min/kg were similar to those previously found in patients with acute myocardial infarctionlO and were in the range of 2 to 4 nmol/ liter. There was no significant difference in the epinephrine levels during’treatment with placebo, ateno101or timolol.g Only modest changes in BP and heart rate occurred and are summarized in Figure 2. Epinephrine increased systolic BP (+ll f 6 mm Hg), decreased diastolic BP (-14 f 9 mm Hg) and increased heart rate (+7 f 9 beats/min]. Atenolol modified all of these hemodynamic effects. After timolol, however, there was a different hemodynamic response to infused epinephrine; the systolic BP increased as before (+12 f 5 mm Hg], but the diastolic BP also increased (+19 f 4 mm Hg) and there was a slowing of heart rate (-8 f 5 beats/min]. In the presence of nonselective fi blockade, infused epinephrine probably stimulated a! adrenoceptors, thereby causing vasoconstriction and thus increased the diastolic BP with a resulting reflex bradycardia. Similar hemodynamic effects have been reported with another nonselective p blocker, propranolol.23 The changes in serum potassium after the infusion of epinephrine in the timolol and atenolol study are shown in Figure 3. During low dose epinephrine infusion, there was a small decrease in serum potassium. At the higher level (0.06 pg/min/kg), epinephrine caused a highly significant (p
tors, which appear to raise potassium.Z4 In a further series of experiments pretreatment with labetalol, a nonselective p blocker with additional al-receptor antagonist properties, 200 mg 2 times a day for 5 days, was studied.lg In a separate study ICI 118,551, a new selective ,& antagonist,l* was given as a single oral dose of 20 mg followed 1 hour later by epinephrine infusion (6.06 pg/kg/min).

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FIGURE 3. Serum potassium (K) during the infusion of 5% glucose solution with and without epinephrine at 0, 0.01 and 0.06 pg min-’ kg-’ after pretreatment with placebo, atenolol and timolol. Results are shown as mean f standard deviation (n = 9). Reproduced with permission from Clin Sci.s

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Serum potassium after 90 minutes of epinephrine infusion is shown in Figure 4 and compared with changes after timolol, atenolol and placebo. Labetalol pretreatment prevented all the changes in systolic and diastolic BPSand heart rate induced by epinephrine.lg ICI 118,551 pretreatment converted the depressor effect of epinephrine into a pressor response.18This was accompanied by a bradycardia as was observed with timolol and consistent with blockade of peripheral vascular /I adrenoceptors.

Discussion Intravenous infusions of epinephrine have hemodynamic, metabolic and electrocardiographic effects. Our study confirms that the levels of plasma epinephrine found after myocardial infarction could cause significant hypokalemia. The pulse rate and pulse pressure also increase. On the electrocardiogram, T-wave flattening and prolongation of the QT interval was observed.17The latter electrocardiographic changes in particular have been associated with a predisposition to ventricular arrhythmias. 25Both atenolol and timolol prevented this potentially arrhythmogenic change in ventricular repolarization.g The metabolic effects of epinephrine on potassium homeostasis were first noted in 1934 by D’Silva,26 who found that an intravenous bolus of adrenaline in cats caused an immediate short-lived increase followed by a prolonged decrease in the serum potassium. In 1960 Lepeschkin et alz7infused adrenaline into normal human subjects and recorded electrocardiographic changes of a reduction in T-wave height and an increase in U-wave amplitude. Subsequently, infused epinephrine at high doses was found to cause hypokalemia in man.16Our study has shown that the levels of plasma epinephrine found after myocardial infarction can cause significant hypokalemia. In coronary care units, approximately 15 to 20% of all patients have hypokalemia on admission.14*28Further, these hypoka-

FIGURE 4. Mean (& standard deviation) change in serum potassium after infusion of epinephrine 0.06 bg/kg/min for 90 minutes. Results from the atenoloi and timolol study are compared with those after labetalol pretreatmenti or ICI 118551, a selective p2 antagonisLi8

lemic patients have an increased incidence of ventricular tachycardia and fibrillation.12*28 Of the patients with potassium levels less than 3.1 mmol/liter, 67% experienced ventricular arrhythmias.12 Previous diuretic therapy can only be implicated in a minority of these patients. Our studies show that epinephrine-induced hypokalemia develops rapidly and also reverses relatively quickly in normal subjects. Hypokalemia during the acute phase of myocardial infarction is often transientzg and the frequency may be underestimated. Recent studies help to characterize the type of ,f? adrenoceptor responsible for epinephrine-mediated potassium influx. Salbutamol-induced hypokalemia was partially blocked by practolol but propranolol completely prevented it. 3oIn man, there is circumstantial evidence linking /I2 adrenoceptors to sodium potassium adenosine triphosphatase in studies of @blockade during open heart surgery.7JJ Using similar protocols, 2 other groups have confirmed our observations.31,32 They have, in addition, presented evidence suggesting that hypokalemia is predominantly the result of activation of receptors of the ,& subtype. While our results with timolol, labetalol and ICI 118551 strongly support the role of 62 receptors, ateno101 did substantially reverse epinephrine hypokalemia.g This observation could indicate that ,& receptors also participate, or it may reflect the well-recognized limitation of classification of drugs as “selective” antagonists Beta1 selectivity may be lost at higher doses. We currently favor the former explanation and believe that P1 receptors may contribute to epinephrine hypokalemia, although their role is likely to be less important than that of 02 receptors. In a recent study2O we confirmed that atenolol, given in doses that did not impair vascular &receptor responses or modify leucocyte P2receptor numbers, could largely prevent epinephrine-induced hypokalemia.20 Further studies are indicated on the receptor types involved. These should include studies of receptor binding in skeletal muscle and the role of adenylate cyclase in this response. Evidence is accumulating that /3 blockade reduces mortality after myocardial infarction.33-38 There are many potentially beneficial properties of p blockade after myocardial infarction in addition to the direct antiarrhythmic or .membrane-stabilizing effect.3g The reduction in oxygen demand with its resulting decreased infarct size also seems to be of prime importance.*OOther factors include the antagonistic effects of /3 blockade on the transmembrane flux of sodium, potassium or calcium 16~1Overall the beneficial effects of ,f3blockade after myocardial infarction are likely to be multifactorial. We believe that the inhibition of epinephrine-mediated potassium influx into skeletal muscle and resulting hypokalemia may be a further mechanism by which P blockers may, in both the short and long term, reduce mortality in ischemic heart disease. If epinephrine-induced hypokalemia is largely mediated by p2receptors, then it may be that nonselective @blockers will have advantages over agents that have high degrees of selectivity for ,& receptors.

April 25, 1986

Acknowledgment: We would like to thank Mrs. S. Thomson for helping to prepare the manuscript.

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10. Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436-444. 11. Videback J, Christensen NJ, Sterndorff B. Serial determination of plasma catecholamines in myocardial infarction. Circulation 1972;46:846-855. 12. Solomon R, Cole A. Arrhythmias and myocardial infarction: the role of potassium (abstr]. Roy Sot Med Int Congress Symposium Series 1980;44:12. 13. Donnelly T, Gray H, Simpson E, Rodger JC. Serum potassium in acute myocardial infarction (abstr). Scot Med J 1980;25:176. 14. Thomas R, Hicks S. Myocardial infarction: ventricular arrhythmias associated with hypokalaemia (abstr). CIin Sci 1981;60:32P. 15. Nordrehaug JE, van der Lippe G. Hypokalaemia and ventricular fibrillation in acute myocardial infarction. Br Heart J 1983;50:525-529. 16. Massara F, Tripodina A, Rotunno M. Propranolol block of epinephrine induced hypokalaemia in man. Eur J Pharmacol1970;10:404-407. 17. Struthers AD, Reid JL, Whitesmith R, Rodger JC. Effect of intravenous adrenaline on electrocardiogram, blood pressure and serum potassium. Br Heart J 1983;49:90-93. 18. Struthers AD, Reid JL. Adrenaline causes hypokalaemio in man by betas adrenoceptor stimulation. Clin Endo 1984;20:409-414. 19, Struthers AD, Whitesmith R, Reid JL. Metabolic and haemodynamic effects of increased circulating adrenaline in man. Effect of labetalol an alpha and beta blocker. Br Heart J 1983;50:277-281. 20. Jones CR, Whyte KF. Reid JL. Haemodynamic, metabolic and lymphocyte beta2 receptor changes following chronic beta adrenoceptor antagonism (abstr]. Br J CIin PharmacoI1985;19:534P. 21. Da Prada M, Zurcher G. Simultaneous radioenzymatic determination of

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