Download The Role of Adrenal Medullary Catecholamines in

Clinical Science (1984)66, 377-382
377
E D I T O R I A L REVIEW
The role of adrenal medullary catecholaminesin potassium
homoeostasis
A. D. STRUTHERS
AND
J . L. REID
University Department of Materia Medica, Stobhill General Hospital, Glasgow, Scotland, U.K.
Introduction
The concentration of potassium in plasma is
maintained within the normal range in man by
many different physiological factors. The kidney
is obviously of prime importance, as demonstrated by the hyperkalaemia which develops in
renal failure [ 11. Several circulating hormones
are, however, also of importance in potassium
homoeostasis. Insulin enhances the uptake of
potassium in muscle, liver and adipose tissue
[2-41. Mineralocorticoids and glucocorticoids
lower the serum potassium, not only by their
kaliuretic effect, but also by increasing potassium
secretion from gut epithelial tissue [5, 61. It has
been known for a long time that a third group of
hormones, namely catecholamines, also influence
potassium balance, but it is only recently that this
physiological mechanism has been shown to be of
clinical relevance. This review concerns the role of
adrenomedullary hormones in potassium homoeostasis and the pathophysiological relevance of this
in man.
Physiology
Animal studies
The effect of adrenaline on potassium was first
noted as far back as 1934 by DSilva, who found
that a rapid injection of adrenaline in cats caused
an immediate short-lived increase followed by a
prolonged decrease in the plasma potassium [7].
A closer analysis has revealed that the initial
hyperkalaemia is due to net release of potassium
from the liver [8]: this effect is probably due to
stimulation of or-adrenoceptors as it is inhibited
by or-receptor blockade [9]. The subsequent proCorrespondence: Dr A. D. Struthers, Department of Clinical Pharmacology, Royal Postgraduate
Medical School, London W 12 OHS.
longed hypokalaemia is due to net uptake of
potassium in skeletal muscle and other tissues: this
effect is due to stimulation of 0-adrenoceptors and
is inhibited by /%receptor blockade [9, 101.
Elegant studies in vitro to characterize this
mechanism have been performed by Flatman &
Clausen, who used rat soleus muscle as a model of
skeletal muscle. They showed that adrenaline
stimulates Na+ efflux and K+ influx in this tissue
[ l l ] . Similar results have been reported in frog
sartorius muscle, rat diaphragm and cat skeletal
muscle [12-141. Potassium uptake by muscle was
found also to occur after isoprenaline and terbutaline [15, 161. Furthermore, adrenaline-induced
Na+,K+-dependent ATPase activity was blocked by
propanolol but not by metoprolol [17]. Overall
these experiments suggest that catecholamines
stimulate a Pz-adrenoceptor linked to membrane
bound Na’,K+-ATPase in skeletal muscle causing
potassium influx.
Interestingly, Buckler and his colleagues have
extended these observations on muscle tissue in
vitro. They found that adrenaline and noradrenaline stimulated Na+ pump activity in frog skeletal
muscle but depressed Na+ pump activity in frog
hemiventricles [18]. In the frog, therefore,
increased circulating catecholamines cause
potassium uptake in skeletal muscle but potassium
loss from cardiac tissue.
Human studies
Confirmation of the role of adrenaline in
potassium homoeostasis in man has depended on
other experimental and clinical approaches. In
1960, Lepeschkin infused adrenaline slowly into
normal human subjects and noted the electrocardiographic changes of T wave flattening and an
increase in U wave amplitude [19]. In retrospect,
it seems likely that these electrocardiographic
changes were due to hypokalaemia but the plasma
378
A. D.Struthers and J. L. Reid
concentration of potassium was not measured in
this study. Another 0-adrenoceptor agonist, salbutamol, was shown to lower serum potassium
when infused into normal man [20]. Overdose of
salbutamol tablets causes profound hypokalaemia
[21, 221. Propranolol completely blocked salbutamol-induced hypokalaemia whereas practolol
had only a modest inhibitory effect, suggesting
that in man as in the animal studies discussed
above, Na+,K+-ATPaseis linked, in some tissues at
least, to Pz-adrenoceptors [23].
In normal man this mechanism has also been
studied by the infusion of potassium chloride in
the presence of adrenaline with an without propranolol [24, 253. When potassium chloride is
infused, plasma and urinary potassium concentration both increase. In the presence of adrenaline,
both of these increases are markedly inhibited.
Propranolol blocks these effects of adrenaline on
both renal and extrarenal potassium metabolism.
Further circumstantial evidence for this
mechanism comes from observations on plasma
potassium concentrations in patients undergoing
open heart surgery [26, 271. In such patients,
circulating catecholamine concentrations are
elevated and intravenous potassium may be required to maintain normokalaemia. When patients
were infused with a standard intravenous regimen,
pretreatment with propranolol caused the plasma
potassium concentration to rise whereas pretreatment with metoprolol had no effect on plasma
potassium.
Massara et al. showed that adrenaline infused at
high doses into normal volunteers caused systemic
hypokalaemia and this was blocked by propranolol
[28]. We have performed similar studies whereby
adrenaline was infused into normal volunteers but,
in our studies, we used lower infusion rates than
Massara et al. We aimed for and achieved steady
state plasma adrenaline levels which were very
similar to those found during pathophysiological
states such as acute myocardial infarction [29,30]
or hypoglycaemia [31]. In normal volunteers,
these plasma levels of adrenaline (3-5 nmol/l)
cause profound hypokalaemia [32]. This was
accompanied by the electrocardiographic changes
of T wave flattening, U waves and Q-T interval
prolongation. Timolol, a non-selective 0-adrenoceptor blocker, completely inhibited adrenalineinduced hypokalaemia, whereas atenolol, a &selective antagonist, had only a small effect [33].
In a subsequent study, a selective &-antagonist
(ICI 118551) completely blocked adrenalineinduced hypokalaemia [33a].
Changes in potassium also occur during physical
exercise. Exercise causes marked efflux of potassium from muscles. This is balanced by potassium
influx into muscles, owing to raised circulating
catecholamines [34]. The importance of 0-receptor mediated potassium influx is demonstrated in
the observation that pretreatment with nonselective 0-blockers causes the plasma potassium
concentration to rise markedly during exercise
[35]. A possible teleological rationale for
catecholamine-induced potassium influx is to
prevent life-threatening hyperkalaemia during
prolonged exercise. Additionally, in the resting
state, basal levels of circulating catecholamines
may help to restore the intracellular potassium
which is lost during the repeated action potentials
involved in normal tonic muscular activity.
The human studies quoted above help to confirm that catecholamines cause hypokalaemia in
man by the stimulation of &-adrenoceptors. However, several other possible mechanisms have to be
excluded. It is conceivable that catecholamines
would stimulate the renin-angiotensin system,
causing aldosterone release and subsequent
kaliuresis. Although plasma renin increases two- to
three-fold during the infusion of adrenaline, there
is, however, no increase in plasma aldosterone
[36]. Furthermore, during the infusion of adrenaline the urinary concentration of potassium falls
in parallel with the plasma potassium [33].
Another possible mechanism is that 0-adrenoceptor
stimulation causes the release of insulin [23],
which is known to stimulate potassium influx
[2, 31. However, adrenaline is not only a 0-agonist
but has in addition a-adrenoceptor stimulating
properties. As insulin release is influenced more
by inhibitory a-adrenoceptors than by stimulatory
0-adrenoceptors [37], insulin release is in fact
inhibited during the infusion of adrenaline [38].
It is, therefore, unlikely that adrenaline-induced
hypokalaemia in man is caused by kaliuresis or
by the release of insulin or aldosterone. It appears
rather to be due to the shift of potassium from the
extracellular to the intracellular space. It is
tempting to extrapolate from animal studies that
adrenaline causes potassium uptake into skeletal
muscle in man. There is, however, no direct
evidence for this. The erythrocyte is the only cell
in which catecholamine-mediated potassium
influx has been demonstrated in man [39].
Clinical significance
In normal volunteers profound hypokalaemia
develops at plasma adrenaline levels which are
similar to those found during pathophysiological
states such as acute myocardial infarction or
hypoglycaemia [32]. Are there any observations
which confirm this in clinical practice?
Adrenal medullary catecholamines in potassium homoeostasis
Transient hypokalaemia has been noted during
the endocrine investigation of an insulin tolerance
test [40].In this particular case, it is uncertain
whether systemic hypokalaemia is due to insulin
itself or to the increases in catecholamines or
cortisol which also occur. 0-Adrenoceptor agonists
are used in the suppression of premature labour
and may cause falls in serum potassium [41]. The
hypokalaemic effect of 0-adrenoceptor agonists
also has a clinical application. In familial periodic
paralysis the plasma concentration of potassium
increases considerably after exercise, leading to
paralytic attacks. This hyperkalaemia can be prevented by &adrenoceptor agonists like salbutamol
[42,43].
Myocardial infarction
Several studies report that hypokalaemia is
frequently observed in the acute phase of myocardial infarction [44-481. The incidence of
hypokalaemia ranged from 15 to 31%in different
studies. Ventricular arrhythmias occurred more
frequently in the hypokalaemic patients than in
the normokalaemic ones. In one study, 23 out of
90 patients with acute myocardial infarction had
plasma potassium concentration <3.5 mmol/l
[44].Ventricular tachycardia and/or fibrillation
occurred in 12% of the normokalaemic and 35%
of the hypokalaemic group. Hospital mortality in
the normokalaemic and the hypokalaemic groups
was 15% and 35% respectively. Furthermore, of
the 23 hypokalaemic patients, only seven were on
diuretic therapy before admission to hospital.
Hypokalaemia was not due to haemodilution or
to increased urinary excretion of potassium and it
resolved spontaneously without potassium supplementation. Plasma catecholamines are raised in
acute myocardial infarction. As hypokalaemia
occurs at these plasma adrenaline levels in normal
subjects, it is possible that the transient hypokalaemia of acute myocardial infarction is due to
increased circulating catecholamines. Another
possible arrhythmogenic effect of catecholamines
may be the Q-T interval prolongation caused by
adrenaline [32]. Q-T interval prolongation has
often been associated with a predisposition to
ventricular arrhythmias [49]. It remains unknown
whether the association between hypokalaemia
and arrhythmias is a direct one or is indirect,
mediated by adrenaline itself or adrenalineinduced changes in ventricular repolarization. It
is likely that a low extracellular potassium is at
least contributory to ventricular arrhythmias,
since spontaneous ectopic activity can readily be
suppressed in isolated cardiac muscle preparations
3 79
by an increase in the concentration of potassium
in the perfusate [50].
The incidence of hypokalaemia in patients with
acute myocardial infarction (1 5-3 1%)may appear
low when compared with the profound hypokalaemia which can be demonstrated in normal
volunteers. However, several factors should be
borne in mind. The figure quoted above represented the incidence of hypokalaemia on a single
blood sample in those patients who reach hospital.
In view of the transient nature of adrenalineinduced hypokalaemia, one single blood sample
may underestimate the numbers with transient
hypokalaemia. Furthermore, this figure does not
include the important group of patients who die
suddenly, presumably from ventricular arrhythmias, before arrival at hospital. Another important
factor is that some patients with acute myocardial
infarction may have poor tissue perfusion and
metabolic acidosis, which would cause the plasma
potassium concentration to rise and offset the
hypokalaemia caused by circulating adrenaline. In
severe cardiogenic shock, plasma catecholamines
may be very high but the plasma potassium concentration normal, owing to the marked acidosis.
There is increasing evidence of the beneficial
effects of @-blockadein the secondary prevention
of myocardial infarction [51-531. The beneficial
effect is likely to be due to a reduction in
arrhythmias, resulting in a reduction in sudden
death. There is also some evidence that intravenous 0-blockers administered immediately after
myocardial infarction are useful [54, 551. The
effects of 0-blockade are likely to be multifactorial.
The direct anti-arrhythmic actions via @-adrenoceptor antagonism or even to a membrane stabilizing effect may be of importance, as also would be
the reduction in oxygen demand with its resulting
decreased infarct size [56, 571. The action of 0blockers on the transmembrane flux of potassium
and the prevention of hypokalaemia may be an
additional factor.
Acutely ill patients
In a study of acutely ill hospital patients in a
2 months period Morgan & Young identified 45
acutely ill patients with plasma potassium concentrations of less than 2.8 mmol/l, although only
25% of them had been on diuretic therapy [58].
Plasma potassium concentrations returned to the
normal range within days although no potassium
supplementation was given. This transient acute
hypokalaemia observed in acutely ill patients
could be due to an intracellular flux of potassium,
mediated by increased catecholamines.
380
A. D. Struthers and J. L. Reid
Diuretic therapy
Several large studies have demonstrated that
antihypertensive therapy reduced the incidence of
cerebrovascular accidents but have failed to show
any corresponding benefit in coronary heart
disease [59-611. In the recent MR FIT TRIAL
[62], hypertensive men with initial ECG abnormalities had a higher coronary heart disease
mortality (+ 65%) and total mortality (+ 55%)
when their blood pressure was treated than the
control untreated group. Treatment was usually
with thiazide diuretics and it has been suggested
that these drugs might predispose to cardiac
arrhythmias or sudden death by reducing the
concentration of plasma potassium [63,64]. There
is, however, no conclusive evidence to confirm
this. However, several studies have demonstrated
even in patients without cardiac disease. an increase
in ventricular ectopic activity and atrioventricular
conduction disturbances in those patients with
hypokalemia [65-681. The frequency of ventricular ectopic beats is increased the lower the plasma
potassium [69]. It may be more relevant to consider the concentration to which plasma potassium
falls during increased sympatho-adrenal activity
rather than the plasma potassium at rest. In our
studies, normal volunteers were pretreated with
either bendrofluazide (5 mg daily) or placebo for
7 days and then infused with adrenaline [70].
After the diuretic, plasma potassium concentration
was lower than after placebo (3.40 vs 3.83 mmol/l)
and fell still lower after the adrenaline infusion
(2.73 vs 3.08 mmol/l). Routine monitoring of the
plasma potassium at rest may therefore underestimate the extent of hypokalaemia at times of
increased sympatho-adrenal activity.
Conclusions
The kidney is primarily responsible for chronic
potassium balance but, in the short term, the
plasma concentration of potassium is regulated
not only by insulin, aldosterone and other corticosteroids but also by circulating levels of catecholamines. Circulating adrenaline in man causes
hypokalaemia by stimulating a &-adrenoceptorlinked Na+,K+-ATPase causing potassium influx
into skeletal muscle, erythrocytes and possibly
other tissues. Profound hypokalaemia occurs at
plasma levels of adrenaline which are found in
pathophysiological states such as acute myocardial
infarction or hypoglycaemia. This mechanism may
be a contributory factor in the association
between ventricular arrhythmias and hypokalaemia
in acute myocardial infarction.
Antihypertensive treatment has not had a
significant effect on coronary heart disease
statistics. It is possible that this may be due in
part to diuretic-induced hypokalaemia and its
exacerbation at times of increased sympathoadrenal activity.
Acknowledgement
We thank Mrs J. Hamilton for help in typing this
manuscript.
References
1. Bia, M.J. & De Fronzo, R.A. (1981) Extrarenal
potassium homeostasis. Americnn Journal of
Physiology, 240, F257-F268.
2. Zierler, K.L. (1968) Effect of insulin on potassium
efflux from rat muscle in the presence and absence
of glucose. American Journal of Physiology, 198,
1066-1070.
3. De Fronzo, R.A., Felig, P., Ferrannini, E. & Wahren,
J. (1980) Effect of graded doses of insulin on splanchnic and peripheral potassium metabolism in man.
American Journal of Physiology, 238 (Endocrinology,
Metabolism l), E421-E427.
4. De Fronzo, R.A., Sherwin, R.S., Dillingham, M.,
Hendler, R., Tamborlane, p.V. & Felig, P. (1978)
Influence of basal insulin and glucagon secretion on
potassium and sodium metabolism. Journal of Clinical
Investigation, 61,472-479.
5 . Charron, R.C., Lemme, C.E., Wilson, D.R., Ing, T.S.
& Wrong, O.M. (1969) The effect of adrenal steroids
on stool composition, as revealed by in vivo dialysis
of faeces. Clinical Science, 31, 151-167.
6. Charney, A.N., Kinsey, M.D., Myers, L., Giannella,
R.A. & Gots, R.E. (1975) Na-K activated adenosine
triphosphatase and intestinal electrolyte transport.
Journal of Clinical Investigation, 56,653-660.
7. D’Silva, J.H. (1934) The action of adrenaline on
serum potassium. Journal of Physiology (London),
82, 393-398.
8 . D’Silva, J.H. (1936) Action of adrenaline on the
perfused liver. Journal of Physiology (London), 81,
181-188.
9. Todd, E.P. & Vick, R.L. (1971) Kalemotropic effect
of epinephrine analysis with adrenergic agonists
and antagonists. American Journal of Physiology,
220,1964-1969.
lO.Vick, R.L., Todd, E.P. & Luedke, D.W. (1972)
Epinephrine induced hypokalaemia: relation t o liver
and skeletal muscle. Journal of Pharmacology and
Experimental Therapeutics, 181, 139-146.
11. Flatman, J.A. & Clausen, T. (1979) Combined effects
of adrenaline and insulin on active electrogenic
Na+-K’ transport in rat soleus muscle. Nature
(London), 281,580-581.
12. Hayes, E.T., Dwyer, J.M., Horowicz, P. & Swift, J.G.
(1979) Epinephrine action on sodium fluxes in frog
striated muscle. American Journal of Physiology,
227,1340-1349.
13. Evans, R.H. & Smith, J.W. (1973) Mode of action of
catecholamines on skeletal muscle. Journal of Physiology (London), 232, 81~-82p.
14. Lockwood, R.H. & Lum, B.K.B. (1974) Effects of
adrenergic agonists and antagonists on potassium
metabolism. Journal of Pharmacology and Experimental Therapeutics, 189, 119-129.
Adrenal medullary mtecholamines in potassium homeostasis
15. Costin, J.C., Cohen, L.S. & Zaret, B.L. (1976) Effect
of the beta adrenergic receptor upon potassium
uptake in skeletal muscle. American Journal of
Ckdwlogy, 37,129.
16. Buur. T., Clausen, T., Holmberg, E-, Johansson, U.
& Waldeck, B. (1982) Desensitisation by terbutaline
of P-adrenoceptors in the guinea pig soleus muscle:
biochemical alterations associated with functional
changes. British Journal of Pharmacology, 76, 313317.
17. Clausen, T. & Flatman, J.A. (1980) &Adrenoceptors
mediate the stimulating effect of adrenaline on active
electrogenic Na-K transport in rat soleus muscle.
British Journal of Pharmacology, 68,749-755.
18. Buckler, K.J., Bhattacharya, S.S. & Flear, C.T.G.
(1982) Actions of catecholamines and beta blockers
on Na pump activity in heart and skeletal muscle.
ClinicaI Science, 63, 38P.
19. Lepeschkin, E., Marchet, H., Schroeder, G.,Wagner,
R., Paula, E., De Silva, P. & Raab, W. (1960) Effects
of epinephrine and norepinephrine on the electrocardiogram of 100 normal subjects. Ameriarn Journal
of Cardblow, 5,594-603.
20. Leitch, A.G., Clancy, L.J., Costello, J.F. & Flenley,
D.C. (1976) Effect of intravenous infusion of salbutamol on ventilatory response to carbon dioxide and
hypoxia and on heart rate and plasma potassium in
normal man. British Medical Journal, i, 365-367.
21. Connell, J.M.C., Cook, G.M. & McInnes, G.T. (1982)
Metabolic consequences of salbutamol poisoning
reversed by propranolol. British Medical Journal,
285,779.
22. O'Brien, I.A.D., Fitzgerald-Fraser, I., Lewin, I.G. &
Corrall. R.J.M. (1981) Hypokalaemia due to salbutamol overdosage. British Medical Journal, 282, 15151516.
23. Berend, N. & Marlin, G.E. (1978) Characterisation of
&stdrenoceptor subtype mediating the metabolic
actions of salbutamol. British Journal of Clinical
Pkmmacdow, 5,207-21 1.
24.De Fronzo, R.A., Bia, M. & Birkhead, G. (1981)
The effect of epinephrine on potassium homeostasis.
Kidney Znternational, 20,83-91.
25. Rosa, RM., Silva, P.De., Young, J.B., Landsberg, L.,
Brown, RS., R o w , J.W. & Epstein, F.H. (1980)
Adrenergic modulation of extrarenal potassium
disposal. New h g h n d Journal of Medicine, 302,
431-434.
%.Bethune, D.W. & MacKay, R. (1978) Paradoxical
changes in serum potassium during cardiopulmonary
bypass in association with non-cardioseleetive beta
blockade. Lancet, i, 380-381.
27. Petch, M.C., McKay, R. & Bethune, D.W. (1981) The
effect of beta, adrenergic blockade on serum
potassium and glucose levels during open heart
surgery. European Heart Journal, 2,123-126.
28. Massara, F., Tripodha, A. & Rotunno, M. (1970)
Propranolol block of epinephrine induced hypokalaemia in man. European Journal of Pharmacology,
10,404-407.
29. Cryer, P.E. (1980) Physiology and pathophysiology
of the human sympathoadrenal nemendocrine
system. New Enghnd Journal of Medicine, 303,
436-444.
30. Mueller, H.S. & Ayres, S.M. (1980) Propranolol decreases sympathetic nervous activity reflected by
plasma catecholamines during evolution of my*
cardial infarction in man. Journal of Clinical Znvestigation, 65,338-346.
381
31. Rizza, R. A., Cryer, P.E. & Gerich, J.E. (1979) Role
of glucagon, catecholamines and growth hormone in
human glucose counter regulation: effects of somatostatin and combined Q- and 6-adrenergic blockade in
plasma glucose recovery and glucose flux rates after
insulin induced hypoglycaemia. Journal of clinical
Investigation, 64,62-71.
32. Struthers, A.D., Reid, J.L., Whitesmith, R. & Rodger,
J.C. (1983) Effect of intravenous adrenaline on
electrocardiogram, blood pressure and serum
potassium. British Hecrrt Journal, 49,gO-93.
33. Struthers, A.D., Reid, J.L., Whitesmith, R. & Rodger,
J.C. (1983) The effects of cardioselective and nonselective beta adrenoceptor blockade on the hypokalaemic and cardiovascular responses to adrenomedullary hormones in man. Cljnfcal Science, 65,
143-147.
33a. Struthers, A.D. & Reid, J.L. (1984) Adrenomedullary
hormones cause potassium influx by adrenoceptor
stimulation in man. Clinicul Endocrinology (In press).
K V a n Beaumont, W., Strand, J.C., Pefroforky, J.S.,
Hipskind, S.G. & Greenleaf, JX. (1973) changes in
total plasma content of electrolytes and proteins with
normal exercise. Journal of Applied Physiology, 34,
102-106.
35. Lim, M., Linton, RAF., Wolff, C.B. & Band, D.M.
(1981) Ropranolol, exercise and arterial plasma
potassium. Lancet, ii,591.
36. Brown, M.J., Brown, D.C. & Murphy, M.B. (1983)
Adrenaline associated hypokalaemia and tachycardia
are selectively antagonised by low dose &-receptor
blockade in man. Clinical Science, 64,71P.
37.Porte, D. (1967) A receptor mechanism for the
inhiiition of insulin release by epinephrine in man.
Journal of Clinical Investigation, 46,86.
38. Porte, D., Grabe, A.L., Kuzuya, T. &Williams, R.H.
(1966) The effect of epinephrine on immunoreactive
insulin levels in man. Journal of CljnicaJ Investigation,
45,228-236.
39. Bodemann, H.H., Irmer, M. & Schlutter, K. (1982)
Catecholamines stimulate Na,K pump of human
erythrocytes in vivo. European Journal of Clinical
Investigation, 12(2), part 11.4.
40. Flier, B.M., Al-Dujaiii E.A.S., C o d l , RJ.M., Pfitchard, J.L. & Edwards, C.R.W. (1982) The effect of
adrenere and chobergic mechanisms on the release
of ACTH and adrenal steroids following hypoglycaemia in man. ClinicaZ Science, 63,63P.
41. Maraveo, M.A. & Hurlbert, B. J. (1980) Hypokalaemia
associated with terbutaline administration in
obstetrical patients. Anesthesia and Analgesia, 59,
917-920.
42. Wang, P. & Clausen, T. (1976) Treatment of attacks
in hyperkalaemic familial periodic paralysis by inhalation of salbutamol. Lancet, i, 221-223.
43. DahMorgensen, K. & Michalsen, H. (1979) Adynamia
episodica hereditaria. Acta Paediahlco Scandinavica,
68,583-585.
44. Rolton, H., Simpson, E., Donnelly, T. & Rodger, J.C.
(1981) Plasma potassium in acute myocardial infarction. European Heart Jounnl, 2 (Suppl. A), 21.
45.Solomon, R. & Cole, A. (1980) Arrhythmias and
myocardial infarction: the role of potassium. Royal
Sociev of Medicine International Congress and
Symposfum Series, 44,47-55.
46. Donnelly, T., Gray, H., Simpson, E. & Rodger, J.C.
(1980) Serum potassium in acute myocardial infarction. Scottish Medical Journal, 25,176.
382
A. D. Struthers and J. L. Reid
47. Thomas, R. & Hicks, S. (1981) Myocardialinfarction:
ventricular arrhythmias associated with hypokalaemia.
Clinical Science, 60,32P.
48. Dyckner, T., Helmers, C., Lundman, T. &Wester, P.O.
(1975) Initial serum potassium level in relation to
early complications and prognosis in patients with
acute myocardial infarction. Acta Medica Scandinavica, 197,207-210.
49. Doroghazi, R.M. & Childers, R. (1978) Time related
changes in the Q
Tinterval in acute myocardial
infarction: possible relation to local hypocalcaemia.
American Journal of Cardiology, 41,684-688.
50. Poole-Wilson, P.A. (1981) The myocardial cell membrane: the effect of diuretics. Royal Society of
Medicine International Congress and Symposium
Series,44,9-16.
51. Wilhelmsson, C., Vedin, J.A., Wilhelmsen, J., Tibbin,
G. & Werkol, L. (1974) Reduction of sudden deaths
after myocardial infarction by treatment with
alprenolol. Lancet, ii, 1157-1160.
52. Norwegian Multicenter Study Groups (1981) Tim0101
induced reduction in mortality and reinfarction in
patients surviving acute myocardial infarction. New
Enghnd Journal of Medicine, 304,801-807.
53. National Heart, Lung and Blood Institute Co-operative Trial (1981) The &blocker heart attack trial.
Journal of the American Medical Association, 246,
2073-2074.
54. Yusuf, S., Ramsdale, D., Peto, R., Furse, L., Bennett,
D., Bray, C. & Sleight, P. (1980) Early intravenous
atenolol treatment in suspected acute myocardial
infarction. Lancet. ii, 273-276.
55. Hjalmarson, A., Elmfeldt, D., Herlitz, J., Holmberg,
S., Malek, I., Nyberg, G., Ryden, L., Swedberg, K.,
Vedin, A., Waagstein, F., Walderstram, A., Walderstram, J., Wedel, H., Wilhelmsen, L. & Wilhelmsson,
C. (1981) Effect on mortality of metroprolol in acute
myocardial infarction. Lancet, ii, 823-827.
56. Khan, M.I., Hamilton, J.T. & Manning, G.W.(1972)
Protective effect of beta adrenoceptor blockade in
experimental coronary occlusion in conscious dogs.
American Journal of Cardiology, 30, 832-837.
57. Mueller, H.S., Ayres, S.M., Religa, A. & Evans, R.G.
(1974) Propranolol in the treatment of acute myocardial infarction. Effect on myocardial oxygenation
and haemodynamics. Circulation, 49,1078-1087.
58. Morgan, D.B. & Young, R.M. (1982) Acute transient
hypokalaemia: new interpretation of a common
event. Lancet, ii, 751-752.
59. Veterans Administration Co-operative Study on
Antihypertensive Agents (1967) Effects of treatment
on morbidity in hypertension. Results in patients with
diastolic blood pressures averaging 115 through 129
mmHg. Journal of the American Medical Association,
202,1028-1034.
60. Veterans Administration Co-operative Study on Antihypertensive Agents (1970) Effects of treatment on
morbidity in hypertension. Results in patients with
diastolic blood pressures averaging 90 through 114
mmHg. Journal of the American Medical Association,
213, 1143-1152.
61. Breckenridge, A., Dollery, C.T. & Parry, E.H.O.
(1970) Prognosis of treated hypertension. Quarterly
Journal of Medicine, 39,411-429.
62. Multiple Risk Factor Intervention Trial (1982) Risk
factor changes and mortality results. Journal o f the
American Medical Association, 248, 146 5-1477.
63. Doyle, A.E. (1976) In: Hypertension and Stroke
Control in the Community, p. 240. Ed. Hatano, S.,
Shigematsu, I. & Strasser, T. World Health Organisation, Geneva.
64. Robertson, J.I.S. (1978) Complications of milt
hypertension. Annals of the New York Academy of
Sciences, 304,64-66.
65. Davidson, S. & Surawicz, B. (1967) Ectopic beats and
atrioventricular conduction disturbances in patients
with hypopotassemia. Archives of Internal Medicine,
120,280-285.
66. Steiness, E. & Olesen, K.H. (1976) Cardiac
arrhythmias induced by hypokalaemia and potassium
loss during maintenance digotoxin therapy. British
Heart Journal, 38, 161-172.
67. Danniell, H.W. (1971) Arrhythmias in hypokalaemia.
New EnglandJournal ofMedicine, 284,1385.
68. McCarthy, S.T. & Wollner, L. (1981) Falls and funny
turns: a possible complication of hypokalaemia. In:
Arrhythmias and Myocardial Infarction: the Role o f
Potassium, Ed. Wood, C . & Sommerville, W. Royal
Society of Medicine International Congress and
Symposium Series, 44,25-28.
69. Hollifield, J.W. & Slaton, P.E. (1981) Cardiac
arrhythmias associated with diuretic induced hypokalaemia and hypomagnesaemia. In: Arrhythmias and
Myocardial Infarction: the Role of Potassium, Ed.
Wood, C. & Sommerville, W. Royal Society of
Medicine International Congress and Symposium
Series, 44, 17-24.
70. Struthers, A.D., Whitesmith, R. & Reid, J.L. (1983)
Thiazide diuretics increased adrenaline induced
hypokalaemia. Lancet, i, 1358-1361.