Does anthracycline administration by infusion in children affect late cardiotoxicity?

The severity of late cardiotoxicity after anthracycline treatment for childhood cancer relates mainly to the cumulative anthracycline dose received, but all dose ranges cause some cardiac dysfunction. Anthracycline administration by infusion in order to lower peak drug concentration has been used in an attempt to reduce cardiotoxicity. Cardiac performance was assessed by echocardiography in children who were relapse-free survivors of treatment for acute lymphoblastic leukaemia (ALL). They received the same cumulative anthracycline dose (daunorubicin 180 mg/m2) either by bolus injection (UKALL X protocol, n = 40) or by infusion (UKALL XI protocol, n = 71) with a follow-up duration of 5.3 +/- 2.0 and 5.4 +/- 1.0 years respectively. On analysis, both the bolus administration and infusion groups showed similar mild impairment of cardiac performance, characterized by increased left ventricular end systolic stress and impaired left ventricular function. In conclusion, subclinical abnormality of left ventricular performance was confirmed in both groups despite the relatively modest cumulative anthracycline dose received. We were unable to demonstrate an advantage of anthracycline administration by 6-h infusion with respect to late cardiotoxicity at this dose.

Decreased muscle strength and contents of Mg and Na,K-pumps in chronic alcoholics occur independently of liver cirrhosis.

OBJECTIVES: To evaluate the influence of established liver cirrhosis on muscle strength and muscle contents of magnesium (Mg), potassium (K) and sodium, potassium pumps (Na,K-pumps) in chronic alcoholic patients. DESIGN: An open cross-sectional study. SETTING AND SUBJECTS: Forty consecutive chronic alcoholics (18 with cirrhosis and 22 without cirrhosis) admitted to the Department of Hepatology, Aarhus University Hospital, Denmark, or to a collaborating alcoholism treatment centre, and 36 healthy control subjects. MAIN OUTCOME MEASURES: Evaluation of participant's subjective physical ability and measurement of maximum isokinetic muscle strength and muscle mass, as well as measurements of Mg, K and Na,K-pumps in skeletal muscle. RESULTS: Maximum isokinetic muscle strength and muscle mass were equally reduced in patients with and without cirrhosis (P < 0.01 all). In keeping with this, both groups of patients felt equally physically restricted. Muscle Mg was reduced to the same extent in the two groups of patients (by 12 and 9%, P < 0.001, both), whereas the muscle K content was only significantly lower in the cirrhotic patients (10%, P < 0.001). The muscle content of Na,K-pumps was reduced by 14%, (P < 0.01) in the cirrhotic patients and by 8% (P < 0.05) in the noncirrhotic patients. CONCLUSION: Our alcoholic patients complained of physical disability, had reduced skeletal muscle mass, isokinetic muscle strength, content of muscle Mg and content of Na,K-pumps. There was no difference between patients with and without cirrhosis. It appears that it is the heavy alcohol intake, and not the cirrhosis per se, that is responsible for the observed defects.

Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver cirrhosis -- relation to spironolactone.

OBJECTIVES: To evaluate the muscle strength in relation to muscle contents of magnesium (Mg), potassium (K) and sodium, potassium (Na,K)-pumps in patients with alcoholic cirrhosis. DESIGN: An open cross-sectional study. SETTING AND SUBJECTS: Fifty-one consecutive patients with liver cirrhosis admitted to the Department of Hepatology, Aarhus University Hospital, Denmark, and 28 age- and sex-matched healthy control subjects. MAIN OUTCOME MEASURES: Biopsies of skeletal muscle were performed in patients and controls for measurements of Mg, K, and Na,K-pumps. Furthermore, maximum isokinetic knee extension and skeletal muscle mass were evaluated. RESULTS: Muscle mass, muscle strength, muscle Mg and muscle K were substantially reduced in the patients (P < 0.01, all), and fell with increasing severity of the liver disease reflected in the Child-Pugh (C-P) class. Patients treated with spironolactone for 2 weeks or more, had increased muscle strength, muscle Mg and content of Na,K-pumps, compared with the rest of the patients (P < 0.05, all). In a multivariate analysis of the patients, skeletal muscle mass, muscle Mg and daily alcohol consumption (g) were independent predictors of isokinetic muscle strength (P < 0.05, all). CONCLUSIONS: Patients with alcoholic liver cirrhosis showed considerably reduced muscle strength and muscle Mg was an independent predictor of muscle strength. Surprisingly, in the spironolactone treated patients, muscle weakness was less pronounced, possibly because of the action of spironolactone on muscle Mg, K and Na,K-pump content.

Glucocorticoids increase sodium pump alpha(2)- and beta(1)-subunit abundance and mRNA in rat skeletal muscle.

Fourteen-day adrenal steroid treatment increases [(3)H]ouabain binding sites 22-48% in muscle biopsies from patients treated with adrenal steroids for chronic obstructive lung disease and in rats treated with dexamethasone (Dex). Ouabain binding measures plasma membrane sodium pumps (Na(+)-K(+)-ATPase) with isoform-dependent affinity. In this study we have established the specific pattern of Dex regulation of sodium pump isoform protein and mRNA levels in muscle. Rats were infused with Dex (0.1 mg/kg per day) or vehicle for 14 days. Abundance of sodium pump catalytic alpha(1)- and alpha(2)-subunits and glycoprotein beta(1)- and beta(2)-subunits was determined by immunoblot in soleus, extensor digitorum longus, whole gastrocnemius, and diaphragm and was normalized to the mean vehicle control value. Dex increased alpha(2) and beta(1) protein in all muscle types by 53-78% and ~50%, respectively. Dex increased alpha(1) protein only in diaphragm (65 +/- 7%). At the mRNA level in whole hindlimb muscle, Dex increased alpha(2) (6.4 +/- 0.5-fold) and beta(1) (1.54 +/- 0.15-fold) and decreased beta(2) (to 0.36 +/- 0.6 of control). In summary, alpha(2)beta(1) is the Dex-responsive pump in all skeletal muscles, and changes in alpha(2) and beta(1) mRNA levels can drive the 50% change in alpha(2)beta(1)-subunits, which can account for the reported increase in [(3)H]ouabain binding.

Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve.

BACKGROUND: Ultrasonographic evaluation of systemic arterial function is widely available, and a close relation of endothelial function in the coronary and brachial arteries has been documented. It is unknown, however, whether a similar correlation exists for their 2 microcirculatory territories and thus whether assessment of the systemic microcirculation can be used similarly as a surrogate marker of myocardial perfusion. METHODS AND RESULTS: Twenty-three patients with documented coronary artery disease (CAD; 66+/-9 years old, 18 men), 16 patients with syndrome X (SX; 56+/-5 years old, 13 women), and 45 healthy control subjects (C; 34+/-9 years old, 22 men) were studied. Myocardial perfusion was measured at rest and after dipyridamole (0.56 mg. kg(-1). min(-1) over 4 minutes) by PET, and brachial artery blood flow was measured at rest and after transient forearm ischemia by standard Doppler ultrasound techniques. Dipyridamole increased myocardial perfusion in all groups (mL. g(-1). min(-1): CAD, 0.89+/-0.27 versus 1.62+/-0.67, P:<0.001; SX, 0.82+/-0.16 versus 1.67+/-0.49, P:<0.001; and C, 0.82+/-0.15 versus 2.32+/-0.64, P:<0.001). Postocclusion forearm flow increased similarly in all groups (CAD, 52+/-18 versus 174+/-77 mL/min, P:<0.001; SX, 49+/-29 versus 202+/-82 mL/min, P:<0.001; and C, 61+/-34 versus 229+/-108 mL/min, P:<0.001). No significant correlations were found between peripheral and myocardial microcirculatory beds for either resting flow, hyperemic flow, or flow reserve in any of the groups (r(2)<0.1, P:=NS). CONCLUSIONS: The peripheral perfusion responses to transient forearm ischemia do not correlate with dipyridamole-induced myocardial hyperemia. The lack of correlation indicates different mechanisms of microvascular activation or regulation and confirms that extrapolations between findings in the 2 vascular beds are not suitable.

Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation.

Normal pregnancy is characterized by reduced systemic vascular resistance, which may be mediated by nitric oxide (NO). We compared endothelial vasomotor function in 71 normal pregnant women (13 in first, 29 in middle, and 29 in last trimester) to 37 healthy age-matched controls. With external ultrasound, brachial artery diameter was measured at rest, during reactive hyperemia [with increased flow causing endothelium-dependent dilation (FMD)], and after sublingual nitroglycerin (causing endothelium-independent dilation). Compared with controls, resting flow and brachial artery diameter were significantly higher during the middle and last trimesters. Reactive hyperemia was reduced in all pregnant groups. FMD increased from the first trimester (by 26%), reaching the highest value in the last trimester (to 47% above nonpregnant values). FMD was significantly correlated to pregnancy status (nonpregnant or pregnant) and to vessel size. Nitroglycerin-induced dilation was similar in pregnant and nonpregnant women. A longitudinal study of eight women evaluated in the first, middle, and last trimesters confirmed an increase in FMD throughout pregnancy. The study supports the idea that basal and stimulated NO activity is enhanced in normal pregnancy and may contribute to the decrease in peripheral resistance.

[Non-invasive assessment of endothelial function]. / Ikkeinvasiv vurdering af endotelfunktionen.

Endothelial dysfunction is an early event in atherosclerosis preceding the formation of plaques. An important functional consequence of endothelial damage is reduced vasodilatory responses to a variety of pharmacological and physiological stimuli including reactive hyperaemia. Hitherto, endothelial function could only be assessed by invasive techniques, but a novel ultrasound based technique has recently been developed, which allows non-invasive evaluation of endothelial function in large systemic arteries such as the brachial artery. The technique is accurate, reproducible and able to differentiate between subjects with and without vascular dysfunction. Impaired endothelial function has been documented in young and adult individuals with various vascular risk factors including cigarette smoking, diabetes mellitus, hypercholesterolaemia, and homocystinuria. A good correlation has been found between both the presence of atherosclerotic lesions and endothelial function in the coronary arteries and the brachial artery. The method may help in identification of individuals with early vascular changes and thereby make risk factor modification possible at a very early stage of the atherosclerotic process. It may furthermore serve as a tool to monitor the impact of prevention and intervention on arterial damage.

[Balloon dilatation of congenital aortic stenosis]. / Ballondilatation af medfødt aortastenose.

We evaluated the catheterization results and follow-up echocardiographic data in all (n = 31) patients undergoing balloon dilatation for congenital aortic valve stenosis at Skejby University Hospital from May 1987 to October 1996. Patients were between three weeks and 35 years of age (median 12.1 years). Peak-to-peak systolic pressure gradient was reduced by 59%, from 74 +/- 17 to 30 +/- 20 mmHg (p < 0.0001). Balloon valvuloplasty was successful in 26 (84%) patients. At follow-up 38 +/- 33 months after balloon valvuloplasty, 19 of these 26 patients (73%) had a persistent reduction in gradient compared with that before valvuloplasty. In the seven patients who had been operated during the follow-up period, balloon valvuloplasty had delayed surgical intervention by 6-97 (median 38) months. Balloon valvuloplasty is an effective, low risk palliative procedure in patients with congenital aortic valve stenosis.

[Increased concentration of Na,K-pumps in skeletal muscles of patients with chronic obstructive lung disease. Significance of magnesium depletion and treatment with glucocorticoids]. / Forøget koncentration af Na,K-pumper i tvaerstribet muskulatur hos patienter med kronisk obstruktiv lungesygdom. Betydning af magnesiumdepletering og behandling med glukokortikoider.

Patients with COLD may develop Mg depletion due to inadequate nutrition or treatment with diuretics and beta 2-agonists. In 36 consecutive COLD patients skeletal muscle concentrations of Mg and K were reduced by 22% and 14%, respectively, compared to 23 age- and sex-matched controls (p < 0.001). Patients receiving diuretics showed a further reduction of muscle Mg (-31%) and K (-27%) compared to controls. The mean concentration of Na,K pumps was increased by 31% (p < 0.001), while a more pronounced increase (+61%) was seen in 12 intensive care patients receiving high dosages of glucocorticoids. Thus muscle concentrations of Mg and K are reduced in COLD patients and are associated with an upregulation of the Na,K-pump concentration. It is plausible that this upregulation may be caused by glucocorticoid treatment. The clinical benefits of glucocorticoids may therefore in part be due to an increased activity and capacity of the Na,K-pump and thereby in a possible enhancement of muscle force.

Micronutrients, minerals and growth control.

(1) Dietary deficiencies of Zn, Mg and K lead to a rapid drop in serum concentrations, with no change (Zn) or a slow decline (Mg and K) in the concentrations in skeletal muscle. (2) These deficiencies all lead to inhibition of growth and protein synthesis in muscle. (3) The inhibition of protein synthesis is faster in onset than the loss of Zn, Mg and K from muscle and therefore unlikely to result from cellular mineral deficiency. (4) The deficiencies are likely to be detected by the early drop in serum concentration, but the mechanism is unknown. (5) Possible mediators of growth inhibition are anorexia, GH and IGF-I. (6) Early detection of mineral deficiencies allows the organism to minimize wasteful protein synthesis and the formation of functionally inadequate tissues.

Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function.

BACKGROUND: Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. However, combined hormone replacement therapy is more frequently used owing to the risk of uterine cancer with estrogen-only therapy. Concurrent progesterone treatment may attenuate the beneficial effects of estrogens not only on the lipid profile but also on the endothelium. METHODS AND RESULTS: We studied endothelial vasomotor function in 100 healthy postmenopausal women aged 53.3+/-2.9 years randomized to either combined hormone replacement therapy (n=46) or no substitution (n=54) 2.9+/-0.5 years earlier. In addition, 30 healthy premenopausal women aged 30.3+/-4.2 years were studied. With external ultrasound, brachial artery diameter was measured at rest, during reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual nitroglycerin (causing endothelium-independent dilation). Compared with premenopausal women, flow-mediated dilation was significantly reduced in both postmenopausal groups. In the postmenopausal women, total cholesterol was lower in the treated women (5.66+/-0.83 versus 6.13+/-0.92 mmol/L; P=.025), whereas HDL cholesterol was similar (1.91+/-0.53 versus 1.85+/-0.46 mmol/L; P=NS). Dilation to flow and to nitroglycerin was similar in the two postmenopausal groups (flow: 2.5+/-2.9% versus 2.2+/-2.2%, P=NS; nitrate: 18.7+/-5.9% versus 17.2+/-6.2%, P=NS). CONCLUSIONS: Long-term combined oral hormone replacement therapy is without beneficial effects on endothelial vasomotor function in healthy postmenopausal women. This supports the view that progesterone may attenuate the beneficial effects of unopposed estrogen replacement.

IGF, type I IGF receptor and IGF-binding protein mRNA expression in kidney and liver of potassium-depleted and normal rats infused with IGF-I.

Dietary potassium (K) depletion is known to reduce body weight gain and organ growth, except for kidney which increases in weight. This renal hypertrophy is preceded by increased renal IGF-I levels. In the present study, we investigated IGF-I and -II, type I IGF receptor and IGF-binding protein (IGFBP) mRNA expression in liver and kidney of K-depleted and normal rats infused with vehicle or recombinant human IGF-I. Body weight gain was almost completely arrested in K-depleted rats without any stimulatory effect of IGF-I infusion. Both absolute and relative kidney weight (kidney weight/body weight) were significantly increased in K-depleted rats and this was further enhanced by IGF-I infusion. In contrast, relative liver weight was comparable in the different groups and unaffected by IGF-I infusion. IGF-I mRNA expression was significantly lower in kidney and liver of K-depleted animals whereas type I IGF receptor levels were unchanged. In contrast, in kidney, K depletion increased IGFBP-1 and -2 mRNA expression with no additional effect of IGF-I infusion. In liver of K-depleted animals, IGFBP-1 mRNA expression was increased whereas increased IGFBP-1 and -2 mRNA expression was observed when these animals were infused with IGF-I. These observations may point towards a differential mode of action of the IGFBPs. In kidney increased IGFBP-1 and -2 mRNA expression may enhance IGF-I bioavailability with subsequent kidney growth. In liver, with clearly detectable type I IGF receptor mRNA expression, increased IGFBP levels may protect from IGF-I-induced organ growth by decreasing IGF-I bioavailability.

The concentration of sodium, potassium pumps in chronic obstructive lung disease (COLD) patients: the impact of magnesium depletion and steroid treatment.

OBJECTIVES: To evaluate the concentrations of magnesium (Mg), potassium (K) and sodium,potassium pumps (Na,K pumps) in skeletal muscle in patients with chronic obstructive lung disease (COLD) treated with or without diuretics. DESIGN: An open cross-sectional study. SETTING: COLD patients admitted to the Medical Department of Vejle Hospital, Denmark. SUBJECTS: Thirty-six consecutive COLD patients and 23 age- and sex-matched controls. MAIN OUTCOME MEASURES: Biopsies of skeletal muscle were performed in patients and controls for measurements of Mg, K and Na,K pumps. In a parallel animal experiment the influence of medical treatment on the concentration of Na,K pumps in skeletal muscle was evaluated by infusing 10-week-old rats for 14 days with vehicle, terbutaline, or dexamethasone. RESULTS: In the patients, mean muscle Mg and K concentrations were reduced by 22 and 14% respectively (P < 0.001), but in those patients who received diuretics muscle Mg and K were further reduced (by 31 and 27%, respectively, of the control values). The concentration of Na,K pumps was increased by 31% (P < 0.001), with a maximum increase of 61% (P < -0.001) in 12 intensive care patients receiving high dosages of glucocorticoids. Linear regression analysis showed a positive correlation between daily glucocorticoid intake and the concentration of Na,K pumps in the biopsy specimens from each patient (r = 0.38, P = 0.02). In the experimental study, dexamethasone induced 27-34% increase in the concentration of Na,K pumps (P < 0.01) in three different muscles, whereas there was no significant change following terbutaline infusion. CONCLUSIONS: COLD patients show reduced concentrations of Mg and K in skeletal muscle, associated with an upregulation of the Na,K pump concentration. It is plausible that this upregulation may be caused by glucocorticoid treatment. The clinical benefits of glucocorticoids may in part be due to an increase in the activity and capacity of the Na,K pump and thereby in a possible enhancement of muscle force.

Effects of adrenal steroids on the concentration of Na(+)-K+ pumps in rat skeletal muscle.

Since adrenal steroids have been shown to upregulate the concentration of Na(+)-K(+)-ATPase in cardiac muscle, similar effects could be expected in skeletal muscle. Following infusion of dexamethasone (0.02-0.1 mg/kg per day) for 7 days in 10-week-old rats, the total concentration of [3H]ouabain-binding sites rose by up to 22-42% in soleus, extensor digitorum longus, gastrocnemius and diaphragm muscle. Dexamethasone produced no or minute changes in the Na(+)-K+ contents of skeletal muscle. In contrast, infusion with aldosterone (0.02-0.5 mg/kg per day) for 7 days produced hypokalemia and a graded reduction in the K+ content of skeletal muscle, which was closely correlated to a downregulation of the [3H]ouabain-binding site concentration (r = 0.65-0.70; P < 0.001). The results indicate that in skeletal muscle high doses of glucocorticoids upregulate the concentration of Na(+)-K+ pumps whereas mineralocorticoids induce a downregulation, which is secondary to the concomitant K+ deficiency. Since adrenalectomy produced no significant change in [3H]ouabain-binding site concentration, basal levels of endogenous adrenal steroids seem to be of minor importance for the regulation of Na(+)-K+ pump concentration in skeletal muscle.

Characterization of bumetanide-sensitive Na+ and K+ transport in rat skeletal muscle.

In isolated rat soleus muscle an average of 23% of the total 22Na influx was found to be suppressible by bumetanide (K0.5 = 0.1 mM) and furosemide (K0.5 = 1 mM), whereas the influx and efflux of 42K were not affected. In extensor digitorum longus muscle, around 25% of the total 22Na influx was suppressible by bumetanide (1 mM). In the presence of ouabain, both diuretics decreased net intracellular accumulation of Na+, but caused no change in K+ content. In extensor digitorum longus (but not in soleus), bumetanide-suppressible 22Na influx was stimulated by increasing extracellular osmolarity with the bumetanide having no effect on 42K influx. Bumetanide-suppressible Na+ influx was almost abolished in Cl(-)-free buffer, but was unaffected by the omission of K+. In rat soleus, the inhibitory effects of bumetanide, amiloride and tetrodotoxin on 22Na influx were found to be additive. The results indicate that a NaCl cotransport system is present in both fast- and slow-twitch skeletal muscles, and may participate in volume regulation. Due to the large pool of muscle cells, activation of NaKCl2 cotransport is likely to entail the hazards of hypokalemia. The advantage of exerting volume control via NaCl cotransport is that this risk can be avoided.

Effects of K+, Mg2+ deficiency and adrenal steroids on Na+, K(+)-pump concentration in skeletal muscle.

Animal studies have shown that deficiency of K+ is associated with a reduction in the concentration of Na+, K+ pumps in skeletal muscle, and that this reduction is closely correlated with the reduction in the muscle K+ concentration. Furthermore, animals deficient in Mg+ show a downregulation of the Na+, K(+)-pump concentration, but this seems to be secondary to the concomitant K+ deficiency, which often accompanies Mg2+ deficiency. Measurements on skeletal muscle biopsies from patients who had been in long-term treatment with diuretics showed that 55% had reduced concentrations of both K+ and Mg2+, and that this was associated with a reduction in the concentration of Na+, K+ pumps. Furthermore, the Na+, K(+)-pump concentration correlated significantly with both muscle K+ and Mg2+, suggesting that the downregulation of the Na+, K+ pumps was related to the loss of K+, as predicted from the animal experiments. In accordance with this, normalization of muscle K+ and Mg2+ in response to oral Mg2+ supplementation, resulted in a restoration of the Na+, K+ pumps. Apart from thyroid hormone, which is another major regulator for the Na+, K(+)-pump concentration, other hormones may be of importance. It is well known that adrenal steroids control the synthesis of Na+, K+ pumps in the kidney and heart. Recently, treatment with dexamethasone was found to increase the Na+, K(+)-pump concentration in rat skeletal muscle. The increase was found in EDL, soleus, gastrocnemius and diaphragm muscles, and amounted to 23-52%. In contrast, treatment with aldosterone induced a decrease in the Na+, K(+)-pump concentration, which was closely correlated to the reduced K+ content of the muscles. The results indicate that in skeletal muscle, high doses of glucocorticoids upregulate the concentration of Na+, K+ pumps, whereas mineralocorticoids induce a downregulation which is secondary to the concomitant K+ deficiency.

Growth hormone (GH) receptor and GH-binding protein deficiency in the growth failure of potassium-depleted rats.

Potassium (K+) deficiency is associated with growth retardation in both man and experimental animals. Growth hormone (GH) administration to such animals prevents, to some extent, weight loss and selective muscle atrophy, but does not affect tail and tibia length even with supraphysiological doses. The present study was undertaken to investigate the possible effect of K+ deficiency on the hepatic GH receptor and GH-binding protein (BP). Young female Wistar rats were maintained on K(+)-deficient fodder and distilled water, and compared with pair-fed and ad-libitum-fed control groups. After 15 days GH-BP and electrolytes were measured in sera, GH receptors were studied in liver membranes by 125I-labeled human GH binding and muscles were weighed and saved for electrolyte measurements. K(+)-deficient rats showed complete growth arrest compared with an intermediate weight gain of the pair-fed group. Serum K+ was very low, at 1.5 +/- 0.1 mmol/l, compared with the mean value of 5.3 mmol/l of control animals. Somatogenic and lactogenic receptors in liver membranes and serum GH-BP levels were significantly (P < 0.05) lower in K+ deficiency, as compared with their pair-fed controls. Liver GH receptors correlated significantly (P < 0.05) with serum GH-BP levels. The growth variables correlated positively with both hepatic somatogenic and lactogenic receptors and serum GH-BP levels, with correlation coefficients that were highest against serum GH-BP and lowest against liver lactogenic receptors. Serum and muscle K+ correlated significantly (P < 0.05) with both liver GH receptors and serum GH-BP, with correlation coefficients that were higher against serum GH-BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor I stimulates active Na(+)-K+ transport in rat soleus muscle.

The functional homology between insulin and insulin-like growth factor I (IGF-I) comprises effects on growth and glucose metabolism. Because insulin stimulates the Na(+)-K+ pump, IGF-I might exert a similar effect. We show here that IGF-I increases 42K and 86Rb uptake and the efflux of 22Na in isolated rat soleus muscle. This leads to a significant decrease (21-55%, P < 0.001) in intracellular Na+ and a small increase in intracellular K+. In extensor digitorum longus (EDL) muscle, similar effects were observed. The stimulation of K+ uptake and the reduction in intracellular Na+ in the soleus were blocked by ouabain, indicating that they reflect an acute stimulation of active Na(+)-K+ transport. This conclusion was further supported by the observation that the [3H]ouabain binding rate was significantly increased by IGF-I. IGF-I increased ouabain-suppressible 42K or 86Rb uptake by 56 and 54%, respectively. The effects of IGF-I and epinephrine on ouabain-suppressible 86Rb influx in rat soleus were additive, whereas the effects of insulin and IGF-I were similar and nonadditive. The effects of IGF-I were seen down to a concentration of 10(-8) M, which is unlikely to stimulate the insulin receptor, and it is therefore plausible that IGF-I exerts its effect on Na(+)-K+ transport through its own receptor. IGF-I may play a role in the maintenance of muscle Na+ and K+ contents also in vivo, especially in patients treated with IGF-I.

86Rb is not a reliable tracer for potassium in skeletal muscle.

For technical reasons, 86Rb is frequently preferred to 42K as a tracer for K+. Systematic comparisons of the two isotopes, however, are rarely done. In this paper we compare the transport of 42K and 86Rb in rat and mouse soleus muscle and in rat erythrocytes. Ouabain-suppressible K+ uptake in rat soleus was the same whether measured with 42K or 86Rb, both when stimulated by insulin, salbutamol and calcitonin-gene-related peptide (CGRP), and when inhibited by graded concentrations of ouabain. Control experiments with rat erythrocytes, where Na(+)-K(+)-Cl- co-transport has earlier been demonstrated, showed closely similar inhibitory effects of bumetanide on 42K and 86Rb uptake. In contrast, bumetanide produced no significant change in 42K uptake of rat and mouse soleus muscle, but clearly inhibited 86Rb uptake at concentrations down to 10(-7) M (P < 0.001). Whereas the addition of 150 mM NaCl had no effect on 42K uptake in rat soleus, 86Rb uptake, and in particular the bumetanide-suppressible component, was markedly increased by this addition. The inhibitory effect of bumetanide on 86Rb uptake gives rise to the false impression that skeletal muscle contains a NaKCl2 co-transport system. Efflux studies showed that the fractional loss of 42K from rat soleus muscle is 2.3 times larger than that of 86Rb. Salbutamol and CGRP increased 86Rb efflux, but inhibited 42K efflux. This implies that for studies of K+ efflux and bumetanide-sensitive K+ transport, 86Rb is not even an acceptable tracer for the detection of qualitative changes. Control experiments with 42K are essential in any characterization of unknown K+ transport processes.