Oxygen free radicals and excitation-contraction coupling.

Oxygen free radicals (OFR) contribute to contractile failure, rigor, and calcium (Ca2+) overload in ischemic/reperfused myocardium. Using both multicellular and isolated single-cell preparations, our laboratory has identified two fundamental mechanisms contributing to the deleterious effects of OFR: (i) impaired myocardial metabolism, and (ii) altered myocardial calcium handling. Impaired metabolism leads to activation of metabolically sensitive K+ currents, which shorten the action potential, thereby decreasing the duration of systole. Ultimately, high-energy phosphate depletion secondary to metabolic failure results in rigor. Altered myocardial Ca2+ handling is evidenced by a decrease in Ca2+ entry via L-type Ca2+ channels [another cause of decreased action potential duration (APD)], a reduction in sarcoplasmic reticulum (SR) Ca2+ content, slowed Ca2+ uptake in diastole, and increased sodium-calcium exchange (NaCaX) activity. The increase in NaCaX activity may contribute to the early increase in developed tension frequently observed in multicellular preparations exposed to free radicals, as well as the SR depletion occurring early on in voltage-clamped isolated cell preparations. Increased NaCaX activity is likely to be a critical factor underlying the late Ca2+ overload that occurs in the setting of increased intracellular Na+, and which leads to irreversible injury. The extent to which free radical-mediated metabolic inhibition participates in the dysfunction of the L-type Ca2+ channel is uncertain. The altered activity of the SR Ca2+ pump and NaCaX are more likely caused by direct actions of OFR on these proteins.

Leg blood flow and increased potassium release during exercise in chronic heart failure: effect of physical training.

BACKGROUND: Exercise-induced hyperkalemia, which may contribute to exercise hyperpnea and exertional fatigue, is increased in patients with chronic heart failure (CHF). This study examined whether differences in leg blood flow during exercise could be responsible for alterations in the level of hyperkalaemia, as well as the effect of physical training. METHODS AND RESULTS: We studied 10 subjects with CHF (ejection fraction 23 +/- 3.9%; mean +/- SD) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary bypass graft surgery (ejection fraction 64 +/- 8.0%; mean +/- SD). Subjects performed incremental cycle exercise to exhaustion before and after physical training. The rises in femoral venous potassium concentration ([K+]), heart rate, lactate, and ventilation (VI) with exercise were all greater in the subjects with CHF than in those with NLVF (P < .05). There was no difference between the groups in leg blood flow during submaximal exercise but peak leg flow was greater in the group with NLVF (P < .01). Physical training was well tolerated and both groups increased their peak VO2 (8 +/- 3.2% CHF (P < .05); 11 +/- 2.7% NLVF (P < .01); mean +/- SE). Training resulted in a reduced rise in femoral venous [K+] and VI (P < .05), but did not affect leg blood flow during submaximal exercise in either group. CONCLUSIONS: The rise in the femoral venous [K+] with exercise is increased in patients with CHF and can be reduced by physical training. These changes are not a consequence of different leg blood flows, either between groups or with training. The study also suggests that femoral venous [K+] is not a powerful regulator of leg blood flow during exercise.

Effect of heart failure and physical training on the acute ventilatory response to hypoxia at rest and during exercise.

We studied the acute ventilatory response to hypoxia (AHVR) in 10 patients with chronic heart failure (CHF) and in 10 subjects with normal left ventricular function (NLVF) before and after 8 weeks of home-based physical training. Subjects were studied at rest and during constant cycle exercise at a work rate equivalent to 40% of their maximum oxygen consumption. The AHVR was not significantly different between the patients with CHF and those with NLVF either at rest (1.32 +/- 0.19 vs. 1.63 +/- 0.20 litres/min/% arterial desaturation; mean +/- SE) or during constant light exercise (2.37 +/- 0.48 vs. 2.86 +/- 0.55 litres/min/% arterial desaturation). Both groups showed evidence of improved physical fitness after training with increases in maximum oxygen consumption of 11 +/- 2.7% (p < 0.01) for the group with NLVF and of 8 +/- 3.2% (p < 0.05) for the group with CHF. Values for the AHVR in the trained state were not significantly different between the patients with CHF and those with NLVF either at rest (1.23 +/- 0.24 vs. 1.63 +/- 0.22 litres/min/% arterial desaturation) or during constant light exercise (2.52 +/- 0.69 vs. 2.24 +/- 0.37 litres/min/% arterial desaturation). Moreover, these responses did not differ from those in the untrained state (see above). The AHVR increased during exercise compared with rest in both groups (p < 0.05). The AHVR is not substantially altered in patients with CHF compared to subjects with NLVF. Physical training may reduce ventilation during exercise, but it has relatively little or no effect on the AHVR. However, exercise increases the AHVR in patients with CHF, as it does in normals.

Effect of raised potassium on ventilation in euoxia, hypoxia and hyperoxia at rest and during light exercise in man.

The purpose of this study was to determine whether changes in arterial plasma potassium concentration [K+]a affect expired ventilation (VE) in euoxia, hypoxia and hyperoxia during rest and light exercise in humans. Three periods of ventilatory measurements were undertaken in eight healthy subjects at rest and in seven other subjects during cycle ergometry (70 W). The first period of measurement was before the ingestion of 64 mmol of potassium chloride (KCl), the second 20 min after ingestion of KCl when [K+]a levels were elevated, and the third 3 h after the ingestion of KCl when [K+]a had returned substantially to normal. During each period, end-tidal PO2 was cycled between euoxia, hypoxia and hyperoxia, whilst the end-tidal PCO2 was maintained constant. The acute ventilatory response to hypoxia (AHVR) was calculated as the difference in VE during hypoxia and hyperoxia within each period of measurement. Oral KCl produced a 1.3 +/- 0.2 mM (mean +/- S.E.M.) increase in [K+]a at rest and a 0.8 +/- 0.2 mM increase during exercise. There was no significant difference in ventilation during euoxia between the three periods of measurement at rest or during exercise. There was a significant increase in AHVR with the rise in [K+]a of 21 min-1 mM-1 at rest (arterial PO2 during hypoxia ca 57 Torr) and 10 l min-1 mM-1 during exercise (arterial PO2 during hypoxia ca 52 Torr). There was a significant difference in the absolute increase in AHVR with [K+]a between rest and exercise, but this difference was not significant if the increase in AHVR with [K+]a was expressed as a percentage of the initial AHVR. We conclude that changes in [K+]a of the order of 1 mM have little effect on euoxic ventilation at rest or during light exercise in humans. We also conclude that [K+]a changes of this order increase AHVR at rest and during light exercise and that increases in [K+]a contribute to the increase in AHVR with exercise in humans.

Effect of hypoxia on arterial potassium concentration at rest and during exercise in man.

Hypoxia has been reported to increase arterial potassium concentration ([K+]a) in anaesthetized cats (Paterson, Estavillo & Nye, 1988). The purpose of this study was to determine whether this phenomenon occurs in humans. The effect of hypoxia on [K+]a was measured in ten male subjects, at rest and during light exercise, before and after 8 weeks of physical training. The [K+]a increased by 0.15 +/- 0.04 mM (mean +/- S.E.M.) at rest, when end-tidal PO2 (PET,O2) was lowered from 100 to 51 +/- 1.6 Torr, and by 0.10 +/- 0.02 mM during exercise, when PET,O2 was lowered from 100 to 66 +/- 6.2 Torr. Physical training did not alter the rise in [K+]a significantly. The magnitude of this effect is small in comparison with that of exercise-induced hyperkalaemia, and is unlikely to be of great physiological significance at moderate levels of hypoxia.

Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines.

BACKGROUND: The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis. METHODS AND RESULTS: We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01). CONCLUSIONS: Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.

Potassium loss from skeletal muscle during exercise in man: a radioisotope study.

Muscle potassium (K+) content decreases during exercise. Previous studies, in humans, have used measurements of arteriovenous plasma potassium concentration differences (AV delta[K+]) and/or muscle biopsy to measure the loss of muscle K+ during exercise. In the current study a non-invasive method was developed to measure skeletal muscle K+ before and after exercise, using an isotope of K+, potassium-43 (43K+). Twelve subjects performed single-leg extension exercise for 2 h at 50% of their maximum predicted heart rate. The level of radioactivity from the quadriceps femoris was determined before exercise and during two periods post-exercise. After correction for counts arising outside the exercised muscle, we estimate a decrease in muscle K+ content of 3.2 +/- 1.55% (mean +/- S.E.M.) following exercise. The muscle K+ was not restored following 75 min of recovery. The decrease in muscle K+ following exercise in our study is considerably less than that suggested by previous studies using AV delta[K+] measurements but not so dissimilar from results obtained using muscle biopsy. We conclude that a small but significant loss of K+ occurs following prolonged dynamic exercise, and that complete recovery of muscle K+ is slow.