钾代谢影响心律失常的研究进展

钾是人体细胞内的主要阳离子，血清钾对维持机体体液的酸碱平衡和保持渗透压的稳定具有重要作用，而细胞内钾是稳定神经、肌肉及细胞电活动的主要离子。钾代谢紊乱就会引起心电活动异常，严重的心律失常甚至可危及生命。     

Regulation of Potassium Homeostasis

Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students.     

Mechanisms of renal ammonia production and protein turnover

Renal synthesis and excretion of ammonia are critical for efficient removal of acids from the body. Besides the rate of ammonia production, the intrarenal distribution of produced ammonia is a crucial step in the renal regulation of acid-base balance. Various acid-base disorders are associated not only with changes in ammonia production but also with its distribution between the urine and the renal veins. The final effect of ammonia production on acid-base balance largely depends on the events that determine the distribution of ammonia produced between urine and blood. Several factors, among which urine pH, urine flow, total ammonia production “per se” and renal blood flow may affect the percent of ammonia excreted into urines in humans with different acid-base disturbances. Among these factors, urine pH is the most important. An additional effect of stimulated ammoniagenesis is kidney hypertrophy. In tubule epithelial cells, the associated increase in ammonia production, rather than the acidosis per se, is responsible for favoring tubular hypertrophy. This effect is related to the inhibition of protein degradation, owing to changes in lysosomal pH and cathepsin activity, without effects on cell cycle. Both changes of PI-3 kinase pathway and the suppression of chaperone-mediated autophagy are candidate mechanism for ammonia-mediated inhibition of protein degradation in tubule cells. Available data in humans indicate that the response of kidney to metabolic acidosis includes both changes in amino acid uptake and suppression of protein degradation. The latter effect is associated woth the increase in ammonia excretion and partition into the urine.     

Gestörter Kaliumhaushalt und Hypokaliämie

Potassium is the most common intracellular cation and approximately 98% is intracellular. The plasma level reflects only 2% of the potassium content. The absorption rate is approximately 70 mmol/24 h and from this 95% is excreted from the kidneys and 5% from the intestines. A 1% shift in potassium from intracellular to extracellular would mean a 100% change in the plasma level meaning that the rapid ingestion of a steak could be fatal. The body is protected from this by a fine regulation of the potassium distribution via the cell membranes. Recent research has also shown that there is also signaling between the gastrointestinal tract and the kidneys, which can immediately result in excretion of potassium without incurring alterations to the plasma or aldosterone levels. In patients with hypokalemia it is necessary to thoroughly investigate the acid-base balance in order to come to the correct diagnosis. The best therapy for hypokalemia is to remove the cause.     

Hyperkalemia in diabetes mellitus

Potassium filtered at the glomerulus is almost completely reabsorbed before the distal tubule; it must therefore be secreted into the collecting duct. The rate of potassium secretion is determined by a number of factors, notably aldosterone, distal sodium delivery, and serum potassium. Normal serum potassium is maintained by the interplay of passive leak of potassium from the cells and its active return to the cells. Transmembrane potassium distribution is influenced largely by acid-base equilibrium and hormones including insulin and catecholamines. In the diabetic with ketoacidosis hyperkalemia, in the face of potassium depletion, is attributable to reduced renal function, acidosis, release of potassium from cells due to glycogenolysis, and lack of insulin. Chronic hyperkalemia in diabetics is most often attributable to hyporeninemic hypoaldosteronism but other conditions including urinary tract obstruction may also contribute. A variety of clinical situations (e.g., volume depletion) and drugs (e.g., nonsteroidal antiinflammatory agents, and heparin) may acutely provoke hyperkalemia in susceptible individuals.     

Internal potassium balance and the control of the plasma potassium concentration

The plasma potassium concentration is determined both by external potassium balance and by the distribution of potassium between extracellular and intracellular fluid compartments, i.e., "internal potassium balance." Whenever external potassium balance is altered, the resultant change in the plasma potassium concentration is strongly influenced by concomitant alterations in internal potassium balance. Several factors alter internal potassium balance independently of changes in external balance. Acid-base disturbances produce shifts of potassium into or out of cells, but attempts to quantify these effects are not likely to be clinically useful. Hypertonicity produces a shift of potassium out of cells. Several hormones (insulin, aldosterone, catecholamines, glucagon, and growth hormone) may have roles in internal potassium balance. Digitalis and succinylcholine, by producing efflux of potassium from cells, may cause hyperkalemia. Potassium is released from skeletal muscle during exercise, causing an increase in the plasma potassium concentration. The periodic paralyses are associated with well-defined transient alterations in internal potassium balance.     

St?rungen des Elektrolytstoffwechsels

Disorders of electrolyte balance are frequent and pathophysiologically complex. Sodium is responsible for a large part of the osmolarity of extracellular fluids. Therefore, pathological concentrations of serum sodium reflect the relation between sodium and water in the extracellular compartment rather than the total body sodium content. The causes of hypo- or hypernatremia can only be deduced if total body volume status is considered. Patients with hyponatremia and volume deficit should receive sodium chloride solution while patients with this disorder in the presence of volume overload need strict water restriction. In certain cases additional specific pharmacotherapy directed at the effects of antidiuretic hormone may be considered. Potassium and calcium are extracellular regulatory ions; their concentrations do not relevantly contribute to osmolarity and water distribution but to electrophysiologically relevant transmembrane potentials. These ions are influenced by active membrane transporters and regulated by several hormones. The rather small extracellular pools are overfilled or depleted by alterations of intake and excretion. In addition, several inborn or acquired defects of transmembrane transporters may severely alter their extracellular concentrations. Therapy needs to consider the specific mechanisms that led to the electrolyte disorder including modification of intake, excretion or extra-intracellular distribution.     

Electrolyte disorders

Disorders of electrolyte balance are frequent and pathophysiologically complex. Sodium is responsible for a large part of the osmolarity of extracellular fluids. Therefore, pathological concentrations of serum sodium reflect the relation between sodium and water in the extracellular compartment rather than the total body sodium content. The causes of hypo- or hypernatremia can only be deduced if total body volume status is considered. Patients with hyponatremia and volume deficit should receive sodium chloride solution while patients with this disorder in the presence of volume overload need strict water restriction. In certain cases additional specific pharmacotherapy directed at the effects of antidiuretic hormone may be considered. Potassium and calcium are extracellular regulatory ions; their concentrations do not relevantly contribute to osmolarity and water distribution but to electrophysiologically relevant transmembrane potentials. These ions are influenced by active membrane transporters and regulated by several hormones. The rather small extracellular pools are overfilled or depleted by alterations of intake and excretion. In addition, several inborn or acquired defects of transmembrane transporters may severely alter their extracellular concentrations. Therapy needs to consider the specific mechanisms that led to the electrolyte disorder including modification of intake, excretion or extra-intracellular distribution.     

Influence of progressive renal dysfunction in chronic heart failure

Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.     

Disorders of body fluids, sodium and potassium in chronic renal failure

A stable volume and composition of extracellular fluid are essential for normal functioning of the body. Since the kidney is primarily responsible for regulating extracellular fluid, loss of kidney function should have catastrophic consequences. Fortunately, even with loss of more than 90 percent of renal function, a remarkable capacity to regulate body fluid volumes and sodium and potassium persists. Nevertheless, this capacity is limited in chronic renal disease and this has important consequences for clinical management of these patients. How can sodium and potassium homeostasis be assessed? Methods for evaluating the steady-state regulation of sodium include measurement of body fluids and their distribution in different compartments and measurement of exchangeable and intracellular sodium. Short-term regulation of body sodium can be assessed from measurement of sodium balance during changes in dietary salt. Potassium is predominantly contained within cells and thus the assessment of its regulation requires special emphasis on measurement of steady-state body stores and potassium distribution across cell membranes. However, the methods used to make all of these measurements require assumptions that may not hold in the altered state of uremia. This raises problems in interpretation requiring critical analysis before conclusions can be made regarding sodium and potassium homeostasis in patients with chronic renal failure. This review focuses on abnormalities of body fluids, sodium and potassium in patients with creatinine clearances of less than 20 ml/min due to chronic renal failure and the impact of conservative therapy, dialysis and renal transplantation on these patients.     

Consequence of Colonic Involvement on Electrolyte and Acid-Base Homeostasis in Crohn''s Disease

We evaluated the relationship existing between the site of intestinal lesions and systemic acid-base balance in 78 patients with active Crohn's disease. Patients with enteritis had a normal acid-base balance, while mild and moderate metabolic alkalosis were present in enterocolitis and colitis. These findings appeared to be related to the electrolyte fecal losses. In enteritis fecal sodium and chloride concentrations were within the normal range (Na 29.2 +/- 18.5; Cl 16.6 +/- 11.2 mEq/l) while in colitis they were significantly higher (Na 52.8 +/- 20.8; Cl 29.6 +/- 12.7 mEq/l). Intermediate values were observed in enterocolitis. The fecal potassium concentrations were similar in the three groups of patients, with a slightly lower concentration in enterocolitis and colitis. The fecal K/Na ratio was normal in enteritis and reversed in enterocolitis and colitis. This study suggests that a relationship exists between the site of lesions, fecal electrolyte losses, and systemic acid-base balance in Crohn's disease. Systemic metabolic alkalosis and an abnormal fecal K/Na ratio occurred in patients with colonic involvement, indicating the important role played by the colon in acid-base and electrolyte homeostasis.     

Hypercalciuria and altered intestinal calcium absorption occurring independently of vitamin D in incomplete distal renal tubular acidosis

Negative calcium balance and calcium nephrolithiasis are two sequelae of chronic metabolic acidosis. To establish the effects of acidosis on calcium and vitamin D metabolism, we have examined a group of nine patients with incomplete distal renal tubular acidosis. Patients were studied during a control phase and after eight months of potassium citrate treatment, 60 to 80 meq daily. Potassium citrate caused a significant decrease in urinary calcium. The fractional intestinal calcium absorption increased significantly, yet no change was observed in serum vitamin D levels. The estimated calcium balance increased significantly from -70.2 +/- 63.8 to +66.7 +/- 48.7 mg/d (P less than 0.01). Thus, potassium citrate treatment improved the estimated calcium balance by lowering urinary calcium while increasing the fractional intestinal calcium absorption. The original hypercalciuric state, its correction to normocalciuria, and the augmentation of intestinal calcium absorption seen in these patients are probably independent of vitamin D control since there was no change noted in serum 1,25-dihydroxyvitamin D levels.     

Diagnostic strategies in disorders of fluid,electrolyte and acid-base homeostasis

Our understanding of the physiology and biochemistry of acid-base and fluid-electrolyte regulation has greatly expanded in recent years. Key physiologic principles have emerged that now permit rational diagnosis and therapy of clinical disorders of serum electrolyte concentration. This paper describes diagnostic strategies based upon these principles.The etiology of the myriad factors in hyponatremia is best derived by first measuring serum tonicity and then assessing extracellular fluid volume. The hyper-, iso- and hypotonic hyponatremias are defined, and the hypotonic group is subclassified into hypo-, iso- and hypervolemic forms. The hypernatremias are best categorized by their state of volume expansion. Classification into the hypo-, hyper- and isovolemic hypernatremias simplifies their diagnosis.Metabolic acidoses are classified in terms of the anion gap. Clinical and chemical aspects of increased and normal anion gap acidoses are described. Metabolic alkaloses require a source of new bicarbonate and its retention by the kidney. The means by which new alkali is synthesized and urinary loss prevented serve to effectively classify the alkaloses.Hypokalemic syndromes are defined in terms of associated changes in body potassium. The potassium-depleted states are further subclassified by whether normotension or hypertension is associated. Hyperkalemia is produced by redistribution of cellular and extracellular potassium or by inceased body potassium. Defects in the renin-angiotensin-aldosterone-distal renal tubule effector arm usually underlie hyperkalemic states, which are then classified in terms of this regulatory hormonal cascade.Classifications for disordered serum concentrations of calcium, magnesium, phosphorus and uric acid are presented. Hormonal, metabolic and renal regulatory factors form the basis for an organized approach to these disorders.     

Low potassium syndrome due to defective renal tubular mechanisms for handling potassium

Prolonged observations were made on the characteristics and the mechanism of production of the low potassium syndrome in a forty-two year old Chinese male with nephritis of unknown etiology. The syndrome consisted of intermittent bouts of muscular weakness, atony of the bladder, constipation and electrocardiographic changes of a broad flattened T wave, prolonged Q-T interval, prolonged P-R interval and dropped beats, all associated with low serum potassium levels.The plasma potassium level varied between 1.5 and 2.3 mEq./L. when the patient was on a regular diet (104 mEq. potassium daily), fell as low as 1 mEq./L. on a low potassium intake (30 mEq. potassium daily) and rarely exceeded 4 mEq./L. even when the potassium intake was six times greater than normal (625 mEq. potassium daily). The potassium balance was negative on an average potassium intake and became positive only when the daily potassium intake was increased to 425 mEq. or more.In general the serum sodium levels were low and sodium balance tended to be negative except when sodium intake was high. A reciprocal relationship between the potassium and sodium balances was apparent when the potassium intake was varied. Variations in sodium intake and balance, however, were not attended by reciprocal changes in the potassium balance.The plasma chloride level was usually low and chloride balance appeared to be related to the sum of the sodium and potassium balance in that chloride was retained when base was retained and vice versa.Potassium depletion appeared to affect adversely muscle strength and the vegetative nervous system. The severity of signs and symptoms referable to these systems varied in the presence of a constant plasma potassium level; nor was development of symptoms inevitable at any particular plasma potassium level. The height of the T wave of the electrocardiogram could be correlated with the plasma potassium level in acute experiments after potassium administration. Although electrocardiographic abnormalities occurred only during periods of potassium depletion, the day-to-day correlation between the height of the T wave and plasma potassium levels was poor.Glomerular filtration rate, renal plasma flow and maximum capacities of the renal tubules to excrete p-aminohippurate and to reabsorb glucose were approximately one-third of normal. The rate of glomerular filtration, but not the other functions, varied directly although not precisely with the level of daily potassium intake. During periods of low potassium intake and in spite of very low plasma potassium levels the kidneys continued to excrete urine containing appreciable amounts of potassium. Loss of potassium in the urine was not due to inability of the kidneys to defend by the usual mechanisms against either alkalosis or acidosis.Under conditions of low potassium intake as much as 50 per cent of the potassium filtered at the glomeruli appeared in the urine (normal = less than 20 per cent). Tubular excretion of potassium was easily demonstrable whenever the patient was on a high potassium intake. Potassium given during a period of potassium depletion and at a time when an abnormal amount was being lost in the urine demonstrated that the tubules were capable of reabsorbing additional potassium. A similar experiment performed during a period of high potassium intake resulted in a greater increase in the amount of potassium in the urine than in the glomerular filtrate.It is probable that both decreased absorption and increased excretion of potassium were a part of the renal tubular defect responsible for the excessive loss of potassium in the urine.     

Hyperkalemia in the elderly

Objective

To review the pathophysiology underlying the predisposition to hyperkalemia in the elderly; the medications that disrupt potassium balance and promote the development of hyperkalemia in the elderly; the prevention of hyperkalemia in elderly patients treated with potassium-altering medications; and the appropriate management of hyperkalemia when it develops.

Methods and main results

A MEDLINE search of the literature (1966–1996) using the terms hyperkalemia, drugs, elderly, and treatment was conducted and pertinent review articles, textbooks, and personal files were consulted. Elderly subjects appear to be predisposed to the development of hyperkalemia on the basis of both innate disturbances in potassium homeostasis and comorbid disease processes that impair potassium handling. Hyperkalemia in the elderly is most often precipitated by medications that impair cellular uptake or renal disposal of potassium. This electrolyte disorder is best prevented by recognition of at-risk physiology in the aged, avoidance of therapy with certain high-risk medications, and monitoring of plasma potassium concentration and renal function at intervals appropriate for the medication prescribed. Management of hyperkalemia entails identification of the clinical manifestations of severe hyperkalemia, stabilization of cardiac tissue, promotion of cellular potassium uptake, and ultimately removal of potassium from the body.

Conclusions

Geriatric patients should be considered at risk of developing hyperkalemia, especially when they are prescribed certain medications. Potassium levels should be monitored at appropriate intervals when these patients are treated with potassium-altering medications. Appropriate management of hyperkalemia in the elderly can avoid life-threatening neuromuscular and cardiac complications.     

Potassium in hypertension

Potassium is the most important ion in the living cell, affecting almost every cellular function. Numerous clinical and epidemiologic studies support the knowledge that potassium is a fundamental factor in blood pressure regulation. The role of potassium in blood pressure regulation is reviewed in this article, focusing on its impact on the vascular vessel and the kidney, which are tissues strongly affected by potassium balance. The role of potassium on nitric oxide synthesis and superoxide formation is analyzed. Finally, the study of cell potassium as a marker for hypertension is discussed.     

Severe hypercapnia associated with a non-respiratory alkalosis.

A case of hypoventilation in response to a non-respiratory alkalosis is presented. It is postulated that the degree of hypoventilation encountered was a normal response and that a fall in intracellular hydrogen ion concentration was responsible for the hypoventilation. This explains why the alkalosis associated with potassium deficiency is not associated with hypoventilation since the intracellular hydrogen ion concentration then remains constant. The renal response in this condition is responsible for maintaining the alkalosis and seems to be aimed at sodium conservation and hence plasma volume control rather than defence of acid-base balance.     

Lactate compartmentation in hippocampal slices: Evidence for a transporter

Lactic acid accumulation has been implicated in the evolution of brain damage after ischemia. Since compartmentation of lactate may play a role in acid-base balance, lactate release from gerbil hippocampal slices was examined during a number of metabolic stresses including elevated [K⁺]_e, ischemia, anoxia, and aglycemia. Slices were preincubated for 1 hr in artificial cerebrospinal fluid (ACSF) equilibrated with 95% O₂/5% CO₂ (pH 7.4 at 37°C) and then transferred to tubes containing 300l of test medium. The rate of lactate release in control slices was 9.64 nmol/min/mg protein and increased 2.6- and 3.2-fold in the presence of 60 mM potassium and anoxia, whereas the rate of lactate release was decreased by 50 and 25% during ischemia and aglycemia. Lactate release was temperature dependent and was only minimally influenced by removing Ca²⁺ or by adding 5 mM d-lactate to the ACSF. In contrast, pyruvate inhibited lactate release with an apparent K_i of 2.4 mM. The results suggest that lactate can be released from cells via a saturable and stereospecific lactate transporter with an apparentK _m of 10.7 mM andV _max of 43.7 nmol/mg protein/min. Such a relatively high-capacity transporter system can rapidly equilibrate brain lactate but is probably not involved in regulating intracellular acid-base balance.     

Analysis of long-term potassium regulation

Potassium regulation is maintained by a system which affects the rate of renal excretion of the ion and its distribution between the intra- and extracellular spaces. Long-term regulation is accomplished by the interactions of several components of the control system. The direct effect of changes in plasma potassium concentration on potassium secretion by the cells of the distal nephron is the most powerful regulator of K excretion. Changes in aldosterone concentration interact multiplicatively with the effect of plasma K on K excretion, and changes in aldosterone also affect the distribution of the ion so that elevations in aldosterone shift a greater proportion of K into the cells of the body. Sodium intake affects K excretion, increases in intake resulting in a higher rate of K excretion. Aldosterone secretion is regulated by a multiplicative interaction between angiotensin II and potassium concentration. An hypothesis that states in essence that long-term K regulation is determined by the interaction of several component systems is developed. A mathematical model constructed from the hypothesis employing data from experiments designed to quantitatively analyze the functions of the individual components is presented. The model is used to test the hypothesis by comparing the operation of the model with the results of experiments in which the potassium control system is subjected to a wide range of challenges and perturbations. General agreement between model predictions and experimental results was obtained, thereby providing support for the validity of the hypothesis. Building the model drew attention to several areas in which experimental investigation is required to obtain understanding of several important physiological processes. Finally, several predictions obtained from the model may have clinical relevance in the areas of renal medicine and hypertension.