Homeostatic regulation of potassium excretion

Multiple systems participate in the homeostatic regulation of potassium excretion. Changes in plasma potassium, above a baseline value, will directly stimulate potassium excretion. Acute variations in aldosterone may have only small and perhaps insignificant effects in stimulating potassium excretion when aldosterone is present within its normal plasma range, but may be highly significant in determining the kaliuretic response to changes in plasma potassium or tubular flow rate. Elevation of plasma aldosterone to supraphysiological levels appears to produce increases in potassium excretion. Chronic variations in aldosterone are important, but not unique in determining renal potassium adaptation to chronic variations in potassium uptake. New lines of evidence point to sensors of potassium intake located in the hepatic portal vein or liver, or in enteric locations. A reflex control of potassium excretion, first demonstrated by Aizman and Finkenshtein et al. [120-123] in the dog, and independently suggested in a more general form for the sheep, may be integral in the regulation of potassium excretion in response to intake. With this feedforward control system, potassium excretion may be regulated without changes in systemic plasma potassium concentration. From diverse lines of investigation we find that there is a compelling argument for an important role for the brain in regulating both potassium excretion and its ICF/ECF ratio. One may speculate, albeit on the basis of preliminary information, that separate but analogous systems exist for sodium and for potassium, each involving the brain and each acting through specific humoral factors. For sodium, evidence is accumulating for a ouabain-like humoral agent, perhaps originating in the brain, which modulates renal sodium excretion and the sodium concentration of ICF. Both of these actions have been proposed to have an important influence on blood pressure regulation. The evidence presented here is compatible with a similar system for potassium. On the basis of these studies reviewed here, it is intriguing to speculate that an analogous humoral factor is involved in the regulation of potassium homoeostasis, and that its effects, when understood, may help to resolve current debates regarding the role of potassium in blood pressure regulation.     

Sodium: a wolf in sheep's clothing

High blood pressure is the main cause of disease-related morbidity and mortality worldwide. It is virtually absent in populations that consume natural foods low in sodium. In other countries, however, where the individual intake of sodium is at least 10 times greater, the prevalence of arterial hypertension is about 40%. Vascular endothelium plays a central role in blood pressure regulation. In addition to the kidney, the vasculature is a major target for aldosterone where it controls nonexcitable sodium channels in the endothelium. High sodium channel expression/activity downregulates the release of nitric oxide (NO), and thus determines endothelial function. Mechanical cell stiffness is therefore the means whereby high sodium channel activity reduces NO release. We have found that small changes of plasma sodium, but only above 139 mM, and potassium above 4 mM regulate the stiffness of the submembrane actin web and thus control the shear stress-dependent activity of endothelial NO synthase, which lies directly beneath the cell membrane. Plasma sodium above 139 mM stiffens the actin web of the endothelial cell, and plasma potassium greater than 4 mM does the opposite. In conclusion, vascular endothelial cells are highly sensitive to changes in extracellular sodium and potassium but only within and above the normal range. This sensitivity may serve as a physiological feedback mechanism to regulate local blood flow. It becomes pathogenic, however, when the concentration of plasma sodium or potassium changes towards and beyond the upper limits of the normal range.     

Serum sodium, potassium, calcium and magnesium and blood pressure in a Dutch population

The relationships between the serum cations sodium, potassium, calcium and magnesium and blood pressure were investigated in a population-based sample of 182 Dutch persons aged 20-59 years. Age, Quetelet index (weight/height2), albumin and gamma-glutamyl transpeptidase (gamma-GT) were taken into account as confounders in the analyses. In univariate and multivariate analyses, serum calcium was strongly positively related to both systolic and diastolic blood pressure in women. These relationships were weaker in men. In the combined analysis, including both men and women and adjusting for the confounders (also including sex), a strong independent positive association was observed between serum calcium and blood pressure. In the combined analysis, a weak inverse relationship was found between serum potassium and diastolic blood pressure; this relationship was also found in women. No relationship was found between either serum sodium or serum magnesium and blood pressure. These results suggest that serum calcium concentrations particularly could play an important role in the regulation of blood pressure.     

Corticosteroid-dependent hypertension: environmental influences

Hypertension is a major disease of later life affecting 25% of the adult population in the industrialized world with most hypertensive individuals diagnosed as having essential hypertension. Approximately one third of these patients have elevated blood pressure due to increased sodium and water retention by the kidney resulting in suppressed plasma renin and aldosterone concentrations with high urinary potassium excretion and low plasma potassium levels. Monogenic forms of corticosteroid-dependent hypertension are rare. However, the discovery of these disorders has revealed genes whose proteins play a key role in the regulation of sodium homeostasis. The impaired function of these proteins, due to altered protein expression or the presence of inhibitors, contributes to the development of corticosteroid-dependent hypertension. This article focuses on the potential impact of environmental influences on corticosteroid-dependent regulation of sodium homeostasis and the development of hypertension.     

Restraining influence of A2 neurons in chronic control of arterial pressure in spontaneously hypertensive rats

OBJECTIVES: The role of A2 noradrenergic neurons in regulating cardiovascular homeostasis chronically is poorly understood. We aimed to genetically target A2 neurons and induce expression of a potassium channel to reduce their electrical excitability and study how this impacts on long-term blood pressure control. METHODS: We used a lentiviral vector with PRSx8 promoter for targeting noradrenergic neurons to express a human inwardly rectifying potassium channel, hK(ir)2.1. The dorsal vagal complex containing the A2 cell group was microinjected with the PRSx8-hK(ir)2.1 lentivirus in both normotensive Wistar rats and spontaneously hypertensive rats fitted with radio telemetry devices. RESULTS: In Wistar rats expression of hKir2.1 increased lability of arterial pressure between 7 to 21 days post-injection with mean arterial pressure not increasing significantly until day 21 (+11+/-1 mmHg; p<0.001; dark phase). Urine output and water intake were both decreased. In contrast, in spontaneously hypertensive rats not only the lability of arterial pressure but also the mean arterial pressure increased by day 7 and persisted during the 21 day recording period (+13+/-1 mmHg; p<0.001 at day 21). In contrast to Wistar rats, body fluid homeostasis was un-affected in hypertensive rats. Neither cardiac baroreceptor reflex gain nor heart rate variability changed in either rat strain. Plasma osmolality levels were also unaffected. CONCLUSIONS: Our data indicate a role for A2 neurons in the chronic regulation of arterial pressure independent of the cardiac baroreceptor reflex. The activity of A2 neurons may constitute an essential part of the central circuitry underpinning chronic regulation of arterial pressure in both, normo- and hypertensive rats.     

Diet,Alcohol and Hypertension

Obesity, diet and alcohol consumption constitute major environmental determinations of blood pressure elevation. The long term setting of blood pressure in response to these factors will be determined by genetic susceptibility, and interactions with effects of physical fitness and smoking. Dietary changes which independently influence both atherosclerosis and hypertension are likely to be of greatest value in helping to control morbidity and mortality from hypertensive cardiovascular disease.

Recommendations should focus on diets low in total and saturated fat intake and high in fruit and vegetables, containing potassium and fibre, coupled with weight control, alcohol moderation to less than two drinks per day in drinkers and regular physical exercise. Sodium restriction will help lower blood pressure in older hypertensives in particular. The role of dietary calcium or fish oils in blood pressure regulation is still uncertain.

Dietary and related recommendations on smoking and exercise should be ‘first line’ treatment in mild hypertensives, and complimentary to therapy in all patients requiring drugs.     

Salt, the kidneys, and arterial hypertension

The kidneys play a major role in the regulation of the salt balance and thereby regulate blood pressure. Salt sensitivity is acquired or genetically-induced and is noted in about 50% of patients with essential hypertension. This property leads to a high cardiovascular risk. In this situation, the benefit of salt restriction is significant, and this dietary change should be associated with a high potassium intake. In patients treated by antihypertensive drugs, salt restriction improves the blood pressure control, which can permit a reduction of the number of drugs required to achieve a normal blood pressure. The recommended maximal salt intake should not exceed 6 grams/day (NaCl). Because most dietary salt comes from processed foods, the help of the food industry is crucial for a long-term compliance with a reduced salt intake, which could yield an additional important benefit in the reduction of cardiovascular risk.     

Electrolytes and dietary fat in hypertensive cardiovascular disease

Nonpharmacologic measures have been increasingly applied to the management of patients with essential hypertension. Published findings concerning dietary factors and blood pressure are reviewed. Specifically, the impact of manipulations of dietary sodium, potassium, magnesium, calcium and dietary fat on blood pressure is considered. The data support a beneficial role for calcium supplementation and sodium restriction, a lesser role for potassium supplementation and a decrease in total and saturated fat intake in at least some hypertensive persons. At this time, no dietary alteration can be recommended for broad application to the population as a whole.     

Assessing cell K physiology in hypertensive patients. A new clinical and methodologic approach

The assessment of potassium (K) effects in hypertension involves a history of complex research in cell K function and body K homeostasis. These studies provide evidence for the role of K ions in vascular and renal function, insulin resistance, glucose uptake, and the renin-angiotensin-aldosterone system; and there have been an impressive number of clinical and epidemiologic research relating dietary intake K and regulation of blood pressure. However, the usual technique by which K metabolism is assessed in clinical practice (plasma or serum K) provides no useful data for estimating disorders in cell K transport that occurs in hypertensive patients or that may follow the administration of diuretics, beta-blockers, or nonsteroidal anti-inflammatory drugs. This fact becomes more crucial if associated with the physiologic decline in body K stores occurring after the age of 30 years, which may impair the long-term treatment of hypertensive individuals. In this context, this article presents a review of the clinical and research methods that can be used to assess more accurately K metabolism and cell K physiology in hypertensive patients, including a heritable defect in red blood cell K transport.     

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

Growth hormone (GH) deficiency is associated with abnormal vascular reactivity and development of atherosclerosis. GH treatment in GH deficient states restores systemic vascular resistance, arterial compliance, endothelium-dependent and endothelium-independent vasodilation, and may reverse markers of early atherosclerosis. However, very little is known about the molecular mechanisms underlying these effects. In the present study, male Sprague Dawley rats were hypophysectomized and treated for two weeks with GH (recombinant human GH, 2 mg/kg/day) or saline as s.c. injections twice daily. GH decreased aortic systolic blood pressure compared with saline-treated animals, while the diastolic blood pressure was not significantly changed. GH treatment increased cardiac output as determined by Doppler-echocardiography and the calculated systemic vascular resistance was markedly reduced. In order to identify GH-regulated genes of importance for vascular function, aortic mRNA levels were analyzed by the microarray technique and correlated to the systolic blood pressure levels. Using this approach, we identified 18 GH-regulated genes with possible impact on vascular tone and atherogenesis. In particular, mRNA levels of the inwardly rectifying potassium channel Kir6.1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both up-regulated by GH treatment and highly correlated to systolic blood pressure. Our findings establish a major role for GH in the regulation of vascular physiology and gene expression. Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone.     

Magnesium and hypertension

Magnesium status has a direct effect upon the relaxation capability of vascular smooth muscle cells and the regulation of the cellular placement of other cations important to blood pressure - cellular sodium:potassium (Na:K) ratio and intracellular calcium (iCa(2+)). As a result, nutritional magnesium has both direct and indirect impacts on the regulation of blood pressure and therefore on the occurrence of hypertension. Hypertension occurs when cellular Na:K ratios become too high, a consequence of a high sodium, low potassium diet or, indirectly, through a magnesium deficient state which causes a pseudo potassium deficit. Like wise, magnesium deficiency alters calcium metabolism, creating high iCa(2+), low serum calcium and low urinary calcium states even when calcium intake is adequate. High iCa(2 + ) and high cellular Na:K ratio both occur when cellular magnesium becomes too low and the Mg-ATP driven sodium-potassium pump and calcium pump become functionally impaired. High iCa(2+) has several vasoconstrictive effects which lead to hypertension, an indirect result of low magnesium status. Dietary calcium is directly proportional to dietary magnesium. Serum magnesium does not reflect true magnesium status as do intracellular magnesium measurements. Several studies on the effect of calcium on blood pressure need these added considerations of magnesium status to fully understand the impact of the Mg:Ca ratio as the primary cause of hypertension and other aspects of Syndrome X. Magnesium supplementation above 15 mmol per day are required to normalize high blood pressure in unmedicated hypertensive patients while 15 mmol per day will lower high blood pressure in patients treated with anti-hypertensive medications. In most humans, healthy blood pressure depends upon a balance of both Na:K and Mg:Ca ratios at both cellular and whole body levels which, in turn, require adequate, long-term intakes of nutritional magnesium. The knowledge that low magnesium causes imbalance in both cellular and physiological calcium widens our view of the studies showing hypertensives have abnormal calcium metabolism.     

Red blood cell K+ could be a marker of K+ changes in other cells involved in blood pressure regulation

The aim of this study is to determine whether red blood cell K(+) content (RBC(Ki)) is associated with blood pressure levels and, if so, could RBC(Ki) be a marker of potassium changes in other cells involved in blood pressure regulation. The study was performed on 50 untreated hypertensives, 32 of their offspring and 50 age- and sex-matched controls. Systolic (SBP) and diastolic (DBP) blood pressures, height, weight, plasma, urine and red blood cell electrolytes were measured in all subjects. RBC(Ki) was significantly lower in hypertensives than in offspring of hypertensives and normotensive controls. Offspring of hypertensives had significantly lower RBC(Ki) than normotensive controls. Plasma K(+) was significantly lower both in hypertensives and offspring of hypertensives when compared to normotensive controls. A significant negative correlation was found in hypertensives between RBC(Ki) and DBP (r=-0.27, P=0.04) and in offspring of hypertensives between RBC(Ki) and DBP (r=-0.43, P=0.02). A significant correlation was found in hypertensives between RBC(Ki) and plasma K(+) (r=0.3, P=0.02). A positive correlation with borderline significance was found in hypertensives between RBC(Ki) and ionized Ca(2+) (r=0.2, P=0.1). In conclusion, our results support the hypothesis that RBC(Ki) is associated with blood pressure levels and that the measurement of RBC(Ki) levels may represent a biochemical marker for K(+) changes in other cells involved in blood pressure regulation. Further studies are necessary to explain the exact mechanisms of reduced RBC(Ki) levels in hypertensive patients and their offspring.     

Effect of short-term supplementation of potassium chloride and potassium citrate on blood pressure in hypertensives

Randomized trials have shown that increasing potassium intake lowers blood pressure. However, most previous trials used potassium chloride, whereas potassium in fruits and vegetables is not a chloride salt. It is unclear whether a nonchloride salt of potassium has a greater or lesser effect on blood pressure compared with potassium chloride. We performed a randomized crossover trial comparing potassium chloride with potassium citrate (96 mmol/d, each for 1 week) in 14 hypertensive individuals. At baseline, blood pressure was 151+/-16/93+/-7 mm Hg with a 24-hour urinary potassium of 81+/-24 mmol. During the randomized crossover part of the study, blood pressure was 140+/-12/88+/-7 mm Hg with potassium chloride (24-hour urinary potassium: 164+/-36 mmol) and 138+/-12/88+/-6 mm Hg with potassium citrate (24-hour urinary potassium: 160+/-33 mmol). These blood pressures were significantly lower compared with that at baseline; however, there was no significant difference in blood pressure between potassium chloride and potassium citrate, mean difference (95% confidence interval): 1.6 (-2.3 to 5.6) mm Hg for systolic and 0.6 (-2.4 to 3.7) mm Hg for diastolic. Our results, in conjunction with the evidence from many previous trials that potassium chloride has a significant blood pressure-lowering effect, suggest that potassium citrate has a similar effect on blood pressure as potassium chloride. These results support other evidence for an increase in potassium intake and indicate that potassium does not need to be given in the form of chloride to lower blood pressure. Increasing the consumption of foods high in potassium is likely to have the same effect on blood pressure as potassium chloride.     

Nutrients and trace elements as they affect blood pressure in the elderly

Hypertension, a major public health problem, becomes more prevalent during aging. Although the pathogenesis is uncertain, epidemiological studies suggest that environmental factors such as nutrition may play a major role in blood pressure regulation. As examples, it is generally accepted that obesity and sodium/alcohol consumption are important factors, and many believe that calcium, magnesium, and potassium consumption are regulatory as well. However, less emphasis has been placed on whether macronutrients and trace elements influence blood pressure (BP) significantly. Accordingly, this review focuses on the ability of macronutrients and foods (sugars, soluble fibers, garlic, and fats), trace elements and natural coenzymes like chromium and NADH to influence BP. Clearly, many natural products, especially those with ability to enhance insulin sensitivity and/or act as antioxidants, have the capability to affect BP.     

Low sodium/high potassium diet for prevention of hypertension: probable mechanisms of action

20 normotensive subjects (10 with a family history of hypertension) were investigated as to whether moderate salt restriction and/or a high potassium intake had a beneficial effect on blood pressure regulation and prevention of hypertension. In all subjects a moderate reduction of salt intake from 200 to 50 mmol/day over 2 weeks reduced the rise in blood pressure induced by various doses of noradrenaline (0.1, 0.2, and 0.4 microgram/kg/min). Furthermore, of 20 subjects 12 (8 with a family history of hypertension) responded to salt restriction with a fall in systolic or diastolic blood pressure of at least 5 mm Hg. There were no significant differences in plasma renin, aldosterone, vasopressin, and catecholamine levels between responders (salt-sensitive subjects) and non-responders, but salt-sensitive subjects had a mean baseline diastolic blood pressure which was higher than that of salt-insensitive subjects by 13 mm Hg (77.3+/-3.26 vs. 64.6+/-2.06, p less than 0.001). A high potassium intake reduced diastolic blood pressure by at least 5 mm Hg in 10 out of 20 subjects, of the 10 7 had a family history of hypertension and 9 responded to salt restriction. A high potassium intake also improved compliance with a low salt regimen, promoted sodium loss, prevented the rise in plasma catecholamines induced by a low salt diet, and increased the sensitivity of the baroreceptor reflex. These four effects occurred in the group as a whole and were probably the means by which a high potassium intake reduced blood pressure. In all subjects 2 weeks of a combined low sodium/high potassium intake reduced blood pressure rises induced by mental stress or noradrenaline infusion by 10 mm Hg. The results of this study suggest that moderate salt restriction combined with a high potassium intake helps to prevent hypertension, that salt-sensitive subjects exist, and that these individuals would profit most.     

Plasma calcium and cortisol as predisposing factors to alcohol related blood pressure elevation

Mechanisms by which alcohol consumption might cause hypertension were examined in 30 pairs of healthy drinking (greater than 275 g ethanol per week) and teetotal men closely matched for age and obesity. Both systolic and diastolic blood pressures were significantly higher in the drinkers. Plasma calcium levels correlated with diastolic blood pressures (r = 0.51, P = 0.004) in drinkers only. After adjusting for plasma albumin, diastolic pressures increased by 6.9 mmHg for each 0.1 mM increment of plasma calcium. It is proposed that regular alcohol consumption predisposes to hypertension by facilitating calcium accumulation in cells involved in blood pressure regulation. In the combined population of drinkers and teetotallers plasma cortisol correlated positively with diastolic pressure (r = 0.35, P = 0.012) and negatively with plasma potassium (r = -0.38, P = 0.006); this suggests a role for the pituitary/adrenal axis as a significant determinant of blood pressure differences between healthy subjects.     

Salt,endogenous ouabain and blood pressure interactions in the general population

OBJECTIVE: Experimental data show that ouabain is a modulator of the sodium-potassium pump, which plays an important role in sodium homeostasis and blood pressure regulation. We investigated the distribution of plasma ouabain in the general population in relation to blood pressure and other determinants of sodium homeostasis. METHODS: In 379 subjects enrolled in a Belgian population study, we measured plasma ouabain, clinical characteristics including blood pressure, serum and urinary electrolytes, urinary aldosterone excretion, various lifestyle factors, and the Gly460Trp polymorphism of the alpha-adducin gene. Our statistical methods included analysis of covariance and multiple linear regression. RESULTS: Plasma ouabain (median, 140 pmol/l) correlated independently and positively with male gender (n = 182, P = 0.002), smoking (n = 116, P = 0.05), urinary potassium excretion (mean 69 mmol/day, P < 0.0001), and mutation of the alpha-adducin gene (n = 161, P < 0.0001). Both before and after adjustment for covariables, continuous as well as categorical analyses revealed a significant interaction (P < or = 0.02) between plasma ouabain and urinary sodium excretion (mean 194 mmol/day) in relation to blood pressure (mean systolic blood pressure/diastolic blood pressure, 123/76 mmHg). In individuals with plasma ouabain values below the median, blood pressure increased by 2.2 mmHg systolic and 1.4 mmHg diastolic for each 50 mmol/day increment in urinary sodium excretion (P < or = 0.01). No association between blood pressure and urinary sodium excretion was found when plasma ouabain exceeded the median. CONCLUSIONS: Plasma ouabain behaves as a blood pressure modulating factor, possibly released in response to potassium, either inhibiting the pressor effect of an excessive salt intake or counteracting the depressor action of sodium depletion.     

Dietary potassium: A key mediator of the cardiovascular response to dietary sodium chloride

Potassium and sodium share a yin/yang relationship in the regulation of blood pressure (BP). BP is directly associated with the total body sodium and negatively correlated with the total body potassium. Epidemiologic, experimental, and clinical studies have shown that potassium is a significant regulator of BP and further improves cardiovascular outcomes. Hypertensive cardiovascular damage, stroke, and stroke-related death are accelerated by salt intake but might be curbed by increasing dietary potassium intake. The antihypertensive effect of potassium supplementation appears to occur through several mechanisms that include regulation of vascular sensitivity to catecholamines, promotion of natriuresis, limiting plasma renin activity, and improving endothelial function. In the absence of chronic kidney disease, the combined evidence suggests that a diet rich in potassium content serves a vasculoprotective function, particularly in the setting of salt-sensitive hypertension and prehypertension.     

The effects of glucose infusion on myocardial performance during acute hypoxia.

The effects of hypoxia with or without glucose infusion on the cardiac contractility, blood pressure, electrocardiogram, blood electrolytes (sodium and potassium), glucose, pH, Po2, and Pco2 in anesthetized dogs were studied. Hypoxia was induced by ventilating the dogs with reduced oxygen (10%) in the inspired air. Hypoxia produced a decrease in the cardiac contractility and blood pressure, and an increase in the heart rate and central venous pressure. It produced a decrease in the blood pH, Po2, and Pco2, and an increase in the blood glucose and potassium. Glucose infusion during hypoxia delayed the rate of decrease in the contractility and blood pressure significantly. The time for decrease in the contracility to 45 to 50% was increased by 67%. Glucose infusion prevented the loss of potassium from the cell. Glucose infusion however, was unable to correct acidosis. These results indicate that glucose infusion during hypoxia might prevent or delay the deterioration of myocardial function.     

Role of sympathetic nerve activity and natriuresis in the antihypertensive actions of potassium in NaCl hypertension

Although the precise mechanism of the antihypertensive action of potassium remains controversial, the natriuretic property of potassium is thought to play an important role. Since the renal nerves have been shown to control urinary sodium excretion, the present study was performed to clarify the role of the sympathetic nervous system in the antihypertensive effect of potassium supplements in DOCA-salt hypertensive rats and in salt-sensitive hypertensive patients. Supplements of a 0.2% or a 1% KCl were able to moderate the development of the DOCA-salt hypertension dose-dependently, in combination with natriuresis. Renal norepinephrine turnover was markedly accelerated in the DOCA-salt rats as compared with the control rats, but the potassium supplements normalized it. Eleven patients, who had taken the potassium supplement (96 mEq/day) on a high-sodium diet, showed a lesser increase in mean blood pressure with sodium loading than 12 patients who did not take the potassium supplement. With a high-sodium diet, the potassium-supplemented patients retained less sodium and showed a lesser increase of plasma volume and cardiac output, and their adrenergic nervous activity was relatively lower during the early period of salt loading. Moreover, in salt-sensitive patients the potassium supplement was more effective for preventing a rise in blood pressure with sodium loading than in non-salt-sensitive ones. These results suggest that potassium may attenuate the rise in blood pressure during the DOCA-salt treatment in the rat and during sodium loading in salt-sensitive patients, mainly as a result of inhibiting sodium retention due to increased renal sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)