Coordination of kidney filtration and tubular reabsorption: considerations on the regulation of metabolic demand for tubular reabsorption

Kidney blood flow is highly regulated by a combination of myogenic autoregulation, multiple neurohormonal systems and the tubuloglomerular feedback system, the later of which specifically relates tubular reabsorption to the filtered load. Oxygen and substrate requirements of the kidney are dictated by both supply of oxygen and substrates and metabolic demands of the kidney. The tubuloglomerular feedback system utilizes mediators which are intimately linked to cellular metabolism, ATP and adenosine. This system based upon communication transfer between the macular densa and the afferent arteriole stabilizes kidney function and is not static but temporally adapts or resets to new external physiologic conditions. Such temporal adaptation occurs via modulators such as nitric oxide (NO), primarily derived from NOS-1, angiotensin II and COX-2 products. These hormonal influences also exert capacities to modulate cellular demands for oxygen, particularly NO which decreases oxygen consumption via multiple mechanisms. The several mechanisms whereby NO and other hormonal systems and transporter activity can regulate and produce changes in kidney metabolic demands are discussed. Modulators which influence temporal adaptation and resetting of TGF are also significant contributors to the regulation of cellular oxygen consumption in the kidney. These systems may act in concert to preserve the coordination of filtered load and tubular reabsorption and the metabolic demands of kidney function, thereby determining the ischemic threshold for kidney function.     

Control of coronary blood flow during exercise

Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the mediator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K(+)(ATP) channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward betaadrenoceptor coronary vasodilation that accounts for approximately 25% of coronary vasodilation observed during exercise. There is also a feed-forward alpha-adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.     

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD+ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD+ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10-15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD+ but had minimal effects on the mitochondrial NADH/NAD+, myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD+ ratio that is independent of substrate supply.     

Enteral nutrition and hepatosplanchnic region in critically ill patients - friends or foes?

Enteral nutrition (EN) is a preferred way of feeding in critically ill patients unless obvious contraindications such as ileus or active gastrointestinal bleeding are present. Early enteral nutrition as compared to delayed EN or total parenteral nutrition decreases morbidity in postsurgical and trauma patients. The hepatosplanchnic region plays a pivotal role in the pathophysiology of sepsis and multiple organ dysfunction syndrome. The beneficial effects of EN on splanchnic perfusion and energy metabolism have been documented both in healthy volunteers and animal models of sepsis, hemorrhagic shock and burns. By contrast, EN may increase splanchnic metabolic demands, which in turn may lead to oxygen and/or energy demand/supply mismatch, especially when hyperemic response to EN is not preserved. Therefore, the timing of initiation and the dose of EN in patients with circulatory failure requiring vasoactive drugs are a matter of controversy. Interestingly, the results of recent clinical studies suggest that early enteral nutrition may not be harmful even in patients with circulatory compromise. Nevertheless, possible onset of serious complications, the non-occlusive bowel necrosis in particular, have to be kept in mind. Unfortunately, there is only a limited number of clinically applicable monitoring tools for the effects of enteral nutrition in critically ill patients.     

Matching coronary blood flow to myocardial oxygen consumption.

At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.     

Repiratory muscle dysfunction in sepsis

It became evident in the past 12 years that venitlatory muscle contractile performance is significantly impaired during the course of septic shock. In animal models of septic shock, depression of ventilatory muscle contractile performance has been shown to cause hypercapneic ventilatory failure and respiratory arrest. Failure of ventilatory muscle contractility in septic shock has never been attributed to a single factor, but two groups of factors are likely to be involved: (a) increased ventilatory muscle metabolic demands due to augmentation of ventilation, hypoxemia and increased pulmonary impedance; and (b) specific cellular, metabolic, immune and hemodynamic defects which interfere with several processes necessary for normal force generation. These defects are mediated by complex interactions between several local and systematic mediator such a bacterial endotoxin, proinflammatory cytokines, prostaglandins, platelet activating factor, reactive oxygen species and nitric oxide. This is a summary of how these interactions are likely to interfere with ventilatory muscle contractile performance in septic shock with particular emphasis on the newly described role of nitric oxide.     

Hemodynamic and metabolic responses of the working heart in relation to the oxygen carrying capacity of the perfusion medium

Hemodynamic and metabolic adaptations of isolated working heart perfused alternatively with normal or low oxygen carrying capacity medium were studied in an experimental model. A step change in arterial oxygen content (1.75 to 15.3 ml O2/100 ml) was followed by a decrease in coronary flow, an increase in aortic flow, external work, myocardial oxygen consumption and efficiency, respectively. Metabolic investigations (steady state values) showed the activities of both glycolysis and the Krebs cycle to increase with the oxygen carrying capacity of the perfusion medium. Within the limits of these aerobic conditions, most of the cardiac changes were reversible. The use of reconstituted blood provides physiological conditions of oxygenation, allows a dynamic equilibrium between oxygen supply and oxygen requirements and maintains a near physiological regulation between cardiac dynamic and metabolic functions. These conclusions stress the importance of optimal O2 carrying capacity of perfusion medium in metabolic studies on isolated working heart.     

Alteration in myocardial oxygen balance during exercise after beta-adrenergic blockade in dogs

The effects of beta-adrenergic blockade upon myocardial blood flow and oxygen balance during exercise were evaluated in eight conscious dogs, instrumented for chronic measurements of coronary blood flow, left ventricular pressure, aortic blood pressure, heart rate, and sampling of arterial and coronary sinus venous blood. The administration of propranolol (1.5 mg/kg iv) produced a decrease in heart rate, peak left ventricular (LV) dP/dt, LV (dP/dt/P, and an increase in LV end-diastolic pressure during exercise. Mean coronary blood flow and myocardial oxygen consumption were lower after propranolol than at the same exercise intensity in control conditions. The oxygen delivery-to-oxygen consumption ratio and the coronary sinus oxygen content were also significantly lower. It is concluded that the relationship between myocardial oxygen supply and demand is modified during exercise after propranolol, so that a given level of myocardial oxygen consumption is achieved with a proportionally lower myocardial blood flow and a higher oxygen extraction.     

Time course of inducible nitric oxide synthase activity following endotoxin administration in dogs.

An increased production of nitric oxide (NO) via the inducible isoform of NO synthase (iNOS) has been incriminated in the pathogenesis of septic shock. Since the time course of iNOS activity is not known during endotoxic shock in dogs, we measured iNOS activity, estimated by the rate of conversion of (14)C-arginine to (14)C-citrulline in the absence of calcium, in the heart, lung, liver, kidney, and gut at 1, 2, 3, 4, and 6 h after a bolus of Escherichia coli endotoxin (2 mg/kg, iv), in the dog. This model, including generous fluid administration, is associated with typical features of human septic shock, including low systemic vascular resistance, altered myocardial function and limited oxygen extraction capability. An increase in iNOS activity was observed at 4 h in the liver (0.24 vs 0.04 mU/mg/min) and at 6 h in the heart (0.26 vs 0.09 mU/mg/min). These findings may contribute to a better delineation of the involvement of NO in endotoxic shock, and to the evaluation of the therapeutic effects of NO inhibitors.     

Andrenomedullin and cardiovascular responses in sepsis.

The typical cardiovascular response to polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Although the factors and/or mediators responsible for producing the transition from the hyperdynamic to the hypodynamic stage are not fully understood, recent studies have suggested that adrenomedullin (AM), a potent vasodilatory peptide, appears to play an important role in initiating the hyperdynamic response following the onset of sepsis. In addition, the reduced vascular responsiveness to AM may result in the transition from the early, hyperdynamic phase to the late, hypodynamic phase of sepsis. It is possible that changes in newly reported AM receptors calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 or -3 (RAMP2, RAMP3) as well as AM binding protein-1 (AMBP-1) may also play distinct roles in the biphasic cardiovascular response observed during sepsis. Although it remains unknown whether AM gene delivery or a chronic increase in vascular AM production in transgenic animals attenuates the development of hypodynamic sepsis and septic shock, it has been shown that modulation of AM vascular responsiveness with pharmacologic agents reduces sepsis-induced mortality. It has been recently demonstrated that AMBP-1 enhances AM's physiologic effects and plasma levels of AMBP-1 decrease following infections. We therefore propose that downregulation of AMBP-1 and the reduced AM receptor responsiveness are crucial factors responsible for the transition from the hyperdynamic phase to the hypodynamic phase of sepsis.     

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MVo?(unloaded)) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MVo?(unloaded), because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MVo?. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MVo? following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF + GW-610742 increased FA oxidation to the same extent, only HF increased MVo?(unloaded). Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MVo?(unloaded). Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MVo? following acute and chronic FA load.     

The effect of light on oxygen consumption in two amphipod crustaceans-the hypogean Niphargus stygius and the epigean Gammarus fossarum

The effects of light on the metabolic rates of the hypogean amphipod Niphargus stygius and the epigean amphipod Gammarus fossarum were compared by measuring oxygen consumption and respiratory electron transport system (ETS) activity. They were exposed to light intensities of 720 and 4700 lx at 10°C. Oxygen consumption increased significantly in N. stygius exposed to both low and high intensities of light, but no significant increase was observed in G. fossarum at either intensity. The increase of oxygen consumption in N. stygius was significantly greater at the higher light intensity. This indicates a stress response in which exploitation of half the metabolic potential for energy production in N. stygius during exposure to high light intensity constitutes an adverse effect on its metabolism, since this species usually uses less than 25% of its total metabolic potential for standard metabolic demands.     

Endotoxin-induced liver hypoxia: defective oxygen delivery versus oxygen consumption.

In vivo EPR was used to investigate liver oxygenation in a hemodynamic model of septic shock in mice. Oxygen-sensitive material was introduced either (i) as a slurry of fine particles which localized at the liver sinusoids (pO2 = 44.39 +/- 5.13 mmHg) or (ii) as larger particles implanted directly into liver tissue to measure average pO2 across the lobule (pO2 = 4.56 +/- 1.28 mmHg). Endotoxin caused decreases in pO2 at both sites early (5-15 min) and at late time points (6 h after endotoxin; sinusoid = 11.22 +/- 2.48 mmHg; lobule = 1.16 +/- 0.42 mmHg). The overall pO2 changes observed were similar (74.56% versus 74.72%, respectively). Blood pressures decreased transiently between 5 and 15 min (12.88 +/- 8% decrease) and severely at 6 h (59 +/- 9% decrease) following endotoxin, despite volume replacement with saline. Liver and circulatory nitric oxide was elevated at these times. Liver oxygen extraction decreased from 44% in controls to only 15% following endotoxin, despite severe liver hypoxia. Arterial oxygen saturation, blood flow (hepatic artery), and cardiac output were unaffected. Pretreatment with l-NMMA failed to improve endotoxin-induced oxygen defects at either site, whereas interleukin-13 preserved oxygenation. These site-specific measurements of pO2 provide in vivo evidence that the principal cause of liver hypoxia during hypodynamic sepsis is reduced oxygen supply to the sinusoid and can be alleviated by maintaining sinusoidal perfusion.     

Myocardial fatty acid oxidation during ischemia and reperfusion

Inhibition of fatty acid oxidation is an early event in myocardial ischemia that most likely contributes to tissue injury by the accumulation of potentially toxic intermediates such as acylCoA and acylcarnitine. After reperfusion both myocardial oxygen consumption and fatty acid oxidation may rapidly recover to preischemic levels, even when contractile function remains depressed. The mechanisms underlying the apparent dissociation between contractile function and oxidative metabolism early during reperfusion are still controversial. In isolated rat hearts subjected to 60 min of no-flow ischemia myocardial oxygen consumption and oxidation of palmitate were lowered during reperfusion by 3 mM of NiCl₂ and by 6 µM of ruthenium red. The results provide indirect evidence for the hypothesis that intracellular calcium transport may be involved in the mechanisms responsible for the high oxidative metabolic rate early after reperfusion     

Effects of salinity and temperature on oxygen consumption in a freshwater population of Palaemonetes antennarius (Crustacea,decapoda)

• 1.1. After step-like increases in salinity the shrimps exhibit the smallest increase in oxygen consumption in the lower salinity range. At higher salinities the shrimps show longer recovery times and greater increases in the metabolic rate after salinity shock.
• 2.2. In steady-state experiments, the shrimps display the lowest oxygen consumption rates near the isosmotic point. The lowest metabolic rates occur at salinities of 3‰ and 10‰ At salinities of 20‰ and above the rate of metabolism increases by 20–30%.
• 3.3. The calculated osmoregulatory work for animals in fresh water amounts to only 2.7% of routine metabolism and drops to 1.1% for shrimps in 3‰ and 0.7% in 5‰ salinity.
• 4.4. Locomotory activity in the form of position change was not responsible for the increased oxygen consumption of the animals after salinity shocks. A “tentative swimming activity” by fast and frequent beating of the pleopods without position change may be an important factor in the increase of metabolic rates.
• 5.5. In its temperature response, the brackish water population has a higher metabolic rate than the freshwater one. Between 5 and 35°C Q ₁₀-values range from 4.01 to 1.37.

     

Cerebral oxidative metabolism during sustained hypoxaemia in fetal sheep

Cerebral oxidative metabolism was determined in 9 unanaesthetized fetal sheep near term, during a normoxic control period and during sustained hypoxaemia induced by lowering maternal inspired O2 concentration to 11-8% with 3% CO2 added. Preductal arterial and sagittal vein blood samples were analyzed for oxygen content, blood gas tensions and pH. Cerebral blood flow was measured with a radioactively-labelled microsphere technique. Induced fetal hypoxaemia resulted in a metabolic acidaemia which was progressive over several h. Cerebral oxygen consumption was initially marginally decreased in response to induced hypoxaemia with cerebral blood flow increased thus maintaining O2 delivery coupled to cerebral oxygen consumption. With a worsening metabolic acidemia, pHa below 7.15, cerebral blood flow fell as mean arterial pressure fell, but cerebral oxygen consumption was little changed as fractional O2 extraction now increased. With sustained hypoxaemia and profound metabolic acidaemia, pHa below 7.00, fractional O2 extraction also fell resulting in a terminal fall in cerebral oxygen consumption to less than 50% of control values. Although the initial marginal decrease in cerebral oxygen consumption in response to induced hypoxia may represent a protective mechanism whereby the fetal brain decreases nonessential functions thus lowering oxidative needs, the terminal fall in cerebral oxygen consumption suggests pathological alterations within the brain at this time.     

不同组织细胞线粒体数量及功能的休克敏感性研究

摘要 目的：探究不同组织细胞线粒体数量及功能的休克敏感性差异。方法：在整体和细胞水平模拟失血性休克和脓毒性休克模型,通过mtDNA检测、线粒体形态分析和线粒体ROS检测观察休克不同时相点肠组织（肠上皮细胞）、血管组织（血管平滑肌细胞）和心肌组织（心肌细胞）中线粒体数量和功能的变化。结果：对于失血性休克（缺氧）刺激,肠组织线粒体数量的休克敏感性明显强于血管和心肌组织（P<0.05）。肠、血管、心肌组织中线粒体数量明显增多分别开始于失血性休克后0.5小时、1小时和2小时。对于脓毒性休克（LPS）刺激,肠组织线粒体数量的休克敏感性明显弱于血管和心肌组织（P<0.05）。肠、血管、心肌组织中线粒体数量明显增多分别开始于脓毒性休克后9小时、6小时和3小时。只有高浓度长时间LPS刺激才会引起肠上皮细胞线粒体数量的明显增高。各组织细胞线粒体功能对各型休克刺激的敏感性和反应程度虽然存在差异,但都晚于线粒体数量异常的发生（P<0.05）。结论：各型休克的组织器官敏感性差异可能与不同组织细胞中线粒体的休克敏感性不同有关。线粒体数量异常增加是引起休克后线粒体损伤和细胞功能障碍的始动环节,不同组织细胞线粒体的休克敏感性差异也是影响休克组织器官损伤差异的重要原因之一。     

The effect of light on oxygen consumption in two amphipod crustaceans–the hypogean Niphargus stygius and the epigean Gammarus fossarum

The effects of light on the metabolic rates of the hypogean amphipod Niphargus stygius and the epigean amphipod Gammarus fossarum were compared by measuring oxygen consumption and respiratory electron transport system (ETS) activity. They were exposed to light intensities of 720 and 4700?lx at 10°C. Oxygen consumption increased significantly in N. stygius exposed to both low and high intensities of light, but no significant increase was observed in G. fossarum at either intensity. The increase of oxygen consumption in N. stygius was significantly greater at the higher light intensity. This indicates a stress response in which exploitation of half the metabolic potential for energy production in N. stygius during exposure to high light intensity constitutes an adverse effect on its metabolism, since this species usually uses less than 25% of its total metabolic potential for standard metabolic demands.     

Hypoxia-inducible factor 1 signalling,metabolism and its therapeutic potential in cardiovascular disease

Cardiovascular disease (CVD) accounts for the largest number of deaths worldwide, necessitating the development of novel treatments and prevention strategies. Given the huge energy demands placed on the heart, it is not surprising that changes in energy metabolism play a key role in the development of cardiac dysfunction in CVD. A reduction in oxygen delivery to the heart, hypoxia, is sensed and responded to by the hypoxia-inducible factor (HIF) and its family of proteins, by regulating the oxygen-dependent signalling cascade and subsequent response. Hypoxia is one of the main drivers of metabolic change in ischaemic disease and myocardial infarction, and we therefore suggest that HIF may be an attractive therapeutic target. In this review, we assess cardiac energy metabolism in health and disease, and how these can be regulated by HIF-1α activation. We then present an overview of research in the field of hypoxia-mimetic drugs recently developed in other treatment fields, which provide insight into the potential of systemic HIF-1α activation therapy for treating the heart.     

Energy turnover and the production of ammonium by the kidney: effect of hypernatremia.

The purpose of this study was to explore further the relation between the rates of oxygen consumption and ammonium (NH4+) production in the kidney during chronic metabolic acidosis. The experimental model was the dog with chronic metabolic acidosis because of the extensive background literature in this species. Chronic metabolic acidosis was produced by the ingestion of 10 mmol NH4Cl/kg body weight for 5 days. There was a significant increase in the rate of oxygen extraction when hypernatremia was present. Despite this rise in the rate of oxygen consumption, there was no increase in the rate of NH4+ production nor in the rate of glutamine extraction. These data suggest that hypernatremia might prevent a further augmentation in glutamine extraction when the rate of oxygen consumption rises. In addition, a larger proportion of the NH4+ produced was excreted in the urine during hypernatremia. This increase was associated with a rise in the urine flow rate, but not with a fall in urine pH.