Edward J. Zambraski

The Renal System

Renal function is markedly altered in response to the stress of acute exercise. The changes include decreased renal blood flow, decreased glomerular filtra-tion rate, decreased excretion of water, decreased excretion of sodium/chloride, the release of renin—angiotensin and norepinephrine, increased excretion of proteins and other macromolecules, and changes in metabolic functions.

Mechanisms of the Nephrotoxicity of Non-steroidal Anti-inflammatory Drugs

Renal cortical prostaglandin synthesis, particularly by arterioles and glomeruli, is important to preserve renal blood flow (RBF) and glomerular filtration rate (GFR). Glomeruli and arterioles synthesize not only the vasodilatory prostaglandins PGE2 and PGI2, but also the vasoconstrictor, thromboxane A2. The primary renal cortical actions of these prostaglandins are renal vasodilatation and maintenance of GFR (PGE2 and PGI2) or renal vasoconstriction and reduction of GFR (thromboxane A2). Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances but play a modulatory role after ischemia or in the presence of increased concentrations of vasoconstrictor substances such as angiotensin II (ANG II), vasopressin or norepinephrine. ANG II and vasopressin stimulate the synthesis of PGE2 in rat glomerular epithelial and mesangial cells maintained in cell culture. These stimulatory actions of constrictor peptides are dependent upon calcium entry into the cells since removal of extracellular calcium or co-incubation with verapamil or nifedipine block the prostaglandin stimulatory capacity of ANG II or vasopressin. In vivo indomethacin potentiates the actions of ANG II on the kidney, particularly the reduction of RBF and GFR. Isolated rat glomeruli contract in response to ANG II and this contractile effect, which reflects reduction in glomerular filtration surface area, can be potentiated by cyclooxygenase blockade. Conversely, arachidonic acid reduces the glomerular contractile effect of ANG II. The importance of renal prostaglandins in support of RBF and GFR has been studied in dogs after chronic bile duct ligation (CBDL). CBDL dogs have significant increase in renal PGE2 and PGI2 which maintain RBF and GFR since cyclo-oxygenase inhibition resulted in a 50% decrease in both RBF and GFR. Indomethacin, ibuprofen, naproxen, and sulindac sulfide had comparable effects. The pro-drug, sulindac sulfoxide, was tested in normal volunteers and found to spare renal prostaglandin synthesis whereas indomethacin reduced renal synthesis of PGE2 and PGF2 alpha by more than 50%. In vitro, sulindac sulfide is a potent inhibitor of renal prostaglandin synthesis by kidney cells in culture. It is, therefore, concluded that renal prostaglandins play an important vasoregulatory role. Furthermore, sulindac sulfoxide may spare renal cyclo-oxygenase and thereby preserve renal function.

Spot Urine Concentrations Should Not be Used for Hydration Assessment: A Methodology Review

A common practice in sports science is to assess hydration status using the concentration of a single spot urine collection taken at any time of day for comparison against concentration (specific gravity, osmolality, color) thresholds established from first morning voids. There is strong evidence that this practice can be confounded by fluid intake, diet, and exercise, among other factors, leading to false positive/negative assessments. Thus, the purpose of this paper is to provide a simple explanation as to why this practice leads to erroneous conclusions and should be curtailed in favor of consensus hydration assessment recommendations.

Exercise-induced proteinuria is attenuated by indomethacin.

The role of the prostaglandin (PG) and renin-angiotensin hormonal systems in exercise-induced proteinuria following 30 min of submaximal, steady-state exercise was evaluated. Eight healthy males performed cycle ergometry at 75% of VO2peak on three occasions after the administration of a placebo (PLACEBO), a prostaglandin inhibitor (indomethacin, INDO), and an angiotensin converting enzyme inhibitor (captopril, CAPTO). Urine and blood samples were collected prior to, immediately following exercise, and over 40-min recovery. Data were evaluated for differences among drug treatments and measurement phases. During PLACEBO, exercise increased total protein excretion from 64.9 +/- 9.5 to 408.6 +/- 160.8 micrograms.min-1 (P < 0.05). PG inhibition with INDO significantly attenuated the increased proteinuria due to exercise (149.2 +/- 64.0 micrograms.min-1). The proteinuric response to exercise was not altered by CAPTO. Resting plasma renin activity (PRA) and aldosterone (ALDO) were significantly reduced during the INDO trial. Although the twofold increment in ALDO with exercise remained intact during the INDO trial, the PRA response to exercise was significantly blunted. No treatment differences were observed for mean arterial pressure, sodium excretion, urine flow, or creatinine clearance values during rest or exercise. These results suggest that the proteinuria associated with steady-state exercise is PG dependent and not related to hemodynamic influences.

Effects of aspirin treatment on kidney function in exercising man.

The effects of aspirin treatment on kidney excretory function were investigated in treadmill-exercised men. Six individuals ran for 30 min at 70% of their maximal oxygen consumption. Exercise tests were conducted for control and aspirin-treated conditions. Aspirin (3.25 g/d) was administered for 3 d prior to testing. Experiments were carried out with the subjects non-hydrated and hydrated (4 ml H2O/kg body weight). Aspirin treatment did not influence the alterations in creatinine clearance, urine volume, osmolar clearance, and/or sodium and potassium excretion seen with exercise. The only effect of aspirin was observed in the recovery samples of the non-hydrated tests in which aspirin treatment significantly decreased urine volume and increased urine specific gravity, osmolality, and the urine/plasma osmolality ratio. These results suggest that aspirin treatment does not have any significant effects on the renal excretory response to short-term moderate exercise.

Chemical sympathectomy alters the development of hypertension in miniature swine.

To determine if the neurotoxin 6-hydroxydopamine could be used to chemically sympathectomize neonatal miniature swine, eight newborn swine were treated with 6-hydroxydopamine beginning on the first day after birth and continuing at regular intervals for the next 6 months. Six littermates served as controls and received vehicle injections. A significant reduction in the pressor response to intravenous tyramine (95%) and in the tissue norepinephrine content of the kidneys, left ventricle, and gastrocnemius muscle (more than 93%) provided evidence for an effective long-term sympathectomy in the 6-hydroxydopamine-treated animals. In addition, the blood pressure response of these young, chemically sympathectomized swine to chronic deoxycorticosterone acetate treatment was evaluated. Mean arterial pressure before deoxycorticosterone was similar in the 6-hydroxydopamine-treated (116±2 mm Hg) and control (125±5 mm Hg) groups. One week after deoxycorticosterone, mean arterial pressure had risen significantly by 20-22 mm Hg in both groups. Blood pressure continued to increase in the control group, reaching a value of 163 ±6 mm Hg by the third week after treatment In contrast, mean arterial pressure in the 6-hydroxydopamine group did not increase further during weeks 2 and 3 after deoxycorticosterone. In conclusion, chronic treatment of neonatal swine with 6-hydroxydopamine produced an animal model with an effective, general, peripheral sympathectomy. The significant attenuation of the hypertensive response in these sympathectomized animals lends further support to the hypothesis that an intact sympathetic nervous system is necessary for the full expression of deoxycorticosterone hypertension in miniature swine.

Renal prostaglandin E2 and F2 alpha synthesis during exercise: effects of indomethacin and sulindac.

To assess the effects of acute exercise on renal prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) synthesis, urine collections were obtained from six women before and after 30 min of treadmill exercise at approximately 80% of their maximal oxygen consumption. After receiving a placebo for 3 days, with acute exercise, there was a significant increase only in recovery urine PGE2 concentration. Due to a decline in urine volume, PGF2 excretion was unchanged and PGF2 alpha excretion was significantly decreased by exercise. Subjects repeated the tests after 3 d of indomethacin treatment (150 mg X d-1), a known renal prostaglandin (PG) inhibitor, and 3 d of sulindac (300 mg X d-1), a non-steroidal anti-inflammatory drug which may not inhibit renal PG synthesis. Pre-exercise urine PGE2 concentrations were decreased by indomethacin but not by sulindac, whereas, PGF2 alpha concentrations were decreased by both drugs. When compared to the control test, indomethacin and sulindac had different effects on pre-exercise urine/plasma osmolality ratios and free water clearances. Neither indomethacin nor sulindac influenced the decreases in free water clearances, which were observed during the placebo tests. Exercise proteinuria was significantly increased by indomethacin but not by sulindac. In conclusion, these data demonstrate that acute exercise may stimulate renal PGE2 synthesis. During exercise, renal PG synthesis attenuates protein excretion. There also appear to be differences between indomethacin and sulindac with regard to the effects on renal PG synthesis and kidney function.

Adenosine A3 Receptors in Muscle Protection

A growing body of evidence has accumulated to indicate an important cyto-protective role of the adenosine A3 receptor. This protective function, originally discovered in ameliorating ischemia–reperfusion injury in the heart, is now also extended to the skeletal muscle. Understanding the pharmacology of various adenosine receptor subtypes allowed their selective activation and delineated the protective role of adenosine A3 receptors as well as that of other receptor subtypes. The use of phospholipase Cβ2/β3 knockout mice showed that the A3 receptor-induced anti-ischemic protection in the skeletal muscle is mediated via this phospholipase isoform. The protective effect of adenosine A1 and A2A receptors, however, does not involve this phospholipase C. Other potential effectors of the adenosine A3 receptor include KATP channels, reactive oxygen species, RISK-reperfusion injury salvage kinase, mPTP-mitochondrial permeability transition pore, matrix metalloproteinases and associated tissue inhibitor of metallproteinases, and metallothionein. Direct muscle protection mediated via muscle cell-surface A3 receptors as well as anti-inflammatory effects exerted at the level of immune cell A3 receptors may contribute to the potent cytoprotective effect of the adenosine A3 receptor.

Oxygen consumption in treadmill-exercised Yucatan miniature swine.

Oxygen consumption was measured in Yucatan miniature swine during various intensities of treadmill exercise. Nine animals were evaluated at rest and at various treadmill velocities ranging from 2.5-4.5 mph. Oxygen consumption was linearly related to treadmill speed during sub-maximal exercise work loads (r = 0.92, P less than 0.01). Maximal oxygen consumption was also determined in two groups of animals. In one group (N = 6) the highest attainable oxygen consumption was 24.0 +/- 1.31 ml . min-1 . kg-1. In the second group (N = 9) an electric prod was utilized to encourage the animals to run. Their maximal oxygen consumptions ranged from 33.9-51.1 ml . min-1 . kg-1 with a mean of 41.7 +/- 1.8 ml . min-1 . kg-1. These data indicated that Yucatan swine have a relatively low aerobic capacity compared to the rat or dog, but their oxygen consumptions are similar to that observed in untrained man.

Prostaglandins and Renal Function after Chronic Ligation of the Common Bile Duct in Dogs

In severe liver disease there can be associated alterations in renal function. These abnormalities include decreased RBF and GFR, sodium retention, decreased capacity to concentrate the urine, and redistribution of renal blood flow away from the outer cortex.1–3 Severe cirrhosis and ascites can ultimately cause progressive renal failure, the so-called hepatorenal syndrome. The mechanisms responsible for the deterioration of renal function are not clearly understood.