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Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores 1 ; these interhemispheric connections may have existed during previous glacial cycles., (© 2022. The Author(s).)

Correlations between the concentrations of arsenic in scalp hair and in drinking water as well as in blood and/or urine have been reported. These correlations clearly show exposure⁻absorption⁻excretion relationships. In addition, arsenic metabolites such as monomethylarsonic acid and dimethylarsinic acid have been identified and quantified in these tissues and fluids, leaving little doubt that elevated levels of arsenic in the hair can reflect systemic arsenic intoxication. Consequently, hair analysis has potential merit as a screening procedure for poisoning by arsenic. However, questions regarding the exogenous versus the endogenous deposition of arsenic in the hair, and uncertainties about the normal level of arsenic in the hair remain unresolved. Pending their resolution, the determination of arsenic in hair should remain a screening tool, and clinical signs and symptoms should be employed to complete the diagnosis of arsenic poisoning.

Background: Worldwide, both acute kidney injury (AKI) and sepsis are significant clinical complications, particularly in critical care patients. Sepsis is an important cause of AKI, and AKI is a common complication of sepsis., Methods: We reviewed the literature, including current practice guidelines, on sepsis-associated AKI., Results: We assessed causes of renal failure, potential mechanisms of sepsis-associated acute kidney injury, current practice guidelines, diagnostic criteria and methods, prevention strategies, treatment options, and outcomes., Conclusion: In patients with sepsis-associated AKI, appropriate fluid resuscitation and maintenance of blood pressure are important to prevent further kidney damage. Despite multiple clinical trials, the mechanisms of sepsis-associated AKI and the best treatment options remain unclear.

Elevated levels of naturally occurring uranium have been found in small geographic areas throughout the world. Exposure of the general public to uranium is most often by the ingestion of food and water containing natural uranium from the hydrogeological environment, but this likelihood is remote. However, the risk is increased in regions where uranium is mined, milled, processed and/or fabricated as well as in the vicinity of former battlefields where depleted uranium munitions were deployed. Exposure in such cases is by the inhalation route. Internalized uranium is a long-term hazard the toxicity of which depends upon the dose and the dose rate as well as other parameters such as the chemical form and site of deposition of the uranium and the physiology of the host. The radiological toxicity and the chemical toxicity of uranium and its compounds are responsible for kidney damage and lung cancer. The vulnerable groups are the very young and the very old, individuals predisposed to hypertension or osteoporosis and individuals with chronic kidney disease. Those subject to long-term exposure from internalized uranium are a greater risk for the long-term implications. The accumulation of uranium may be mitigated by decreasing its absorption, distribution and deposition and increasing its elimination with chelating agents. The formation of soluble chelates may enhance the mobilization of uranium deposited in tissue and expedite its transport to and elimination from the renal system. The focus of this review is on the use of chelating agents to enhance decorporation of uranium thereby reducing the risk of intoxication.

In spite of the ease with which samples may be collected and the stability of the samples after collection, the use of hair mineral analysis for monitoring environmental exposures and evaluating heavy metal poisonings has remained controversial since its initial applications for these purposes in the early 1950s. Among the major arguments against using hair mineral analysis in general were the absence of biokinetic models and/or metabolic data that adequately described the incorporation of trace elements into the hair, the absence of correlations between the concentrations of trace elements in the hair and their concentrations in other tissues, the inability to distinguish between trace elements that were deposited in the hair endogenously and those that were deposited on the hair exogenously, the absence of reliable reference ranges for interpreting the results of hair mineral analysis and a lack of standard procedures for the collecting, preparing and analyzing the hair samples. The developments of the past two decades addressing these objections are reviewed here, and arguments supporting the use of hair analysis for monitoring environmental and/or occupational exposures to uranium are made on the basis of the information presented in this review.

Whereas adipose tissue possesses a local renin-angiotensin system, the synthesis and regulated release of renin has not been addressed. To that end, we utilized differentiating 3T3-L1 cells and analyzed renin expression and secretion. Renin mRNA expression and protein enzymatic activity were not detectable in preadipocytes. However, upon differentiation, renin mRNA and both intracellular and extracellular renin activity were upregulated. In differentiated adipocytes, forskolin treatment resulted in a 28-fold increase in renin mRNA, whereas TNFalpha treatment decreased renin mRNA fourfold. IL-6, insulin, and angiotensin (Ang) II were without effect. In contrast, forskolin and TNFalpha each increased renin protein secretion 12- and sevenfold, respectively. Although both forskolin and TNFalpha induce lipolysis in adipocytes, fatty acids, prostaglandin E(2), and lipopolysaccharide had no effect on renin mRNA or secretion. To evaluate the mechanism(s) by which forskolin and/or TNFalpha are able to regulate renin secretion, a general lipase inhibitor (E600) and PKA inhibitor (H89) were used. Both inhibitors attenuated forskolin-induced renin release, whereas they had no effect on TNFalpha-regulated secretion. In contrast, E600 potentiated forskolin-stimulated renin mRNA levels, whereas H89 had no effect. Neither inhibitor had any influence on TNFalpha regulation of renin mRNA. Relative to lean controls, renin expression was reduced 78% in the epididymal adipose tissue of obese male C57Bl/6J mice, consistent with TNFalpha-mediated downregulation of renin mRNA in the culture system. In conclusion, the expression and secretion of renin are regulated under a complex series of hormonal and metabolic determinants in mature 3T3-L1 adipocytes.

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

1. Renal denervation (RDNX) chronically lowers mean arterial pressure (MAP) in normal rats but mechanisms leading to this hypotensive response remain unknown. 2. We hypothesized that this sustained decrease in arterial pressure was because of a loss of beta1-adrenoceptor mediated renin secretion. Male Sprague-Dawley rats were assigned to sham (SHAM; n = 9), unilateral (UniRDNX; n = 9), or bilateral (RDNX; n = 10) renal denervation groups and instrumented for telemetric MAP measurements, plasma renin concentration (PRC) measurements and intravenous infusion. Twenty-four h MAP, heart rate, sodium and water balances were recorded 5 days before, 3 days during and 3 days after 1-adrenoceptor blockade with atenolol. 3. The 5-day control MAP was significantly lower in RDNX (97 +/- 1 mmHg) compared to SHAM (105 +/- 2 mmHg) and UniRDNX (102 +/- 2 mmHg) rats. No significant differences in basal PRC were observed between RDNX (2.2 +/- 0.3 ngAng1/mL per h), UniRDNX (2.6 +/- 0.4 ng/Ang1/mL per h) and SHAM (2.6 +/- 0.4 ngAng1/mL per h) rats. By day 1 of atenolol, PRC was significantly lower in UniRDNX rats (1.8 +/- 0.2 ngAg1/mL per h) compared to control values, but was unchanged during atenolol infusion in the other groups. By day 3 of atenolol, MAP was significantly decreased in all groups, but the absolute levels of MAP remained statistically different between RDNX (87 +/- 1 mmHg) and SHAM (91 +/- 1 mmHg) groups. 4. We conclude that the arterial pressure lowering effect of RDNX is not solely dependent on the loss of neural control of renin release.

Plasma renin activity (PRA) is often found to increase after myocardial infarction (MI). Elevated PRA may contribute to increased myocardial angiotensin II that is responsible for maladaptive remodeling of the myocardium after MI. We hypothesized that MI would also result in cardiac release of cathepsin D, a ubiquitous lysosomal enzyme with high renin sequence homology. Cathepsin D release from damaged myocardial tissue could contribute to angiotensin formation by acting as an enzymatic alternate to renin. We assessed circulating renin and cathepsin D from both control and MI patient plasma (7-20 hours after MI) using shallow gradient focusing that allowed for independent measurement of both enzymes. Cathepsin D was increased significantly in the plasma after MI (P < 0.001). Furthermore, circulating active cathepsin D metabolites were also significantly elevated after MI (P < 0.04), and contained the majority of cathepsin D activity in plasma. Spiking control plasma with cathepsin D resulted in a variable but significant (P = 0.005) increase in PRA using a clinical assay. We conclude that 7-20 hours after MI, plasma cathepsin D is significantly elevated and most of the active enzymatic activity is circulating as plasma metabolites. Circulating cathepsin D can falsely increase clinical PRA determinations, and may also provide an alternative angiotensin formation pathway after MI.

A recent agreement between the United States Environmental Protection Agency (USEPA) and the wood-treating industry will result in a phase-out of building timbers preserved with chromated copper arsenate (CCA). This agreement was motivated by a desire to reduce exposure to arsenic in the production, utilization and disposal of such material. The leaching of chromium, copper and arsenic from CCA-treated building timbers into water and soil and the subsequent environmental effects have been reviewed, as have the laboratory and epidemiological studies on the toxicology of CCA-treated building timbers. The benefits of the phase-out agreement are questionable because much arsenic will remain in the environment, and the alternatives to wood preservation with CCA are not without environmental consequences., (Copyright 2005 John Wiley & Sons, Ltd.)

Purpose: To highlight the management of a Jehovah's witness surgical patient presenting for cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest., Clinical Features: A 47-yr-old male, Jehovah's Witness, with renal cell carcinoma was admitted for left radical nephrectomy and excision of tumour thrombus extending into the junction of the inferior vena cava (IVC) and right atrium (RA). The preoperative goals were to maximize red blood cell mass, delineate the extent of tumour extension and develop a surgical plan incorporating blood conservation strategies to minimize blood loss. A midline abdominal incision was made to optimize removal of the non-caval portion of the tumour from the intra-abdominal region. CPB and deep hypothermic circulatory arrest were instituted to aid in removing the tumour from the IVC and RA. Intraoperative blood conservation strategies included the use of acute normovolemic hemodilution, antifibrinolytics, cell salvage, point-of-care monitoring of heparin and protamine blood concentrations, leukocyte-depleting filter, and meticulous surgical techniques. The patient was successfully weaned from CPB and was transported to the cardiothoracic intensive care unit without complication. The patient was discharged home one week after the operation with a hemoglobin of 10.2 g x dL(-1) and a hematocrit of 31.2%., Conclusion: Multiple blood conservation techniques were employed to manage this Jehovah's Witness patient through complex cardiac surgery, which was previously denied to him at other institutions. The successful outcome of this patient, while respecting the right to refuse allogeneic blood products, is a result of a multidisciplinary collaboration as well as the application of established blood conservation techniques.

A local renin-angiotensin system is present within the myocardium and can play a role in the initiation and maintenance of cardiac hypertrophy. The source of myocardial renin maybe direct cardiac renin gene expression, or plasma renin of renal origin. A primary indication that myocardial renin is derived from plasma renin of renal origin was from work showing that cardiac renin activity was no longer detected 30 hours after bilateral nephrectomy (BNX). However, more recent studies have been able to detect myocardial renin after BNX. We measured normal rat cardiac renin before and after 48-hour BNX using a myocardial renin assay with improved sensitivity. The myocardial renin assay was also used to assess normal rat cardiac myocyte renin levels. Since cardiac tissue contains cathepsin D, a lysosomal enzyme capable of renin-like activity, a rat cathepsin D assay was also developed to assess cathepsin D contribution to renin-like activity. Several artifacts were shown to contribute to myocardial renin-like enzymatic activity levels after BNX, including initial plasma renin stimulation during BNX surgery, assay pH, and cardiac cathepsin D activity. Myocardial renin concentration after 48-BNX was found to be only approximately 1% of normal control levels, and renin concentration in normal cardiac myocytes was only 2-fold greater than assay blanks. Both results were probably overestimated due to cathepsin D contamination. In conclusion, no evidence was found for myocardial renin synthesis in the normal adult rat heart, and myocardial renin decays to near zero levels after 48-hour BNX.

To determine whether effects of angiotensin converting enzyme (ACE) inhibitors on well-established pressure overload-induced cardiac hypertrophy and coronary remodeling depend upon normal plasma renin levels, the influence of enalapril on ventricular mass and coronary vascular resistance (CVR) was determined in a low-renin female rat model of chronic pressure overload, (deoxycorticosterone acetate hypertension, DOCA), and compared to its effect in a normal-renin model, (aortic construction, AC). Six weeks after experiment initiation, plasma renin activity of DOCA-treated rats was reduced to approximately 12% that of sham-treated and AC-treated groups. Enalapril was then added to the drinking water of half the animals in each group for two additional weeks. Comparing experimental groups to controls, this delayed enalapril treatment had 1) no effect on the elevated arterial pressures, 2) no effect on the elevated coronary resistance, and, in the DOCA group, 3) no effect on cardiac hypertrophy. However, this brief enalapril treatment reduced absolute and relative ventricular weights of AC rats. These data suggest that circulating renin is required for the anti-hypertrophic efficacy of late-onset brief treatment with enalapril. Since enalapril-induced reversal of cardiac hypertrophy in AC rats was not accompanied by reversal of coronary remodeling, growth signals other than angiotensin II may be involved in coronary remodeling.

We tested the hypothesis that the myocardial renin-angiotensin system (RAS) is both necessary and sufficient to initiate and maintain all classes of ventricular hypertrophy. Myocardial and plasma renin and angiotensinogen were measured in rats during initiation and maintenance of ventricular hypertrophy associated with DOCA implants and 1% NaCl drinking water, with and without the AT(1) ANG II receptor blocker losartan. Additional groups of rats were given a low-sodium diet (0.04%) for 3 wk. Ventricular hypertrophy was initiated within 7 days and maintained for 35 days in DOCA-treated rats despite significantly low myocardial and plasma renin, normal or low myocardial and plasma angiotensinogen, or the presence of losartan. Furthermore, there was no ventricular hypertrophy in low-salt diet-fed animals despite increased myocardial and plasma renin levels and normal angiotensinogen levels. Therefore, the myocardial RAS is not necessary to initiate or maintain cardiac hypertrophy in DOCA-treated rats and is not sufficient to initiate cardiac hypertrophy in low-salt diet-fed rats. Additionally, myocardial renin and angiotensinogen were significantly correlated with corresponding plasma levels.

The renin-angiotensin system promotes cardiac hypertrophy after myocardial infarction. The purpose of this study was to measure renin and angiotensinogen in plasma and myocardium 10 days after myocardial infarction. Infarction involving 45 +/- 4% of left ventricular circumference with accompanying hypertrophy was induced in rats (n = 14). Plasma and myocardial renin were increased after infarction compared with sham controls (n = 8) (27.4 +/- 3.2 vs. 7.5 +/- 1.8 ng ANG I. ml plasma. h-1, P < 0.0002; and 8.8 +/- 1.6 vs. 2. 5 +/- 0.1 ng ANG I. g myocardium-1. h-1, P < 0.008, respectively). After infarction, myocardial renin was correlated with infarct size (r = 0.62, P < 0.02) and plasma renin (r = 0.55, P < 0.04). Plasma angiotensinogen decreased in infarct animals, but myocardial angiotensinogen was not different from shams (1.1 +/- 0.08 vs. 2.03 +/- 0.06 nM/ml plasma, P < 0.002; and 0.081 +/- 0.008 vs. 0.070 +/- 0.004 nM/g myocardium, respectively). In conclusion, myocardial renin increased after infarction in proportion to plasma renin and infarct size, and myocardial angiotensinogen was maintained after infarction despite decreased plasma angiotensinogen and increased levels of myocardial renin.

Plasma and left ventricular (LV) renin and angiotensinogen concentrations were assessed in a rat model of pressure-overload cardiac hypertrophy to determine if myocardial levels remained proportional to plasma levels over time. Three days after subdiaphragmatic aortic constriction (AC), LV hypertrophy was evident and renin concentrations in both plasma and LV, although not significantly elevated, were positively correlated with relative cardiac mass. After 42 days AC, LV hypertrophy remained, plasma and LV renin and angiotensinogen levels were not different from shams, and there was no correlation between renin and relative cardiac mass. Furthermore, LV renin and angiotensinogen concentrations remained at approximately 25 and 4%, respectively, of those in plasma throughout the experiment. Myocytes from 3-day AC and sham-treated rats contained little renin as did LV from 48-h anephric rats. Incubations using calculated concentrations of myocardial interstitial renin and angiotensinogen revealed significant angiotensin I generation. These data suggest that LV renin in this model varies directly with plasma renin, is confined to the interstitial space, and can generate significant intramyocardial angiotensin I.

In an attempt to clarify the relationship of the circulating and myocardial renin-angiotensin systems, active renin concentration, its constituent major glycoforms (active renin glycoforms I through V), and angiotensinogen were measured in plasma and left ventricular homogenates from sodium-depleted rats under control conditions or 2 minutes, 3 hours, 6 hours, and 48 hours after bilateral nephrectomy (BNX). Control myocardial renin concentration was 1.4+/-0.1 ng angiotensin I (Ang I) per gram myocardium per hour and plasma renin concentration was 6.7+/-1.1 ng Ang I per milliliter plasma per hour. Control myocardial angiotensinogen was 0.042+/-0.004 micromol/kg myocardium and plasma angiotensinogen was 1.5 micromol/L plasma. Two minutes after BNX and corresponding stimulation of renin secretion by anesthesia and surgery, plasma renin concentration was increased disproportionately compared with myocardial renin. Three, 6, and 48 hours after BNX, renin decay occurred significantly faster from the plasma than from the myocardium. Forty-eight hours after BNX, myocardial renin concentrations had fallen to 15% of control values, while myocardial angiotensinogen concentrations had increased 12-fold and plasma angiotensinogen concentrations had increased by only 3.5-fold. Myocardial renin glycoform proportions were identical in myocardial homogenates and plasma in control animals. At 6 hours BNX, the proportions of plasma active renin glycoforms I+II fell, while those in the myocardium significantly increased. We conclude that in control rats, active renin and active renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space. After BNX, myocardial renin concentration falls dramatically, suggesting that most cardiac renin is derived from plasma renin of renal origin. After BNX, renin glycoforms I+II are preferentially cleared from the plasma but preferentially retained by the myocardium. Control myocardial angiotensinogen concentrations are too low to result from simple diffusion equilibrium between plasma and the myocardial interstitium.

Active renin and five major active renin glycoforms were measured in plasma and the carotid wall of anesthetized rabbits before and after 1.5- and 24-h bilateral nephrectomy (BNX). Before BNX, there was no difference in renin glycoform proportions between plasma and the carotid wall. Plasma renin concentration (PRC) fell by 67% after 1.5-h BNX due to preferential clearance of renin glycoforms I+II, but no significant change in renin concentration was seen in the carotid artery (or aorta). Twenty-four hours after BNX, PRC and carotid wall renin concentrations were reduced by 99.7 and 97.7%, respectively, while the proportion of renin glycoforms I+II in the carotid wall was significantly elevated. These data are consistent with the view that vascular renin is derived from plasma renin of renal origin. After BNX, renin disappearance from the carotid (and aortic wall) is slower than renin decay from plasma, and the less negatively charged active renin glycoforms I+II exit the carotid wall much more slowly than the more negatively charged glycoforms. After 24-h BNX, renin glycoforms I+II were still effluxing from the vascular wall and represented the only glycoforms present in the carotid wall.

Plasma active renin consists of multiple glycoforms, which are differentially stored and secreted by the kidney, have varying plasma half-lives, and appear to have differing effects on renal sodium and water metabolism. Acute stimulation of renal renin secretion results in a disproportionate increase in plasma concentrations of the less negatively charged renin glycoforms and a decrease in the plasma half-life of active renin. The effects of chronic stimulation have not been well studied. We studied the effect of acute and chronic (42 days) stimulation of the renin angiotensin system with the AT1 selective angiotensin II receptor antagonist losartan on plasma active renin, active renin glycoforms separated by isoelectric focusing, and inactive renin in 11 essential hypertensive patients. A single 50 mg dose of losartan significantly increased plasma active renin concentration (ARC) from a pretreatment baseline of 3.2 +/- 1.1 to 7.2 +/- 2.3 ng AI/mL/h, 4 h postdose. This was primarily due to an increase in plasma concentrations of the less negatively charged active renin forms. After 42 days of losartan monotherapy, plasma ARC at losartan trough had increased significantly to 7.8 +/- 3.1 ng AI/mL/h, although the proportions of active renin forms were identical to baseline. Plasma ARC also increased significantly from 7.8 +/- 3.1 to 14.9 +/- 6.0 ng AI/mL/h acutely after the losartan dose on day 42 primarily due to increased plasma concentrations of less negatively charged active renin forms. Although plasma inactive renin concentrations did not change acutely after losartan dosing on day 1 or 42 they did increase from 27.3 +/- 7.8 before losartan day 1 to 37.0 +/- 13.7 ng AI/mL/h (P = .14) before losartan day 42. Thus, both acute and acute on chronic stimulation of renal renin secretion increased circulating ARC and shifted the profile of circulating renin toward the less negatively charged forms but did not change inactive renin concentrations. Chronic stimulation of renal renin secretion with losartan increased plasma concentrations of both active and inactive renin, but did not alter the proportions of active renin forms. Since the less negatively charged active renin forms have relatively short plasma half-lives, acute, but not chronic renal renin secretion is associated with a change in plasma renin half-life. Chronic stimulation of renal renin secretion with losartan presumably increased renin gene expression and resulted in increased constitutive secretion of inactive renin, increased constitutive secretion of negatively charged active renin forms, and increased renal storage of less negatively charged renin forms that were then available for acute regulated release.

Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.

Continued progress in the theory and practice of trace element analytical chemistry has made possible significant advances in investigating the role and fate of trace elements in biological systems. Public health commissions and environmental protection agencies have subsequently established requirements for intakes of and exposures to trace elements both from the nutritional (copper-zinc) and from the toxicological (cadmium-mercury) perspectives. Some trace elements demonstrate the properties of both categories, and consequently give rise to questions about the toxicity of essential dietary minerals. Selenium and chromium are typical examples of this toxicity-essentiality paradox. The systemic intoxication by and/or nutritional importance of these elements are reviewed as are the criteria for assessing their toxicity and essentiality.

Active renin can be separated into multiple isoelectric forms using shallow gradient isoelectric focusing and into multiple glycoforms using concanavalin A (Con A) affinity chromatography. The relationship between renin isoelectric forms and glycoforms has not been previously determined. In this study, each of three renin Con A glycoforms from rat kidney was composed of significantly different proportions of six renin isoelectric forms; glycoforms with the greatest affinity for Con A contained proportionally less of the acidic isoelectric forms than those with the least affinity for Con A. A set of compartmental models accurately predicted previously measured differential plasma clearance rates of the three renin glycoforms based on their corresponding isoelectric form proportions. We conclude that 1) each Con A renin glycoform is composed of significantly different proportions of isoelectric forms, and 2) the different proportions of isoelectric forms found in Con A glycoforms are sufficient to account for the differential renin plasma clearance rates demonstrated previously for renin glycoforms in the rat. These data suggest that the isoelectric and glycoform heterogeneity of active renin are, in fact, closely related and may result from variable and interrelated mannose (Con A affinity) and sialic acid (charge) attachments to renin.

Recently, the obese Zucker rat (OZR), an animal model of non-insulin-dependent (type II) diabetes, was shown to respond to converting enzyme inhibition with decreased albuminuria and a marked attenuation of glomerular injury. It was hypothesized that the OZR would possess low plasma renin values and an increased vascular responsiveness to angiotensin II, and therefore, the renin-angiotensin system (PRA, active renin, inactive renin, renal renin content, and plasma angiotensinogen) and vascular reactivity in OZR at 10 and 24 wk of age were investigated. PRA and renin concentration, inactive plasma renin, and renal renin content were all significantly (P < 0.05) reduced in OZR when compared with age-matched lean controls. The ratio of inactive to total renin was significantly increased in the OZR. OZR aortic ring vascular reactivity to KCl, norepinephrine, and angiotensin II was assessed. Despite essentially equal or increased contractile responses to KCl and norepinephrine at both 10 and 24 wk of age, the OZR was not more sensitive to angiotensin II and displayed a significantly reduced contractile response to angiotensin II at 24 wk of age, when compared with lean age-matched controls. It was concluded that the renal protective effect of converting enzyme inhibition in OZR, despite significantly reduced PRA and concentration, inactive plasma renin, and renal renin content, may not be due to a diabetes-induced increased vascular reactivity to angiotensin II.

Renin is a glycoprotein that is heterogeneous with respect to carbohydrate content and net charge. In an attempt to clarify the role of renin isoelectric heterogeneity in renal renin storage and secretion, the isoelectric profile of renal renin, secreted renin, and circulating renin were directly assessed and compared under basal and stimulated conditions by the use of an in vivo blood perfused rabbit kidney preparation. Under basal conditions, the kidney preferentially stored and secreted the relatively basic isoelectric forms of renin. Acute stimulation of renin secretion (reduced renal perfusion pressure and angiotensin-converting enzyme inhibition) significantly increased the secretion of the relatively basic isoelectric forms but had very little effect on the secretion of the relatively acidic renin forms. Circulating renin was composed primarily of relatively basic forms, which increased disproportionately after stimulation of renin secretion. These findings suggest that the isoelectric heterogeneity of renin is important in the cellular processing of renin and can be explained by a two-pool model in which the relatively acidic isoelectric forms of renin are constitutively secreted (and not stored) and the relatively basic isoelectric forms represent a regulated pathway in which they are stored and rapidly released in response to acute secretory stimuli. Preferential hepatic extraction of the more basic isoelectric forms has previously been described. Data from this study suggest that the disproportionate increase in circulating basic forms of renin observed after acute stimulation reflects the net effect of preferential renal the more basic renin isoelectric forms. The disproportionate increase in relatively basic circulating renin forms after acute secretory stimulation results in an overall circulating renin activity with a shorter half-life.

The properties of trivalent and hexavalent chromium are reviewed with respect to acute and chronic oral toxicity, dermal toxicity, systemic toxicity, toxicokinetics, cytotoxicity, genotoxicity and carcinogenicity. The hexavalent chromium compounds appear to be 10-100 times more toxic than the trivalent chromium compounds when both are administered by the oral route. Dermal irritancy and allergy are more frequently caused by contact with soluble hexavalent chromium compounds. The cytotoxicity of soluble and insoluble hexavalent chromium compounds to fibroblasts is 100-1000 times greater than that demonstrated by trivalent chromium compounds. In short-term tests, the hexavalent chromium compounds demonstrated genotoxic effects four times more frequently than did the trivalent chromium compounds. Carcinogenicity appears to be associated with the inhalation of the less soluble/insoluble hexavalent chromium compounds. The toxicology of chromium does not reside with the elemental form. It varies greatly among a wide variety of very different chromium compounds. Oxidation state and solubility are particularly important factors in considering the toxicity of chromium with respect to its chemical speciation.

Renin activity appears to be present in low concentrations in the plasma of anephric humans but could be artifactual secondary to inadvertent activation of prorenin during specimen collection and handling or from a renin-like enzyme. We studied the effects of specimen collection, storage, different assay conditions, trypsin activation, and the renin inhibitor EMD 56133 (E Merck, Darmstadt) on plasma renin activity (PRA) in anephric man. PRA was detectable in all seven bilaterally nephrectomized (BNX) patients (0.2 +/- 0.1 ng AI/ml/hr, range 0.1-0.7) but was significantly lower than normals (2.4 +/- 0.3 ng AI/ml/hr, range 1.5-3.1, p = 0.001). PRA was not different in BNX whether blood samples were collected on ice or at room temperature and assayed immediately or whether samples were frozen and assayed several days later. Prolonged cold storage of samples and five freeze-thaw cycles over six to seven months did not significantly increase PRA in normals or anephrics. However, deliberate repeated freezing and thawing over the period of a single day increased PRA 4.1-fold in BNX and 1.6-fold in normals. Renin-like activity was also detected in BNX individuals using renin concentration determinations with either excess human or sheep angiotensinogen. The inhibition of renin activity (IC-50% = 3.16 x 10(-9) molar) by EMD 56133 was not different between BNX and normals. Thus, active renin is present in the plasma of anephric humans and does not result from the inadvertent activation of prorenin due to sample handling. Although the source of PRA in BNX is unknown, the enzyme appears functionally normal as evidenced by the dose-response to a single renin inhibitor.

Acute gastroenteritis is a leading cause of visits to physicians among children in the United States. Oral rehydration therapy has prevented or reversed dehydration among millions of children in developing countries. Although most U.S. health care providers are familiar with oral rehydration therapy, its proper use is still not widespread in industrialized nations. Viral pathogens in diarrheal illness can destroy absorptive cells at the intestinal villous tip while leaving secretory cells intact. Oral rehydration therapy takes advantage of the remaining intact absorptive cells, is less invasive than intravenous rehydration and allows parents to be involved in their children's care. This article outlines how to select patients for oral rehydration therapy, what fluids to use and how to implement therapy.

Various animal models have been employed for research on the significance of measuring trace element concentrations in the human scalp hair. The objects of such research were the establishment of relationships between the concentrations of trace elements in human scalp hair and (1) their concentrations in other compartments of the human body or (2) specific pathophysiological conditions. The guinea pig appears to be the animal of choice for such studies because the elemental composition and growth pattern of its hair parallel those of the human scalp hair.

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.

Angiotensin-converting enzyme inhibitors may ameliorate experimental glomerular injury by either hemodynamic or nonhemodynamic mechanisms. In a long-term study, we examined the effects of 30 wk of enalapril treatment on the development of glomerular disease in obese Zucker rats (OZR). Enalapril significantly (P less than 0.05) lowered blood pressure, fasting serum cholesterol, and urine albumin excretion in OZR throughout the experimental period. At 38 wk of age, enalapril-treated OZR had a sixfold reduction in the percent glomeruli exhibiting focal glomerulosclerosis and a 20-30% reduction in kidney weight and glomerular area. A separate micropuncture study in 22- to 26-wk-old rats revealed that untreated OZR with albuminuria and increased blood pressure had elevated glomerular capillary pressure (Pgc). Enalapril-treated OZR had less albuminuria and lower blood pressure, but Pgc was not reduced. The value of the transcapillary hydraulic pressure difference (delta P) in enalapril-treated OZR was intermediate between values in untreated OZR and lean Zucker rats. Thus enalapril markedly attenuated the development of glomerular injury in OZR. The salutary effects of enalapril may have involved a reduction in delta P coupled to a nonhemodynamic action, possibly restriction of glomerular growth or lowering of serum cholesterol.

A method for the separation and quantitation of multiple forms of active renin in human plasma is described. Shallow gradient isoelectric focusing of plasma resolved active renin into seven distinct components in each of 10 healthy normal individuals. Plasma renin activity focused at isoelectric points of 5.71, 5.57, 5.47, 5.22, 5.08, 4.93, and 4.82 with corresponding proportions of 16.3, 15.4, 21.1, 20.3, 14.0, 10.0, and 2.5%. Silicon dioxide treatment of plasma significantly increased the yield of renin in the focusing gels. Although each individual plasma sample contained the same seven renin forms, there was variability in the relative proportions of the multiple renin forms between individuals. This variance was significantly greater than the variance introduced by the determination itself. The same seven active renin forms were also present in human renal cortical tissue. In conclusion, a method for the determination of multiple renin forms in plasma and renal cortical tissue is presented. At least seven active multiple renin forms were resolved in human plasma and renal cortex.