Alterations In Renal Blood Flow Research Articles

Doppler renal resistivity index in horses: A systematic review.

The resistivity index (RI) evaluates haemodynamic based on arterial resistance. Alterations in renal blood flow are important for the early detection of kidney damage, as perfusion might be one of the first affected aspects. To retrieve published studies on equine renal RI to develop a standardised method of renal ultrasonographic examination and to evaluate the current reference range for the renal RI in horses. Systematic review. An electronic search in Science Direct, PubMed, Scopus and Web of Science databases was performed in February 2023 using the terms 'RI' OR 'resistivity index' OR 'IP' OR 'pulsatility index' AND (kidney OR renal) AND (equine OR horse) in titles, keywords and abstracts. The studies were screened for inclusion based on pre-determined criteria and data on the variables of interest were collected from included studies. The SYRCLE risk of bias tool was used to assess the methodological quality. The electronic searches identified 134 studies, of which 5 were eligible for inclusion in this review. The studies had been conducted in healthy non-sedated horses through the transabdominal technique. The upper limit of normality for the renal RI was 0.58 ± 0.06 for the right kidney of untrained horses, which is considerably lower than the value of 0.70 currently used for humans, cats and dogs. There were heterogenous outcomes among the studies: two of the five demonstrated a difference between the right and left renal RI values, and one of the five showed an increased renal RI in elderly horses compared with foals and adult horses. Data regarding the RI in horses are still scarce. Additional studies that establish a reference range for the renal RI in horses are needed and there is a need to ensure consistency of techniques.

A Study Assessing the Role of Renal Grayscale Ultrasonography and Flowmetry in Correlation With Renal Function Tests Across Various Renal Diseases.

Background Renal insufficiency, a critical concern in native and transplant kidneys, necessitates effective screening modalities for evaluation and management. Grayscale sonography has been a cornerstone in renal diagnostics, providing basic anatomical insights such as renal length, cortical thickness, and collecting system dilatation. Despite technological advancements, its impact on the differential diagnosis or management of renal disease remains limited, often showing normal findings in the presence of severe renal dysfunction. On the other hand, Doppler sonography, particularly the Doppler resistive index (RI), has shown potential in enhancing the assessment of renal dysfunction by quantifying alterations in renal blood flow and correlating with various renal pathologies and prognoses. Thus, this study aims to assess and compare the sensitivity of transabdominal and Doppler sonography as a diagnostic modality to evaluate medical renal diseases with altered renal function tests (RFTs). Methodology Participants included patients visiting the ultrasonography (USG)room at our hospital for USG of the kidneys, ureters, and bladder (USG KUB) and USG of the whole abdomen(USG W/A) with altered RFTs. Each underwent renal grayscale USG and RImeasurement, alongside standard RFTs, aiming to investigate the relationship between USG and RI findings and RFT outcomes to assess their predictive accuracy for renal function. Renal grayscale USG assessed parameters including renal dimensions, echogenicity, corticomedullary differentiation, and RI. Data management and charting were conducted with Microsoft Excel 2021 and Microsoft Word 2021. IBM SPSS Statistics for Windows, Version 24 (IBM Corp.,Armonk, NY) was utilized for data analysis. The analysis of variance (ANOVA) test examined relationships between renal parameters and RI across diagnostic groups. Furthermore, the chi-square test evaluated associations of renal ultrasound findings with RFTs and their significance. Results The study analyzed 93 patients with altered RFTs. Chronic kidney disease (CKD) affected 68 patients, primarily males in their fifth and sixth decades, showing reduced renal dimensions, increased cortical echogenicity, and elevated Doppler RI mean (RIm) with 83% sensitivity. Acute kidney injury (AKI) was found in 12 patients, mainly in their fourth decade, displaying increased renal parameters and elevated RIm with 75% sensitivity. Glomerular diseases, including nephrotic syndrome (NS) and nephritic syndrome (NeS), occurred in 9 patients, predominantly males in their fourth decade, with heightened renal cortical echogenicity and elevated RIm with 55.5% sensitivity. Lupus nephritis (LN) was detected in 4 female patients, despite normal renal parameters, showing elevated serum creatinine levels. Conclusions Doppler assessment of renal vascular waveforms effectively identifies chronic renal changes, aiding in the diagnosis of altered RFTs and guiding prognosis. While it detects typical changes like decreased size and parenchymal atrophy, it may not be as indicative of diabetic nephropathy. Key ultrasound indicators such as changes in echotexture and size, along with associated findings like ascites and effusions, help recognize altered renal function and minimize unnecessary interventions.

Drug-induced Kidney Disease: Revisited.

Drug-induced kidney disease (DIKD) is a frequent cause of acute and chronic kidney disease (CKD) that leads to high morbidity, hospitalization, and increased healthcare costs. There is a need to constantly update our knowledge in this field, given the ever-burgeoning list of newer treatments that are emerging, especially in the field of cancer immunotherapy. Generalizing the complex pathways causing DIKD from different agents, the common mechanisms include direct toxicity, immune-mediated injury, and drug-induced alterations in renal blood flow. Proper management of this condition involves risk minimization, early detection of renal damage, and timely discontinuation of potential agents to avoid irreversible renal damage.

Molecular Mechanisms Associated with Aging Kidneys and Future Perspectives

The rapid growth of the elderly population is making the need for extensive and advanced information about age-related organ dysfunction a crucial research area. The kidney is one of the organs most affected by aging. Aged kidneys undergo functional decline, characterized by a reduction in kidney size, decreased glomerular filtration rate, alterations in renal blood flow, and increased inflammation and fibrosis. This review offers a foundation for understanding the functional and molecular mechanisms of aging kidneys and for selecting identifying appropriate targets for future treatments of age-related kidney issues.

Collectrin (Tmem27) deficiency in proximal tubules causes hypertension in mice and a TMEM27 variant associates with blood pressure in males in a Latino cohort.

Collectrin (Tmem27), an angiotensin-converting enzyme 2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance and increased proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) expression. Collectrin is located on the X chromosome where genome-wide association population studies have largely been excluded. In the present study, we generated PT-specific collectrin KO (PT KO) mice to determine the precise contribution of PT collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single-nucleotide polymorphisms with blood pressure traits in 11,926 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Hispanic/Latino participants. PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity or a reduction in renal blood flow compared with control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific single-nucleotide polymorphism associations with diastolic blood pressure. In conclusion, loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on blood pressure and salt sensitivity in humans.NEW & NOTEWORTHY The findings of our study are significant in several ways: 1) loss of an amino acid chaperone in the proximal tubule is sufficient to cause hypertension, 2) the results in global and proximal tubule-specific collectrin knockout mice support the notion that vascular dysfunction is required for salt sensitivity or that impaired renal tubule function causes hypertension but is not sufficient to cause salt sensitivity, and 3) our study is the first to implicate a role of collectrin in human hypertension.

Renal denervation as a management strategy for hypertension: current evidence and recommendations

Introduction The concept of targeting the renal sympathetic nerves therapeutically to lower blood pressure (BP) is based on their crucial role in regulating both renal and cardiovascular control. These effects are mainly mediated via three major mechanisms including alteration of renal blood flow, renin-release, and Na+ retention. Initial surgical approaches applying crude and unselected sympathectomy, while rendering significant BP lowering and cardiovascular event reducing properties, where plagued by side effects. More modern selective catheter-based denervation approaches selectively targeting the renal nerves have been shown to be safe and effective in reducing BP in various forms of hypertension and multiple comorbidities. Areas covered This article covers the background relevant for the concept of renal denervation (RDN), the evidence obtained from relevant randomized controlled trials to substantiate the safety and efficacy of RDN, and recently published clinical recommendations. Expert Opinion Catheter-based RDN is safe and has now been shown in sham-controlled randomized clinical trials to result in clinically meaningful BP lowering in both drug naïve hypertensive patients and those on concomitant antihypertensive therapy. Real world data from a large global registry further supports the clinical utility of RDN. It now seems time to embed renal denervation into routine clinical care.

Impaired renal hemodynamics and glomerular hyperfiltration contribute to hypertension-induced renal injury

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1BN Add3KO (Add3KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3KO rats. The degree of renal injury was greater in Add3KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3KO rats.

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations.

Pregnancy is associated with numerous physiological changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® simulator. The Simcyp pregnancy-PBPK model accounts for the known physiological changes that occur during pregnancy. For each medication, plasma concentration-time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. The predicted systemic exposure metrics (Cmax , AUC) were compared with published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture the observed changes in Cmax and AUC across each trimester of pregnancy compared with post-partum for metformin (FE range 0.86-1.19), tacrolimus (FE range 1.03-1.64) and oseltamivir (FE range 0.54-1.02). Simcyp model outputs were used to correlate these findings with pregnancy-induced alterations in renal blood flow (metformin, oseltamivir), hepatic CYP3A4 activity (tacrolimus) and reduced plasma protein levels and hemodilution (tacrolimus). The results illustrate how PBPK modeling can help to establish appropriate dosing guidelines for pregnant patients and to predict potential changes in systemic exposure during pregnancy for compounds undergoing clinical development.

Renal denervation in the treatment of resistant hypertension: Dead, alive or surviving?

Hypertension is one of the most common chronic clinical problems encountered by physicians. The prevalence of resistant hypertension is estimated at 9% in the US. Patients with resistant hypertension have been shown to be at higher risk for adverse cardiovascular events, hence the need for greater efforts in improving the treatment of hypertension. The renal sympathetic nerves play an important role in the development of hypertension, mediated via sodium and water retention, increased renin release and alterations in renal blood flow. The proximity of the afferent and efferent renal sympathetic nerves to the adventitia of the renal arteries suggested the feasibility of an endovascular, selective, minimally invasive approach to renal denervation; a potential treatment option for resistant hypertension. While the RAPID, Reduce-HTN, EnligHTN, DENERHTN and Symplicity HTN-1 and -2 studies showed significant benefit of renal denervation in the treatment of resistant hypertension, the results of Oslo RDN, Prague-15 and Symplicity HTN-3 were not so favorable. Future well-designed clinical trials are needed to ascertain the benefits or otherwise of renal denervation in treatment-resistant hypertension.

Renal denervation in the treatment of resistant hypertension: Dead, alive or surviving?

Hypertension is one of the most common chronic clinical problems encountered by physicians. The prevalence of resistant hypertension is estimated at 9% in the US. Patients with resistant hypertension have been shown to be at higher risk for adverse cardiovascular events, hence the need for greater efforts in improving the treatment of hypertension. The renal sympathetic nerves play an important role in the development of hypertension, mediated via sodium and water retention, increased renin release and alterations in renal blood flow. The proximity of the afferent and efferent renal sympathetic nerves to the adventitia of the renal arteries suggested the feasibility of an endovascular, selective, minimally invasive approach to renal denervation; a potential treatment option for resistant hypertension. While the RAPID, Reduce-HTN, EnligHTN, DENERHTN and Symplicity HTN-1 and -2 studies showed significant benefit of renal denervation in the treatment of resistant hypertension, the results of Oslo RDN, Prague-15 and Symplicity HTN-3 were not so favorable. Future well-designed clinical trials are needed to ascertain the benefits or otherwise of renal denervation in treatment-resistant hypertension.

Dynamic evaluation of renal resistive index in normoalbuminuric patients with newly diagnosed hypertension or type 2 diabetes

Renal resistive index is a useful measure for quantifying alterations in renal blood flow. In the present study we evaluated resistive index at baseline and after vasodilation induced by nitroglycerine in normoalbuminuric patients with type 2 diabetes or essential hypertension, relating the values to indices of systemic vascular dysfunction. Newly diagnosed treatment-naïve type 2 diabetic (n = 32) and hypertensive patients (n = 49) were compared with 27 age- and sex-matched healthy controls. Renal resistive index was obtained by duplex ultrasound at baseline and after 25 μg sublingual nitroglycerine. Endothelium-dependent (flow-mediated dilation) and -independent (response to nitroglycerine) vasodilation in the brachial artery was assessed by computerised edge detection system. Carotid-femoral pulse-wave velocity and augmentation index were assessed by applanation tonometry. Nitrotyrosine levels, an index of oxidative stress, were also measured. Resistive index was higher in diabetic than in hypertensive patients and controls (p < 0.001), while changes in resistive index induced by nitroglycerine were lower in hypertensive patients compared with controls (p < 0.01), and were further reduced in type 2 diabetic patients. Hypertensive and diabetic patients showed significantly increased arterial stiffness, nitrotyrosine levels and reduced endothelial function than controls (p < 0.05). Changes in resistive index induced by nitroglycerine were independently related to serum glucose, reactive hyperaemia and aortic pulse-wave velocity in the overall population. These results support the dynamic evaluation of renal resistive index as an early detector of renal vascular alterations in the presence of type 2 diabetes and hypertension, even before the onset of microalbuminuria.

A mathematical model of diffusional shunting of oxygen from arteries to veins in the kidney

To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive-advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po(2). The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney Vo(2) must change, in the face of altered renal blood flow, to maintain cortical tissue Po(2) at a stable level. It is demonstrated that oxygen shunting increases as renal Vo(2) or arterial Po(2) increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney Vo(2) increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po(2) when arterial Po(2) changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases.

Comparing Kidney Perfusion Using Noncontrast Arterial Spin Labeling MRI and Microsphere Methods in an Interventional Swine Model

The purpose of this study was to assess the ability of a flow-sensitive alternating inversion recovery-arterial spin labeling (FAIR-ASL) technique to track renal perfusion changes during pharmacologic and physiologic alterations in renal blood flow using microspheres as a gold standard. Fluorescent microsphere and FAIR-ASL perfusion were compared in the cortex of the kidney for 11 swine across 4 interventional time points: (1) under baseline conditions, (2) during an acetylcholine and fluid bolus challenge to increase perfusion, (3) initially after switching to isoflurane anesthesia, and (4) after 2 hours of isoflurane anesthesia. In 10 of the 11 swine, a bag of ice was placed on the hilum of 1 kidney at the beginning of isoflurane administration to further reduce perfusion in 1 kidney. Both ASL and microspheres tracked the expected cortical perfusion changes (P < 0.02) across the interventions, including an increase in perfusion during the acetylcholine challenge and decrease during the administration of isoflurane. Both techniques also measured lower cortical perfusion in the iced compared with the non-iced kidneys (P ≤ 0.01). The ASL values were systematically lower compared with microsphere perfusion. Very good correlation (r = 0.81, P < 0.0001) was observed between the techniques, and the relationship appeared linear for perfusion values in the expected physiologic range (microsphere perfusion <550 mL/min/100 g) although ASL values saturated for perfusion >550 mL/min/100 g. Cortical perfusion measured with ASL correlated with microspheres and reliably detected changes in renal perfusion in response to physiologic challenge.

Intra-abdominal Hypertension and Abdominal Compartment Syndrome

Increased intra-abdominal pressure (IAP), also referred to as intra-abdominal hypertension (IAH), affects organ function in critically ill patients and may lead to abdominal compartment syndrome (ACS). Although initially described in surgical patients, IAH and ACS also occur in medical patients without abdominal conditions. IAP can be measured easily and reliably in patients through the bladder using simple tools. The effects of increased IAP are multiple, but the kidney is especially vulnerable to increased IAP because of its anatomic position. Although the means by which kidney function is impaired in patients with ACS is incompletely elucidated, available evidence suggests that the most important factor involves alterations in renal blood flow. IAH should be considered as a potential cause of acute kidney injury in critically ill patients; its role in other conditions, such as hepatorenal syndrome, remains to be elucidated. Because several treatment options (both medical and surgical) are available, IAH and ACS should no longer be considered irrelevant epiphenomena of severe illness or critical care. An integrated approach targeting IAH may improve outcomes and decrease hospital costs, and IAP monitoring is a first step toward dedicated IAH management. IAH prevention, most importantly during abdominal surgery but also during fluid resuscitation, may avoid ACS altogether. However, when ACS occurs and medical treatment fails, decompressive laparotomy is the only option.

Effect of Body Position on Renal Parenchyma Perfusion as Measured by Nuclear Scintigraphy

To compare differential renal perfusion in various body positions in healthy volunteers, to help postulate factors responsible for recurrent unilateral stone formation. Ten volunteers with normal renal function and no history of urinary disease were evaluated with diuretic renography using mercaptoacetyl-triglycine. Scintigraphy was performed 1 week apart in each of three typical sleep positions (supine, left lateral decubitus, right lateral decubitus), and renal perfusion was measured. Symmetric renal perfusion was noted in all volunteers in the supine position. Subjects positioned in the left lateral decubitus position had a mean renal perfusion of 61.3% in the dependent (left) kidney, compared with 38.7% in the nondependent (right) kidney (P <0.05). In the right lateral decubitus position, the mean renal perfusion in the right kidney was 63.3%, whereas that in the left kidney measured 36.7% (P <0.05). Renal perfusion in the dependent kidney was increased when compared with the same kidney in the supine position in both the left and right kidneys. Body position had a significant effect on renal perfusion as measured by nuclear renal scintigraphy. If altered renal blood flow contributes to urinary calculogenesis, these data suggest that the urinary and vascular milieu in the decubitus position may contribute to risk factors for stone formation.

DETERMINATION OF GLOMERULAR FILTRATION RATE IN DOGS USING CONTRAST‐ENHANCED COMPUTED TOMOGRAPHY

The purpose of this project was to establish a procedure and reference values for glomerular filtration rate (GFR) using contrast-enhanced computed tomography (CT) in eight healthy dogs. A single section of the kidney was scanned sequentially after bolus injection (3 ml/s) of iohexol (300 mg/kg). Time-attenuation curves were constructed and the GFR per volume of kidney was calculated using Patlak graphical analysis software. The GFR was then converted from contrast clearance per unit volume (ml/min/ml) to contrast clearance per body weight (ml/min/kg). Individual kidney and global GFR were calculated using both CT and nuclear scintigraphy. Global GFR for each dog was also determined by plasma iohexol clearance. Contrast-enhanced CT underestimated the global GFR compared with the other two methods. The average global GFR was 2.57 +/- 0.33 ml/ min/kg using functional CT and 4.06 +/- 0.37 ml/min/kg using plasma iohexol clearance. There was significant (P < 0.05) interobserver variability of CT GFR of the right kidney and total GFR. There was decreased interobserver variability for the left kidney. There was no difference in the intraobserver variability for CT-determined individual kidney and global GFR. There was no difference between the motion corrected and nonmotion corrected values for individual and global CT GFR. Nuclear scintigraphy produced a slightly higher coefficient of variation than contrast-enhanced CT, 2.9% and 1.0%, respectively. It is hypothesized that altered renal blood flow, hematocrit of the small vessels, and nephrotoxicity play a role in the underestimation of GFR by contrast-enhanced CT.

A positive feedback loop contributes to the deleterious effects of angiotensin

When a basic scientist looks at heart failure, he sees a disease that appears to originate from any damage that causes low cardiac output, is progressive, and elicits a variety of physiological responses that attempt to correct the depressed cardiac function. Furthermore, these reflex physiological responses to low cardiac output—increased sympatho-adrenal tone, increased activity of the renin–angiotensin system and other systems that maintain blood pressure, left ventricular remodeling, and cardiac hypertrophy—seem deleterious, because the pump is overworked and failing and cannot be expected, in the long run, to respond well to increased load or increased inotropic stimulation. The disease looks like a downward spiral, a spiral that therapy must interrupt. Models of heart failure have provided rationales for therapy and experimentation. A cardio-renal model viewed heart failure as a problem of salt and water retention originating with alterations in renal blood flow; a cardio-circulatory, or hemodynamic, model ascribed heart failure to vasoconstriction and reduced pumping capacity of the heart. These models provided rationales for the use of diuretics, vasodilators, and inotropic agents as therapies but mechanistically did not account for the progressive worsening of the disease or the fact that inotropic interventions produce improvements in cardiac contractility but do not slow the progression of the disease or reduce mortality. More recently, attention has focused on some of the neural/paracrine/autocrine mechanisms that constitute the reflex responses to low output and on the importance of signaling pathways regulating cell growth, apoptosis, and cell survival (1–3). Mann and Bristow (4) have suggested a synthesis, the biomechanical model, that emphasizes that the components of altered cardiac function and cardiac remodeling interact, such that one will invariably cause the other, and both will be sustained by neurohumoral responses. Among the humoral factors involved, much attention has been focused on the renin–angiotensin–aldosterone axis and …

Superoxide scavenging attenuates renal responses to ANG II during nitric oxide synthase inhibition in anesthetized dogs.

To assess the role of superoxide (O2-) and nitric oxide (NO) interaction in mediating the renal actions of ANG II, we examined the renal responses to intra-arterial infusion of ANG II (0.5 ng x kg(-1) x min(-1)) before and during administration of a superoxide dismutase mimetic, tempol (0.5 mg x kg(-1) x min(-1)), in the presence or absence of NO synthase inhibitor, nitro-L-arginine (NLA; 50 microg x kg(-1) x min(-1)), in anesthetized dogs pretreated with enalaprilat (33 microg x kg(-1) x min(-1)). In one group of dogs (n = 7), ANG II infusion before tempol infusion caused decreases of 24 +/- 4% in renal blood flow (RBF), 55 +/- 7% in urine flow (V), and 53 +/- 8% in urinary sodium excretion (U(Na)V) with a slight decrease in glomerular filtration rate (GFR; -7.8 +/- 3.4%). Tempol infusion alone did not cause significant alterations in RBF, GFR, V, or U(Na)V; however, ANG II in the presence of tempol caused a smaller degree of decreases in RBF (-12 +/- 2%), in V (-16 +/- 5%), and in U(Na)V (-27 +/- 10%) with a slight increase in GFR (6.6 +/- 2.8%) than the responses observed before tempol. In another group of NLA-treated dogs (n = 6), tempol infusion also caused significant attenuation in the ANG II-induced responses on RBF (-13 +/- 3% vs. -22 +/- 7%), GFR (-19 +/- 5% vs. -33 +/- 3), V (-15 +/- 12% vs. -28 +/- 4%), and U(Na)V (-11 +/- 14% vs. -32 +/- 7%). These data demonstrate that renal responses to ANG II are partly mediated by O2- generation and its interaction with NO. The sodium-retaining effect of ANG II is greatly influenced by O2- generation, particularly in the condition of NO deficiency.

Blood flow-dependent changes in intrarenal nitric oxide levels during anesthesia with halothane or sevoflurane

We previously demonstrated that intrarenal nitric oxide (NO) levels and renal blood flow are reduced during halothane anesthesia. Studies were performed to determine if volatile anesthetics-induced reductions in renal NO levels are associated with blood flow changes. Halothane and sevoflurane at 0.8 and 2.4 Mac were administered by inhalation to dogs, and cGMP and NOx concentrations in the renal interstitial fluid were measured by a microdialysis method. Neither halothane nor sevoflurane at 0.8 Mac altered renal blood flow and renal interstitial cyclic guanosine monophosphate (cGMP) and NOx levels, but both anesthetics significantly decreased these values at 2.4 Mac. Using an adjustable aortic clamp, renal perfusion pressure was reduced in 2 steps without halothane and sevoflurane anesthesia. Renal blood flow as well as cGMP and NOx concentrations in the renal interstitial fluid were unchanged within the autoregulatory range, but significantly decreased below the autoregulatory range. Changes in cGMP and NOx concentrations in the renal interstitial fluid were highly correlated with renal blood flow changes during halothane or sevoflurane anesthesia, and during stepwise reductions in renal perfusion pressure. The results suggested that halothane- and sevoflurane-induced decreases in intrarenal NO levels result from reductions in blood flow.

Interspecies Differences in the Nephrotoxic Response to Cyclooxygenase Inhibition

In contrast to cyclooxygenase‐1 (COX‐1), the basal expression of renal cyclooxygenase‐2 (COX‐2) varies among species. High basal levels of COX‐2 in the renal cortex and papilla in dogs compared with monkeys suggest that COX‐2 inhibition may lead to distinct nephrotoxic responses. In this study, we compared the renal effects of COX inhibition between dogs and cynomolgus monkeys (n = 6/group) following the administration of naproxen sodium, a non‐selective COX‐1/COX‐2 inhibitor. Dogs and monkeys were treated with 50 or 150 mg/kg/day naproxen sodium, respectively, for 2 to 6 weeks. Naproxen doses used in this study resulted in equivalent inhibition of COX activity in both species as measured by reductions in urinary prostaglandin E2 (PGE2) and 6‐keto‐PGF1‐α levels. There was prominent reduction in renal blood flow (43%) and urinary sodium excretion (62%) in dogs but no alterations in renal blood flow and only minimal change (19%) in urinary sodium excretion in monkeys. The canine but not monkey kidney showed prominent COX‐2 expression in the macula densa, thick ascending limb of Henle and papillary interstitial cells by immunohistochemistry. After treatment, the canine but not monkey kidneys had mild to moderate renal tubular atrophy and interstitial fibrosis and renal papillary necrosis. Obstructive nephropathy secondary to intra‐tubular drug accumulation was seen in monkeys but not in dogs. Collectively, these data demonstrate species differences in the renal response to COX inhibition. The nature of functional and morphologic changes suggests a more prominent role of COX‐2 in renal hemodynamics and natriuresis in dogs than in monkeys.