Decrease In Renal Plasma Flow Research Articles

S-41-5: NEW INSIGHTS INTO THE OPTIMAL ANTIHYPERTENSIVE THERAPY IN CKD PATIENTS

Chronic kidney disease (CKD) is defined as continuous existence of reduced renal function, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, and/or proteinuria including microalbuminuria. CKD patients are not only prone to progress to renal failure but also at high risk for developing cardiovascular diseases (CVD) as the concept of cardio-renal syndrome is assumed. As the cause of CKD, diabetic kidney disease and nephrosclerosis are dominating and their progression is promoted by aging and lifestyle-related diseases (LSD) such as hypertension and diabetes. Therefore, in order to maximally prevent renal failure and CVD in CKD patients, aggressive intervention achieving strict control of LSD starting at its earliest stage is important. Renal function is generally evaluated by eGFR, however, the fundamental aspect of renal function is renal blood flow or renal plasma flow (RPF), and the decrease of RPF is compensated by the increase in filtration fraction yielding the maintenance of GFR value. Accordingly, if eGFR is less than 60, it should be recognized that the extent of renal injury is not mild but moderate or worse. However, the measurement of RPF requires laborious and invasive procedure. Albuminuria may reflect the increase in glomerular capillary pressure (glomerular hypertension) elicited by reduced nephron number but the urinary albumin excretion is highly variable and is not necessarily parallel to the degree of renal injury. Among LSD, hypertension plays a pivotal role as the risk factor for renal failure and CVD, and the strict blood pressure control targeting < 130/80mmHg is recommended in the guidelines. As antihypertensive agents, renin-angiotensin system inhibitors such as ARB and ACE inhibitors are preferred because of dilating the efferent arterioles resulting in the alleviation of glomerular hypertension and the reduction in albuminuria. Calcium channel blockers have advantage in preserving RPF and GFR by dilating the afferent arterioles. In addition, recent randomized controlled trials have demonstrated that sodium-glucose cotransporter 2 inhibitors retard the GFR decrease in diabetic and non-diabetic CKD patients. Angiotensin receptor neprilysin inhibitor, now used for hypertension, has also been shown to reduce the risks of GFR decrease and worsening of renal function in heart failure patients. Nonsteroidal mineralocorticoid receptor antagonists are expected to provide renoprotective effects such as albuminuria reduction with affordable risk of hyperkalemia. Thus, in future strategy of antihypertensive therapy for CKD aiming maximum renal and cardiovascular protection, practical evaluation of renal injuries at early stages and incorporation of drugs with new evidence are the key issues.

EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS

Objective: The tetrahydrobiopterin-analogue VAS203, an in vivo inhibitor of predominantly the inducible nitric oxide synthase (iNOS), was developed to reduce secondary damage in patients with severe traumatic brain injury. However, its effect on micro- and macrocirculation is less well established. The aim of the present study was to characterize in detail the pharmacological effects of VAS203 on micro- and macrocirculation in humans. Design and method: In this single-centre, double-blind, randomized, placebo-controlled cross-over phase I study 16 healthy male subjects were included. A constant infusion of VAS203 (total 10 mg/kg body weight) or placebo was administered for 6 hours. After a wash-out phase of 28 days the second course with either placebo or VAS203 was applied. Renal hemodynamics were assessed with constant-infusion input-clearance technique with para-aminohippuric acid (PAH) for renal plasma flow (RPF). In addition, we assessed retinal capillary flow, as microvascular parameter by scanning laser Doppler flowmetry (SLDF) at 670 nm and used pulse wave analysis by SphygmoCorTM device for assessment of central systolic pressure, as macrovascular parameter of systemic circulation. Results: Intravenous infusion of VAS203 resulted in a reduction of RPF, but remained unchanged with placebo (Figure), resulting in a significant decrease of RPF with VAS203 compared to placebo (p < 0.0001).In contrast, mean retinal capillary flow (mirroring cerebral circulation) remained preserved at any time-point during as well as up to 2 hours after intravenous infusion of VAS203 (all p > 0.4). Compared to placebo, there was no change of brachial blood pressure due to VAS203 infusion (p > 0.2). In addition, no significant effect of VAS203 infusion on central systolic pressure was observed, indicative of no clinical meaningful effects of VAS203 on systemic circulation (p > 0.1). Conclusions: Our phase I study in humans indicate that a dose of 10 mg/kg body weight VAS203 reduces renal perfusion within a physiological range, but has no other acute effects on assessed parameters of micro- and macrocirculation.

Reversal of an unfavorable effect of hydrochlorothiazide compared to angiotensin converting enzyme inhibitor on serum uric acid and oxypurine levels by estrogen–progestin therapy in hypertensive postmenopausal women

Background: The aim was to assess the effect of estrogen–progestin therapy (EPT) on serum levels of uric acid (SUA) and its precursors xanthine (X) and hypoxanthine (HX), and on uric acid (UA) renal excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic (HCTZ) (ClinicalTrials.gov identifier: NCT03921736, registered 19 April 2019).Methods: Postmenopausal women with untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure. Hypertensive women were randomized to two groups: hydrochlorothiazide (n = 50) or perindopril (n = 50) and to a group receiving or not receiving EPT (EPT+/EPT−) due to vasomotor symptoms. The follow-up period was one year. Blood pressure measurements as well as blood tests for SUA and its precursors X and HX were performed at baseline and after 12 months.Results: In hypertensive women, baseline serum X and HX were significantly higher when compared to the group of normotensive women. Treatment with HCTZ led to a statistically significant increase in SUA in the subgroup of EPT- women. In this group concentrations of X and HX increased significantly after 12 months. UA/X significantly decreased after treatment with HCTZ. Lack of EPT resulted in a decrease of renal plasma flow in the HCTZ group. However, in the HCTZ and EPT + group, SUA decreased significantly when compared to baseline. None of these unfavorable effects was observed in the ACEI group regardless of EPT.Conclusions: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.

Renal and Hormonal Effects of Systemic Nitric Oxide Inhibition in Patients With Congestive Heart Failure and in Healthy Control Subjects

BackgroundThe significance of basal renal nitric oxide (NO) availability in the regulation of renal perfusion and sodium excretion in human congestive heart failure (CHF) has not been described previously. Methods and ResultsWe studied the effects of acute systemic NO synthesis inhibition with NG-monomethyl-L-arginine (L-NMMA) in 12 patients with CHF and 10 healthy control subjects (CON) in a randomized placebo-controlled study. Effect parameters were renal plasma flow (RPF), renal vascular resistance (RVR), glomerular filtration rate (GFR), urine sodium excretion and plasma levels of vasoactive hormones. L-NMMA was associated with a significant decrease in RPF (CON-LNMMA: −13 ± 3% [P = .014]; CHF-LNMMA: −17 ± 7% [P = .017]) and a profound increase in RVR in both CHF and CON (CON-LNMMA: +26 ± 6% [P = .009]; CHF-LNMMA: +37 ± 70% [P = .005]). Significant decreases in sodium excretion were found in both CHF-LNMMA and CON-LNMMA. Relative changes from baseline were not statistically different between CHF-LNMMA and CON-LNMMA. After L-NMMA, RPF values correlated inversely with plasma aldosterone in CHF-LNMMA (P = .01). L-NMMA induced an increase in A-type natriuretic peptide (ANP) only in CHF-LNMMA (+18 ± 8%; P = .035), which correlated significantly with basal ANP levels (P = .034). ConclusionsThere was no difference in the renal response to L-NMMA in CHF vs CON, suggesting that the impact of NO on renal perfusion and sodium excretion is maintained in stable CHF. We suggest that NO influences the release of ANP during high levels of atrial stretch in CHF.

Two-Year Renal Hemodynamic Effects of Deferasirox in Patients with Transfusion-Dependent β-Thalassemia

AbstractAbstract 3257 Background:In previous studies with deferasirox (Exjade®), some patients experienced dose-dependent, non-progressive increases in serum creatinine, mostly within normal limits and mostly reversible with dose reduction/interruption. Although the cause of these increases is not fully understood, the most likely mechanism is hypothesized to be a reduction in glomerular filtration rate (GFR) as a result of a pharmacological effect of deferasirox on the kidney, specifically on its intraglomerular hemodynamics (Schetz et al. 2005). This study was initiated to test this hypothesis and estimate the long-term effect of deferasirox 30 mg/kg/day on renal hemodynamics by measuring changes in renal function markers, specifically GFR, renal plasma flow (RPF) and filtration fraction (FF), in β-thalassemia patients with transfusional iron overload. Methods:This study enrolled deferasirox-naïve β-thalassemia patients aged ≥18 yrs receiving transfusions every 2–5 wks (iron intake ≥0.25 mg/kg/day), transfusion history ≥20 units packed red blood cells and serum ferritin ≥500 ng/mL or liver iron concentration (LIC) ≥2 mg Fe/g dry weight (dw). Patients were excluded if they had serum creatinine >upper limit of normal (ULN), estimated creatinine clearance (CrCl) <60 mL/min, urinary protein:creatinine ratio >0.5 mg/mg, ALT >5 × ULN, history of nephrotic syndrome, or treatment with drugs known to affect renal parameters. As per the initial protocol, patients received deferasirox 30 mg/kg/day for 8 weeks, followed by a 2-week washout. In order to provide long-term data the study was amended: following the initial 10-week period, patients could receive deferasirox for an additional 94 weeks (up to Week 104) followed by a 4-week washout. GFR and RPF were measured using chromium-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) and 123ortho-iodohippurate (123I-OIH). Parameters were assessed at baseline, 2, 8, 10, 104 and 108 weeks. Results:Eleven patients were enrolled (mean age 35.2 yrs; 7:4 male:female). For these 11 patients at baseline, median serum ferritin was 2110 ng/mL (range 840–3131 ng/mL); mean LIC 7.3 ± 4.0 mg Fe/g dw. Mean GFR (111.5 ± 17.5 mL/min), RPF (603.5 ± 94.3 mL/min) and FF (0.2 ± 0.03) were normal. Ten patients completed 10 weeks of treatment (one discontinued due to voluntary withdrawal). Five of these patients did not enter the extension trial as they had completed the initial trial prior to the protocol amendment extending the study duration (no patient discontinued due to adverse events [AEs]) and five patients completed the 108-week study.For the five patients completing the 108-week study, mean GFR decreased from 108.5 ± 18.1 mL/min at baseline to 90.2 ± 17.8 mL/min at Week 104; mean RPF decreased from 595.4 ± 43.1 mL/min at baseline to 479.5 ± 87.6 mL/min at Week 104 (a mean relative decrease of 19.6%; Figure). After 4 weeks’ washout following the 104-week period, both mean GFR and RPF recovered to near baseline values: from 90.2 ± 17.8 mL/min at Week 104 to 103.5 ± 17.1 mL/min at Week 108 and from 479.5 ± 87.6 mL/min at Week 104 to 553.5 ± 91.8 mL/min at Week 108, respectively. Mean percentage change for GFR from baseline was –9.5% at Week 8, +2.1% at Week 10, –17.2% at Week 104, and –4.5% at Week 108. For RPF, mean percentage change from baseline was –17.8% at Week 8, –9.0% at Week 10, –19.6% at Week 104 and –7.3% at Week 108. Mean FF showed only mild fluctuations (0.18–0.21) during the study. Serum creatinine was 61.5 ± 15.1 μmol/L at baseline, 65.4 ± 15.1 μmol/L at Week 104 and 62.9 ± 10.7 μmol/L at Week 108; CrCl was 115.0 ± 21.3 mL/min at baseline, 107.4 ± 13.8 mL/min at Week 104 and 109.9 ± 8.8 mL/min at Week 108.For the 11 patients enrolled, AEs regardless of study drug relationship were mainly gastrointestinal (diarrhea and upper abdominal pain n=3 each, abdominal pain n=2), pyrexia (n=3), rhinitis (n=3), back pain (n=2), headache (n=2), cough (n=3), oropharyngeal pain (n=3), rash (n=2). There were no deaths or serious AEs. Discussion:Deferasirox appears to produce a mild effect on renal hemodynamics, reflected by a decrease in RPF, leading to a decrease in GFR; these effects were reversible after drug interruption over the short and long term. Both mean GFR and RPF recovered to near baseline values after washout, suggesting that renal function is stable with up to 2 years' treatment with deferasirox. [Display omitted] Disclosures:Piga:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cappellini:Novartis: Speakers Bureau. Habr:Novartis: Employment. Wegener:Novartis: Employment. Bouillaud:Novartis: Employment.

Management of Refractory Ascites

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, high-dose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction (<90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (<78 mmol/d). Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated paracentesis and improves the quality of life. Several treatments that act at different steps in the pathogenesis of ascites are investigational, and some show promising results. Splanchnic and peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial volume and decrease activation of the renin-angiotensin system with resultant increase in renal sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid mobilization of ascites by significantly decreasing the sympathetic activity and renin-aldosterone levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign, liver transplantation should be considered and incorporated early in the treatment plan.

Renal Vascular Endothelial Function in Hypertensive Patients With Type 2 Diabetes Mellitus

Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. Prospective observational-study during a mean follow-up of 2.1 years. 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). Patients were treated according to the discretion of the individual primary care physician. During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.

Effects of Rituximab on Morphofunctional Abnormalities of Membranous Glomerulopathy

In idiopathic membranous nephropathy (IMN), CD(20) B-cell depletion by rituximab may induce nephrotic syndrome (NS) remission. Whether this is associated with kidney function restoration and regression of the glomerular pathology was evaluated. Treatment-induced morphofunctional changes were evaluated in 7 IMN patients consenting to repeat functional and morphologic evaluations after stable disease remission achieved by four weekly rituximab (375 mg/m(2)) infusions. Over a median of 21 mo from rituximab administration, NS remission was associated with 8.5-fold increase versus baseline in sodium fractional clearance from 1.56 to 13.25, decrease in renal plasma flow from 440.8 to 276.6 ml/min per 1.73 m(2), stable glomerular filtration rate, and increased renal vascular resistances. Changes in sodium fractional clearance and hemoglobin concentration were positively correlated (r = 0.82). Biopsy reevaluations showed complete or partial reabsorption of subepithelial deposits. Median (interquartile range) IgG4 staining score decreased from 3 (3-3) to 1 (0-2), whereas total numbers of slit diaphragms (0.27; range, 0.19 to 0.30 versus 0.86; range, 0.53 to 1.16 slits/mum glomerular basement membrane) and percentages of those with electron-dense diaphragm (55.2; range, 42.0 to 62.0 versus 78.5; range, 73.0 to 82.7 of all slits) significantly increased in parallel with amelioration of glomerular ultrastructural changes. Changes in slit frequency and albumin fractional clearance were negatively correlated (r = -0.79). In human IMN, treatment-induced NS remission is associated with restoration of sodium homeostasis and kidney hemodynamics, and regression of the glomerular changes underlying proteinuria. These effects are likely to translate into long-term renoprotection.

Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans

Experimental data suggest that increased nitric oxide synthase (NOS) activity contributes to preglomerular vasodilation and subsequent glomerular hyperfiltration. Whether such a relationship also exists in the human renal vasculature has not yet been adequately determined. We assessed systemic, renal, and intragomerular haemodynamics in 310 subjects with normal renal function [glomerular filtration rate (GFR) > 60 ml/min per 1.73 m], before and after NOS inhibition with L-Nmonomethyl arginine (L-NMMA). Subjects were arbitrarily divided into tertiles according to their basal NOS activity, as assessed by the decrease in renal plasma flow in response to L-NMMA (high -23.4 +/- 8.1 versus medium -10.8 +/- 2.2 versus low -1.0 +/- 4.8%). Resting GFR differed significantly between tertiles: high 114 +/- 21 versus medium 109 +/- 19 versus low 104 +/- 21 ml/min per 1.73 m; analysis of variance P = 0.003. In a multiple stepwise regression analysis, basal NOS activity was the major factor to explain resting GFR (beta = -0.344; P < 0.001). Body weight (beta = -0.295; P < 0.001) and age (beta = -0.164; P < 0.001) emerged as additional factors, whereas body mass index and blood pressure did not enter the final model. The close relationship between resting GFR and basal NOS activity was also mirrored in the renal microcirculation, as demonstrated by an exaggerated effect of L-NMMA on the increase in arteriolar resistance, particularly that of the afferent (RA) arteriole, with higher basal nitric oxide (NO) activity (RA: high +1542 +/- 1065 versus medium +1024 +/- 718 versus low +675 +/- 861 dyne/s per cm; P < 0.001). Our data clearly support experimental evidence linking NOS activity with increased glomerular filtration, and suggest that basal NO activity is also a major determinant of glomerular haemodynamics in the human renal vasculature.

Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia

Objective Impaired endothelium-dependent vasodilation represents an early manifestation of atherosclerosis. Prospective studies have demonstrated that impaired endothelial function in the peripheral circulation of hypercholesterolemic patients predicts CV events and can be restored by statin treatment. Whether this also holds true in the renal circulation has not yet been adequately addressed. Methods In a double-blind, randomized, placebo-controlled cross-over trial, 40 hypercholesterolemic patients were randomly assigned to receive rosuvastatin (10 mg/day) and matching placebo. The primary objective of the study was to assess the effect of 6-week treatment with rosuvastatin on basal NOS activity of the renal vasculature, as assessed by measuring renal plasma flow (RPF) both before and after blockade of NOS with systemic infusion of N G-monomethyl- l-arginine ( l-NMMA). In a subgroup of 20 patients we also studied the effects of a 3-day treatment regimen. Results Compared to placebo treatment, rosuvastatin decreased LDL-cholesterol levels both after 3 days and 6 weeks of treatment. The decrease in RPF in response to l-NMMA was significantly more pronounced after 6-week therapy with rosuvastatin compared to placebo (−13.7 ± 1.0% versus −11.3 ± 0.7%; p = 0.046), indicating increased basal NOS activity with rosuvastatin treatment. A trend towards improved basal NOS activity was already evident after 3-day treatment. Conclusion Treatment with rosuvastatin improved basal NOS activity in the renal circulation of hypercholesterolemic patients, suggestive of a nephroprotective effect. In view of the close relation between altered renal function and cardiovascular events, these nephroprotective effects may contribute to the improved CV prognosis associated with statin treatment.

Effects of Long-Term Oral Administration of Ketoprofen in Clinically Healthy Beagle Dogs

To investigate the adverse effects of long-term administration of ketoprofen in dogs, ketoprofen (1 mg/kg) was administered to five clinically healthy beagle dogs (ketoprofen group) and gelatin capsules (control group) were administered to four clinically healthy beagle dogs for 30 days. We monitored the dogs through periodic physical examination, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests, urinalysis, urinary enzyme indices and cuticle bleeding time analysis. The lesions in the stomach, especially in the pyloric antrum, and fecal occult blood progressively worsened in the ketoprofen group. However, the differences between the ketoprofen group and the control group were not statistically significant. One dog in the ketoprofen group temporarily exhibited a decrease in renal plasma flow and two dogs exhibited enzymuria. However, these changes did not persist and the other examinations showed no significant difference between premedication and postmedication in the ketoprofen group. Therefore, the adverse effects of long-term administration of ketoprofen observed in this study were not clinically important in healthy dogs. Nevertheless, further investigation of adverse renal effects from long-term administration of ketoprofen is necessary in the dogs with subclinical renal disease.

The role of nitric oxide in the regulation of glomerular haemodynamics in humans.

According to experimental data, the afferent glomerular arteriole is particularly under control of nitric oxide (NO). By use of pharmacological manoeuvres, we examined whether this finding holds true in the human renal circulation in vivo. Seventy-seven volunteers (aged 50+/-9 years) with mild to moderate essential hypertension (n = 57) or arterial normotension (n = 20) were examined. Basal NO activity in the renal circulation was assessed by the change of renal plasma flow (RPF) through systemic infusion of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). Hypertensive patients were treated over 8 weeks with either the calcium-channel blocker amlodipine or the AT(1)-receptor blocker valsartan, primarily dilating the afferent and efferent arteriole, respectively. Subsequently, renal haemodynamics and NO activity in the renal circulation were determined again. L-NMMA reduced RPF in normotensive (by 57+/-70 ml/min/1.73 m(2); P<0.01) and hypertensive subjects (by 46+/-56 ml/min/1.73 m(2); P<0.001) with no significant difference between the two groups. The decrease of RPF through L-NMMA was closely related with the glomerular filtration rate (GFR; r = 0.39, P<0.001). Administration of amlodipine increased GFR by 7.1+/-12.1 ml/min/1.73 m(2); (P<0.01) and in parallel reduced the response of RPF to L-NMMA to 19+/-48 ml/min/1.73 m(2); (P<0.05). In contrast, valsartan maintained GFR and left the response of RPF to L-NMMA unchanged. NO plays an important role in the regulation of human glomerular haemodynamics, probably with a greater contribution to afferent than to efferent arteriolar tone in man.

Vitamin C augments the renal response to L-arginine in smokers.

In the coronary and the forearm circulations, endothelium-dependent vasomotion is impaired in smokers, but can be augmented by -arginine or vitamin C. We examined whether smoking similarly affects the renal circulation. In 20 smokers (age 26 +/- 4 years) and in 20 non-smokers (age 28 +/- 3 years) changes of renal plasma flow (RPF), glomerular filtration rate (GFR), blood pressure and heart rate in response to the subsequent intravenous infusions of N(G)-monomethyl--arginine (L-NMMA), -arginine and -arginine plus vitamin C were studied by use of a constant infusion input clearance technique. Systemic haemodynamic parameters did not differ between smokers and non-smokers during each experimental phase. At baseline, RPF and GFR were similar between the groups. The infusion of L-NMMA led to a similar decrease of RPF, while GFR did not change in either group. During the infusion of -arginine RPF increased similarly. Finally, the co-infusion of -arginine plus vitamin C led to a significantly greater increase of RPF (+277 +/- 395 vs +79 +/- 76 ml/min, P = 0.03) and GFR (+12.1 +/- 10.6 vs +3.4 +/- 11.2 ml/min, P = 0.02) in smokers as compared to non-smokers. L-NMMA-induced vasoconstriction of the renal vasculature was similar in smokers compared to non-smokers. -arginine alone induced a similar increase of RPF. The co-infusion of vitamin C and -arginine led to a greater increase of RPF and GFR in smokers. This might suggest that oxidative stress is increased in the renal vasculature of smokers.

Does allopurinol prevent side effects of cyclosporine a treatrment?

Side effects of cyclosporine A (CsA) treatment, such as vasoconstriction and reduced renal plasma flow, are partly endothelium-dependent. Allopurinol improves endothelial function in diabetic and hypertensive patients. We examined the effects of allopurinol-application (50 mg/kg over 14 days) on arterial blood pressure, renal blood flow and vasoreactivity of CsA-treated (8 mg/kg over 14 days) Wistar rats. Mean arterial pressure (MAP) of CsA-treated rats was 106 ± 4 mmHg (MAP of CsA + allopurinol-treated rats: 103 ± 4 mmHg), renal plasma flow was 6.3 ± 1.5 ml/min in CsA-treated rats as compared to 5.3 ± 1.1 ml/min in rats treated with CsA + allopurinol. Bolus injection of norfenefrin (0.1 mg/kg) increased MAP to 168 ± 9 (CsA-group) and to 128 ± 8 mmHg (CsA + allopurinol-group). The elevation of blood pressure was significantly higher in the CsA-treated-group than in the CsA+allopurinol-treated animals (62 ± 6 vs. 24 ± 5 mmHg, p<0.05), while renal plasma flow decreased to 1.3 ± 0.5 (CsA-group) and to 3.5 ± 0.7 ml/min respectively (CsA + allopurinol-group). The difference of the decrease of renal plasma flow between the groups was significant (p<0.05). Allopurinol seems to have beneficial effects on vasoreactivity and renal blood flow in CsA-treated animals and might attenuate CsA-induced nephrotoxicity.

Nitric oxide synthase inhibition does not improve renal function in cirrhotic patients with ascites

Objectives Based mainly on animal experiments, nitric oxide (NO) has been proposed to account for the peripheral arterial vasodilation and hyperdynamic circulation in liver cirrhosis. The aim of this study was to clarify whether a reduction of NO synthesis would ameliorate the circulatory and renal dysfunction in decompensated cirrhotic patients. Methods The effects of N G-monomethyl-L-arginine-acetate (L-NMMA), an NO synthesis inhibitor, were studied. After a 60-min basal period, a total of 10 patients received increasing doses of L-NMMA, five patients (Low) received 12.5, 25, and 50 μg/kg/min, and five patients (High) received 25, 50, and 100 μg/kg/min as a constant infusion during 3 h, followed by a postinfusion period. Five patients (Placebo) received saline infusions only. Glomerular filtration rate and renal plasma flow were measured by clearance techniques with 99mTc-diethylenetriamine-pentaacetate and 131I-Hippuran. Results L-NMMA infusion resulted in an increased blood pressure, decreased heart rate, and dose-dependent suppression of renin of up to 42.1 ± 7.1% ( p < 0.01) and angiotensin II of up to 39.9 ± 9.6%, ( p < 0.01) levels. Sodium and water excretion were not improved, most likely because of a reduction in renal blood flow of up to 29.1 ± 8.1% ( p < 0.01). Conclusion Despite a partial correction of the hyperdynamic circulation, inhibition of NO synthesis does not improve sodium and water excretion in decompensated cirrhosis, probably because of an accompanying decrease in renal plasma flow. Intrarenal NO synthesis may be important for maintaining intrarenal hemodynamics in decompensated cirrhotic patients.

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension

Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.

Determinants of hypofiltration during acute renal allograft rejection.

This study sought to determine the extent to which GFR is decreased during acute renal allograft rejection in human subjects and to determine the mechanism of the decrease in GFR. Eight patients with biopsy-proven acute rejection were compared with 18 recipients of optimally functioning renal allografts. GFR and renal plasma flow (RPF) were measured as the clearance of inulin and para-aminohippuric acid, respectively. Arterial BP was determined, blood was sampled, and plasma oncotic pressure (pi(A)) was measured. Glomeruli obtained by biopsy during rejection were subjected to morphometric analysis, for determination of K(f). Control morphometric values for healthy glomeruli were provided by 10 living donors from whom biopsies were obtained at the time of organ donation. The subjects in the acute rejection group exhibited a significantly reduced GFR of 17 +/- 4 ml/min per 1.73 m(2), compared with 72 +/- 4 ml/min per 1.73 m(2) for control subjects (P < 0.001). With the use of a sensitivity analysis to take into account the unknown para-aminohippuric acid extraction ratio, the RPF rate was calculated to have likely been significantly decreased, by 45 to 70%, in the acute rejection group. Neither the plasma oncotic pressure nor the mean arterial pressure differed between the two groups. Morphometric analysis revealed no difference in the single-nephron K(f) values for the acute rejection group, compared with the control group. These results indicate that acute renal allograft rejection causes a profound decrease in GFR, which is attributable to a decrease in RPF alone or in combination with a decrease in the glomerular transcapillary hydraulic pressure gradient (DeltaP).

Role of neuronal nitric oxide synthase in mediating renal hemodynamic changes during pregnancy.

Renal plasma flow (RPF) and glomerular filtration rate (GFR) are markedly increased during pregnancy. We recently reported that the renal hemodynamic changes observed during pregnancy in rats are associated with enhanced renal protein expression of neuronal nitric oxide synthase (nNOS). The purpose of this study was to determine the role of nNOS in mediating renal hemodynamic changes observed during pregnancy. To achieve this goal, we examined the effects of the nNOS inhibitor 7-nitroindazole (7-NI) on kidney function in normal conscious, chronically instrumented virgin (n = 6) and pregnant rats (n = 9) at day 16 of gestation. Infusion of 7-NI had no effect on RPF (4.7 +/- 0.7 vs. 4.8 +/- 0.9 ml/min), GFR (2.2 +/- 0.2 vs. 2.5 +/- 0.4 ml/min), or mean arterial pressure (MAP; 127 +/- 7 vs. 129 +/- 10 mmHg) in virgin rats. In contrast, 7-NI infused into pregnant rats decreased RPF (8.9 +/- 1.6 vs. 6.5 +/- 1.4 ml/min) and GFR (4.4 +/- 0.7 vs. 3.3 +/- 0.7 ml/min) while having no effect on MAP (123 +/- 4 vs. 123 +/- 3 mmHg). In summary, inhibition of nNOS in pregnant rats at midgestation results in significant decreases in RPF and GFR. nNOS inhibition in virgin rats had no effect on renal hemodynamics. These data suggest that nNOS may play a role in mediating the renal hemodynamic changes that occur during pregnancy.

Role of nNOS in regulation of renal function in angiotensin II-induced hypertension.

Previous studies have indicated that in normotensive rats, NO produced by neuronal NO synthase (nNOS) plays an important role in modulating tubuloglomerular feedback (TGF)-mediated afferent arteriolar constriction. It has also been shown that in angiotensin (Ang) II-infused hypertensive rats, there is a reduced ability of nNOS-derived NO to counteract this vasoconstriction. The present study was performed to (1) assess in vivo renal functional responses to intrarenal nNOS inhibition in control and Ang II-infused rats and (2) determine whether changes in renal function following nNOS inhibition are mediated by unopposed stimulation of Ang II receptor subtype 1 (AT(1)). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SAL- and Ang II-infused rats on day 13 after implantation averaged 121+/-4 (n=28) and 151+/-5 (n=30), respectively (P<0.05). There were no differences in glomerular filtration rate (GFR) (0.68+/-0.09 versus 0.59+/-0.09 mL. min(-1). g(-1)), renal plasma flow (RPF) (2.66+/-0.31 versus 2.34+/-0.39 mL. min(-1). g(-1)), and absolute sodium excretion (0.37+/-0.07 versus 0.42+/-0.09 micromol. min(-1). g(-1)). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n=7) or Ang II-infused rats (n=8). Acute intrarenal administration of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.3 mg/h) decreased GFR, RPF, and sodium excretion in SAL-infused rats (n=9) by 29+/-4%, 38+/-4%, and 70+/-4% compared with control values (P<0.05). The pretreatment by the AT(1) receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n=7) effectively prevented the decrease in RPF (-3+/-3%) elicited by nNOS inhibition and resulted in an increase in GFR (+25+/-12, P<0.05) and a concomitant greater increase in sodium excretion (84+/-12%, P<0.05) compared with control values. In contrast, in Ang II-infused rats (n=10) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (-2+/-2%, -15+/-10%, and -14+/-10%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II-mediated vasoconstriction in the pre- and postglomerular microcirculation. Furthermore, Ang II-infused rats exhibit an impaired ability to release NO by nNOS. Decreased nNOS activity is likely to account at least partially for the enhanced TGF responsiveness in Ang II-infused rats and thus may contribute to the maintenance of hypertension in this model.

Angiotensin II–Induced Hypertension in Bradykinin B 2 Receptor Knockout Mice

The present study was performed to examine the role of endogenous bradykinin (BK) in the development of angiotensin II (Ang II)-induced hypertension in mice. BK B2receptor knockout (B2R-/-) and wild-type (B2R+/+) mice (22to 26 g) were infused with either saline (SAL) or Ang II (40ng/min) via an osmotic minipump implanted intraperitoneally. On day 12after implantation, there was no difference in systolic blood pressure (SBP, tail-cuff plethysmography) between SAL/B2R+/+ and SAL/B2R-/- mice(128+/-5 versus 133+/-6 mm Hg, n=24/group). In contrast, SBP was higher on day 12 of infusion in Ang II/B2R-/- than in Ang II/B2R+/+ mice (173+/-6versus 156+/-5 mm Hg; P<0.05, n=27 and 28). Mean arterial pressure (MAP)was also higher in anesthetized Ang II/B2R-/- mice than in Ang II/B2R+/+mice (139+/-3 versus 124+/-3 mm Hg; P<0.05, n=16 and 14). Unlike Ang II, long-term norepinephrine (NE) infusion via an osmotic minipump (45ng/min) caused equivalent increases in SBP in B2R+/+ and B2R-/- mice measured on day 12 after implantation (151+/-4 versus 149+/-5 mm Hg, n=9and 8). MAP also did not differ on day 13 after implantation between NE/B2R+/+ and NE/B2R-/- mice (120+/-6 versus 122+/-4 mm Hg, n=9 and 8). There were no differences in glomerular filtration rate and urinary sodium excretion among the groups. However, renal plasma flow (RPF) was lower in Ang II/B2R-/- mice than in Ang II/B2R+/+ mice (2.34+/-0.06 versus 4.33+/-0.19 mL x min-1 x g-1; P<0.05). Acute inhibition of NO synthase (NOS)with nitro-L-arginine-methyl ester (0.5 microg x g-1 x min-1) in SAL/B2+/+ and SAL/B2-/- mice caused equal increases in MAP (142+/-1 versus 145+/-1 mmHg) and decreases in RPF (2.06+/-0.06 versus 2.12+/-0.15 mL x min-1 x g-1).However, short-term NOS inhibition caused a greater increase in MAP of Ang II/B2R+/+ mice than of Ang II/B2R-/- mice, such that MAP after NOS inhibition in Ang II/B2R+/+ approached that of Ang II/B2R-/- mice (156+/-2versus 159+/-2 mm Hg). These changes were associated with a decrease in RPF in Ang II/B2R+/+ mice to values similar to those of Ang II/B2R-/- mice before NOS inhibition (2.12+/-0.09 versus 2.34+/-0.06 mL x min-1 x g-1). These results demonstrate that the kallikrein-kinin system selectively buffers the vasoconstrictor activity of Ang II. Furthermore, the enhanced susceptibility of B2R-/- mice to Ang II-induced hypertension and renal vasoconstriction is likely due to an impaired ability to release NO by endogenous kinins.