The effect of orally administered nitrate on renal function and blood pressure in a randomized, placebo-controlled, crossover study in healthy subjects.

BACKGROUND: Several studies have shown inorganic nitrate/nitrite to reduce blood pressure in both healthy subjects and hypertensive patients. An effect presumably caused through bioconversion to nitric oxide. However, studies on inorganic nitrate/nitrite have shown inconsistent results on renal functions such as GFR and sodium excretion. The current study investigated whether orally administered nitrate would decrease blood pressure and increase GFR and urinary sodium excretion. METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 18 healthy subjects received a daily dose of 24 mmol potassium nitrate and placebo (potassium chloride) during 4 days in a randomized order. Subjects also ingested a standardized diet and completed a 24-h urine collection. GFR was determined by the constant infusion technique and during GFR measurement, brachial blood pressure (BP) and central blood pressure (cBP), heart rate, and arterial stiffness were measured every half hour using the Mobil-O-Graph®. Blood samples was analyzed for nitrate, nitrite, cGMP, vasoactive hormones and electrolytes. Urine was analyzed for nitrate, nitrite, cGMP, electrolytes, ENaCγ, NCC, CrCl, CH2O and UO. RESULTS: No differences in GFR, blood pressure or sodium excretion were found between the treatments with potassium nitrate and placebo. However, both nitrate and nitrite levels in plasma and urine were significantly increased by potassium nitrate intake and the 24-h urinary excretion of sodium and potassium were stable, showing adherence to the standardized diet and the study medication. CONCLUSION: We found no decrease in blood pressure or increase in GFR and sodium excretion of 24 mmol potassium nitrate capsules as compared to placebo after 4 days of treatment. Healthy subjects may be able to compensate the effects of nitrate supplementation during steady state conditions. Future research should focus on long-term studies on the difference in response between healthy subjects and patients with cardiac or renal disease.

Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement - a randomized trial.

BACKGROUND: Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. METHODS: In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. RESULTS: IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] µg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] µg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064). FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019). CONCLUSION: A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015.

Urine concentration ability is reduced to the same degree in adult dominant polycystic kidney disease compared with other chronic kidney diseases in the same CKD-stage and lower THAN in healthy control subjects - a CASE control study.

BACKGROUND: Concentration of the urine is primarily regulated via vasopressin dependent aquaporin-2 water channels in the apical membrane of kidney principal cells. It is unclear whether urine concentration ability in ADPKD differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine concentration ability in ADPKD patients compared to non-ADPKD patients and healthy controls. METHODS: A seventeen hour long water deprivation test was carried out in 17 ADPKD patients (CKD I-IV), 16 non-ADPKD patients (CKD I-IV), and 18 healthy controls. Urine was collected in 4 consecutive periods during water deprivation (12 h, 1 h, 2 h and 2 h, respectively) and analyzed for osmolality (u-Osm), output (UO), fractional excretion of sodium (FENa), aquaporin2 (u-AQP2) and ENaC (u-ENaC). Blood samples were drawn trice (after 13-, 15-, and 17 h after water deprivation) for analyses of osmolality (p-Osm), vasopressin (p-AVP), and aldosterone (p-Aldo). RESULTS: U-Osm was significantly lower and FENa significantly higher in both ADPKD patients and non-ADPKD patients compared to healthy controls during the last three periods of water deprivation. During the same periods, UO was higher and secretion rates of u-AQP2 and u-ENaC were lower and at the same level in the two groups of patients compared to controls. P-AVP and p-Osm did not differ significantly between the three groups. P-Aldo was higher in both groups of patients than in controls. CONCLUSIONS: Urine concentration ability was reduced to the same extent in patients with ADPKD and other chronic kidney diseases with the same level of renal function compared to healthy controls. The lower urine excretion of AQP2 and ENaC suggests that the underlying mechanism may be a reduced tubular response to vasopressin and aldosterone. TRIAL REGISTRATION: Current Controlled Trial NCT04363554 , date of registration: 20.08.2017.

Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects - a randomized controlled trial.

BACKGROUND: Chloride is speculated to have nephrotoxic properties. In healthy subjects we tested the hypothesis that acute chloride loading with 3% saline would induce kidney injury, which could be prevented with the loop-diuretic furosemide. METHODS: The study was designed as a randomized, placebo-controlled, crossover study. Subjects were given 3% saline accompanied by either placebo or furosemide. Before, during and after infusion of 3% saline we measured glomerular filtration rate (GFR), fractional excretion of sodium (FENa), urinary chloride excretion (u-Cl), urinary excretions of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ), neutrophil gelatinase-associated lipocalin (u-NGAL) and kidney injury molecule-1 (u-KIM-1) as marker of kidney injury and vasoactive hormones: renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and arginine vasopressin (p-AVP). Four days prior to each of the two examinations subjects were given a standardized fluid and diet intake. RESULTS: After 3% saline infusion u-NGAL and KIM-1 excretion increased slightly (u-NGAL: 17 ± 24 during placebo vs. -7 ± 23 ng/min during furosemide, p = 0.039, u-KIM-1: 0.21 ± 0.23 vs - 0.06 ± 0.14 ng/ml, p <  0.001). The increase in u-NGAL was absent when furosemide was given simultaneously, and the responses in u-NGAL were not significantly different from placebo control. Furosemide changed responses in u-KIM-1 where a delayed increase was observed. GFR was increased by 3% saline but decreased when furosemide accompanied the infusion. U-Na, FENa, u-Cl, and u-osmolality increased in response to saline, and the increase was markedly pronounced when furosemide was added. FEK decreased slightly during 3% saline infusion, but simultaneously furosemide increased FEK. U-AQP2 increased after 3% saline and placebo, and the response was further increased by furosemide. U-ENaCγ decreased to the same extent after 3% saline infusion in the two groups. 3% saline significantly reduced PRC, p-AngII and p-Aldo, and responses were attenuated by furosemide. p-AVP was increased by 3% saline, with a larger increase during furosemide. CONCLUSION: This study shows minor increases in markers of kidney injury after 3% saline infusion Furosemide abolished the increase in NGAL and postponed the increase in u-KIM-1. The clinical importance of these findings needs further investigation. TRIAL REGISTRATION: (EU Clinical trials register number: 2015-002585-23 , registered on 5th November 2015).

Renal and hormonal effects of systemic nitric oxide inhibition in patients with congestive heart failure and in healthy control subjects.

BACKGROUND: The 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 RESULTS: We studied the effects of acute systemic NO synthesis inhibition with N(G)-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). CONCLUSIONS: There 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.

Comparison of [18F] NaF PET/CT dynamic analysis methods and a static analysis method including derivation of a semi-population input function for site-specific measurements of bone formation in a population with chronic kidney disease-mineral and bone disorder.

PURPOSE: The purpose of this study is to compare dynamic and static whole-body (WB) [18F]NaF PET/CT scan methods used for analysis of bone plasma clearance in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). METHODS: Seventeen patients with CKD-MBD underwent a 60-min dynamic scan followed by a 30-min static WB scan. Tracer kinetics in four thoracic vertebrae were analysed using nonlinear regression and Patlak analysis using image-derived arterial input functions. The static WB scan was analysed using a simplified Patlak method requiring only a single data point in combination with a fixed y-intercept value (V0), both obtained using a semi-population function. The semi-population function was constructed by combining a previously derived population input function in combination with data from venous blood samples. Static WB scan analysis data, obtained from the semi-population input functions, was compared with paired data obtained using dynamic input functions. RESULTS: Bone plasma clearance (Ki) from Patlak analyses correlated well with nonlinear regression analysis, but Ki results using Patlak analysis were lower than Ki results using nonlinear regression analysis. However, no significant difference was found between Ki obtained by static WB scans and Ki obtained by dynamic scans using nonlinear regression analysis (p = 0.29). CONCLUSION: Bone plasma clearance measured from static WB scans correlates with clearance data measured by dynamic analysis. Static [18F]NaF PET/CT scans can be applied in future studies to measure Ki in patients with CKD-MBD, but the results should not be compared uncritically with results obtained by dynamic scan analysis.

A Comparison of Urine Dilution Ability between Adult Dominant Polycystic Kidney Disease, Other Chronic Kidney Diseases, and Healthy Control Subjects: A Case-Control Study.

The final dilution of urine is regulated via aquaporin-2 water channels in the distal part of the nephron. It is unclear whether urine dilution ability in autosomal dominant polycystic kidney disease patients (ADPKD patients) differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine dilution ability in ADPKD patients compared to non-ADPKD patients and healthy controls. Methods. Eighteen ADPKD, 16 non-ADPKD patients (both with chronic kidney disease, stage I-IV), and 18 healthy controls received an oral water load of 20 ml/kg body weight. Urine was collected in 7 consecutive periods. We measured free water clearance (CH2O), urine osmolality, urine output, fractional excretion of sodium, urine aquaporin2 (u-AQP2), and urine epithelial sodium channel (u-ENaC). Blood samples were drawn four times (at baseline, 2 h, 4 h, and 6 hours after the water load) for analyses of plasma osmolality, vasopressin, renin, angiotensin II, and aldosterone. Brachial and central blood pressure was measured regularly during the test. Results. The three groups were age and gender matched, and the patient groups had similar renal function. One hour after water load, the ADPKD patients had an increased CH2O compared to non-ADPKD patients (2.97 ± 2.42 ml/min in ADPKD patients vs. 1.31 ± 1.50 ml/min in non-ADPKD patients, p0.029). The reduction in u-AQP2 and u-ENaC occurred earlier in ADPKD than in non-ADPKD patients. Plasma concentrations of vasopressin, renin, angiotensin II, and aldosterone and blood pressure measurements did not show any differences that could explain the deviation in urine dilution capacity between the patient groups. Conclusions. ADPKD patients had a higher CH2O than non-ADPKD patients after an oral water load, and u-AQP2 and u-ENaC were more rapidly reduced than in non-ADPKD patients. Thus, urine-diluting capacity may be better preserved in ADPKD patients than in non-ADPKD patients.

Glomerular filtration rate and blood pressure are unchanged by increased sodium intake in atorvastatin-treated healthy men.

OBJECTIVE: Improved cardiovascular survival during statin treatment might be due to effects in addition to cholesterol lowering. We hypothesize that sodium intake affects renal function and vasoactive hormones in atorvastatin-treated healthy subjects. METHODS: In a randomized, placebo-controlled, double-blind, crossover study we measured the effect of a moderate change in sodium intake on glomerular filtration rate (GFR), blood pressure (BP), renal tubular function, plasma concentrations of vasoactive hormones and urinary excretion of aquaporin-2 (u-AQP2) in 22 healthy subjects. The subjects were randomized to standardized fluid intake and diet corresponding to the need for calories in the 4 days before each of the 2 examination days. In one of the periods they were randomized to receive sodium chloride tablets (2 g) thrice daily for 4 days. Two doses of atorvastatin (80 mg) were given; one at 2200 h the evening before the study day, the other at 0830 h in the morning. RESULTS: 24-h urinary sodium excretion increased by 23%. GFR and BP were unchanged. Sodium clearance, fractional excretion of sodium and u-AQP2 increased, whereas free water clearance decreased during high sodium intake. PRC and aldosterone were suppressed during the high sodium diet. CONCLUSIONS: A change in dietary sodium intake of approximately 100 mmol daily does not change GFR and BP in atorvastatin-treated healthy men. The lack of change in BP might reflect that the subjects studied were not sodium sensitive, or that atorvastatin treatment modified sodium sensitivity.

Short-term telemedical home blood pressure monitoring does not improve blood pressure in uncomplicated hypertensive patients.

Telemonitoring of home blood pressure measurements (TBPM) is a new and promising supplement to diagnosis, control and treatment of hypertension. We wanted to compare the outcome of antihypertensive treatment based on TBPM and conventional monitoring of blood pressure. Participants were recruited from a prevalence study among citizens aged 55-64 years in the municipality of Holstebro, Denmark. The study was a randomized, controlled, unblinded 3 months' trial. In the intervention group, antihypertensive treatment was based on TBPM with transmission of the measurements and subsequent communication by telephone or e-mail. In the control group, patients received usual care. Primary outcome was reduction in daytime ambulatory blood pressure measurements (ABPM) from baseline to 3 months' follow-up. Of 375 participants randomized, primary outcome data were available for 356 (95%). In both groups, daytime ABPM decreased significantly. The decrease in daytime ABPM in the intervention group was systolic/diastolic, -8±12/-4±7 mm Hg. This did not differ significantly from the control group's -8±13/-4±8 mm Hg. An equal number of participants obtained normal daytime ABPM, in the intervention group 17% (31/175) versus control 21% (37/181), P=0.34. We found that both TBPM patients and controls achieved a significant blood pressure reduction in this randomized, controlled, unblinded 3-month trial. We found no difference in blood pressure reduction or number of patients reaching blood pressure goals. Further information and education of some general practitioners seem to be relevant regarding blood pressure management and control of hypertension.

L-arginine-induced growth hormone secretion is not influenced by co-infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine in healthy men.

In animals, it has been demonstrated that nitric oxide (NO) is a potent neuroregulatory substance. By intravenous infusion, L-arginine is converted to NO and citrulline, but it is unknown whether NO is responsible for the GH stimulating effect of L-arginine in humans. We investigated whether intravenous infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) influenced L-arginine stimulated GH secretion. Ten healthy men, aged 28.6 +/- 1.9 (mean +/- SEM) years were examined twice. L-arginine was infused intravenously in a dose of 0.5 g/kg, max 35 g, from 0 to 30 min, accompanied by either: (1) L-NMMA from -5 to 0 min, in a dose of 3 mg/kg, max 250 mg, and in a dose of 3.5 mg/kg, max 250 mg from 0 to 60 min; or (2) a saline infusion. Heart rate increased (P = 0.032), and diastolic blood pressure decreased (P < 0.001) in the two situations. Plasma cGMP was unchanged and identical in the two situations (P = 0.679). Urine cGMP/creatinine ratio increased during both examinations (P = 0.041). Growth hormone secretion increased significantly during L-arginine infusion (P = < 0.001) without any effect of L-NMMA (P = 0.848). We did not find evidence that NO influences GH secretion. It remains to be tested, however, whether a higher dose of L-NMMA may influence L-arginine stimulated GH secretion.

Acute effects of atorvastatin on glomerular filtration rate, tubular function, blood pressure, and vasoactive hormones in patients with type 2 diabetes.

Statins improve cardiovascular survival in both nondiabetic and diabetic patients, but diabetic patients benefit more, in both primary and secondary prevention. Statins seem to have multiple effects beyond cholesterol lowering, that is, pleiotropic effects that may include changes in renal function. This study tests the hypothesis that acute treatment with atorvastatin may change glomerular filtration rate, tubular function, vasoactive hormones, blood pressure, and pulse rate in patients with type 2 diabetes. In an acute, randomized, placebo-controlled, double-blinded, crossover trial, the effects of atorvastatin on renal function, vasoactive hormones, blood pressure, and pulse rate are measured in 21 patients with type 2 diabetes. Patients are randomized to either 2 doses of atorvastatin 80 mg or placebo before 2 different study days. Treatment with atorvastatin induces a significant reduction in fractional sodium excretion compared with placebo, and sodium clearance tends to be reduced. No significant differences in glomerular filtration rate, albumin/creatinine ratio, vasoactive hormones, and blood pressure by acute treatment with atorvastatin are found in diabetic patients. Acute treatment with atorvastatin reduces renal fractional sodium excretion in patients with type 2 diabetes. No changes are measured in glomerular filtration rate, albumin/creatinine ratio, vasoactive hormones, and blood pressure.

Increased urinary aquaporin-2 excretion in response to furosemide in patients with chronic heart failure.

OBJECTIVE: Patients with chronic heart failure (CHF) have decreased ability to excrete water and increased urinary excretion of aquaporin-2 (U-AQP2). The natriuretic and diuretic effects of furosemide are antagonized by an increased reabsorption of sodium and water in the collecting ducts. It is unknown whether aquaporin-2 (AQP2) renal water channels are involved in this compensatory reabsorption. We tested the hypothesis that U-AQP2 increases after a single intravenous dose of furosemide in CHF patients. MATERIAL AND METHODS: In a randomized, single-blind, placebo-controlled, crossover study, we measured the effect of furosemide (80 mg) on U-AQP2, urine volume, free water clearance (C(H2O)) and fractional excretion of sodium (FE(Na)) in 12 CHF patients. Plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), atrial (ANP) and brain natriuretic peptides (BNP) were measured during the study. U-AQP2 and hormones were determined by radioimmunoassays. RESULTS: Furosemide increased U-AQP2 (140 %), urine volume (280 %), C(H2O) (95 %) and FE(Na) by a factor of 15 (p<0.008 for all), and also AVP (51 %), PRC, Ang II (86 %) and Aldo (59 %) (p<0.021 for all). ANP and BNP did not change. CONCLUSIONS: In CHF, furosemide increased the vasopressin level, which stimulated water reabsorption via the APQ2 water channels. This is most likely a compensatory phenomenon in addition to the increase in the renin-angiotensin system to prevent excess loss of sodium and water. However, both these effects were overridden by the effect of furosemide, as shown by increased free water clearance and sodium excretion.

Urinary excretion of alpha-GST and albumin in rheumatoid arthritis patients treated with methotrexate or other DMARDs alone or in combination with NSAIDs.

OBJECTIVE: To evaluate the effect of methotrexate (MTX) and other disease-modifying anti-rheumatic drugs (DMARDs) alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) on the urinary excretion of alpha-glutathione S-transferase (alpha-GST) and albumin in rheumatoid arthritis (RA) patients. METHODS: Nineteen RA patients starting treatment with MTX were followed for 1 year with measurements of urinary alpha-GST, urinary albumin, and urinary and plasma creatinine at the start of treatment, and after 16, 28, and 52 weeks. A larger group of RA patients (n = 72) undergoing long-term treatment with different DMARDs was compared with 79 healthy controls regarding urinary alpha-GST and albumin. alpha-GST was quantified by an enzyme immunoassay. Urine albumin was measured turbidimetrically. RESULTS: The urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio did not change during 52 weeks of treatment with MTX. The long-term DMARD-treated RA patients and the healthy controls were comparable with regard to the urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio. All patients had preserved renal function as assessed by plasma creatinine, and none had proteinuria using urine dipstick methods. CONCLUSION: DMARD-treated RA patients with normal serum creatinine had no detectable renal injuries assessed by the urinary excretions of alpha-GST and albumin.

Epoprostenol increases plasma level of atrial natriuretic peptide in humans.

1. In a placebo-controlled, randomized dose-response study the effect of the prostaglandin analogue epoprostenol (Flolan) on the plasma level of atrial natriuretic peptide has been investigated in 14 healthy control subjects. 2. During epoprostenol infusion, atrial natriuretic peptide increased significantly in a dose-dependent manner, while it remained unchanged during placebo infusion [2 ng min-1 kg-1: epoprostenol 13.2% versus placebo -2.9%; 4 ng min-1 kg-1: epoprostenol 13.4% versus placebo -6.1%; 8 ng min-1 kg-1: epoprostenol 40.7% versus placebo -7.8% (medians), P < 0.01 for all]. 3. Mean blood pressure and heart rate increased significantly after epoprostenol, but were unchanged during placebo infusion [8 ng min-1 kg-1; mean blood pressure: epoprostenol -5.6% versus placebo 3.2%; heart rate: epoprostenol 32.7% versus placebo 3.1% (medians), P < 0.01]. 4. It is concluded that epoprostenol given intravenously increases the plasma level of atrial natriuretic peptide. The results support the hypothesis of an interaction between the prostaglandin system and atrial natriuretic peptide.

Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans.

Animal studies have implicated an important role of nitric oxide (NO) in the regulation of blood pressure, renal hemodynamics, and renal excretion of sodium. NG-monomethyl-L-arginine (L-NMMA) is a specific, competitive inhibitor of NO synthesis interfering with NO synthase. The purpose of the present study was to investigate the effect of L-NMMA on renal plasma flow (RPF), glomerular filtration rate (GFR), urinary sodium excretion (UNa), fractional sodium excretion (FENa), fractional lithium excretion (FELi), mean arterial blood pressure (MAP), and heart rate (HR) in healthy humans. In a randomized placebo-controlled study, 23 healthy subjects were randomized to receive either bolus injection of L-NMMA (3 mg/kg in 10 ml saline, n = 12 subjects) or placebo (10 ml saline, n = 11). GFR and RPF were measured using the renal clearances of 51Cr-labeled EDTA and 125I-labeled hippuran by the constant infusion technique. L-NMMA treatment induced 60 min after injection a 14.6% decrease in RPF, a 5.8% decrease in GFR, a 9.8% increase in filtration fraction, a 34.7% decrease in UNa a 28.6% decrease in FENa, and a 12.1% decrease in FELi. These changes were still evident 120 min after injection. None of the effect parameters were changed after placebo, except FENa, which increased 9.9% 60 min after injection. Ten minutes after L-NMMA injection, MAP increased significantly (80 vs. 88 mmHg), and HR decreased (58 vs. 47 beats/min). The changes in HR and MAP normalized within 30 min. L-NMMA significantly reduced the plasma level of cGMP 60 min (3.0 vs. 3.7 pmol/l) and 120 min after injection (2.5 vs. 3.7 pmol/l). It is concluded that, in healthy humans, NO is a regulator of renal hemodynamics as a tonic vasodilator and a regulator of sodium excretion, due at least in part to a proximal tubular effect.

Effects of prostacyclin on renal haemodynamics, renal tubular function and vasoactive hormones in healthy humans. A placebo-controlled dose-response study.

AIMS: To investigate the acute effects of prostacyclin (Flolan) on renal haemodynamics, renal tubular function, plasma concentration of angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP), arginine vasopressin (AVP), mean arterial blood pressure (MBP), and heart rate (HR). METHODS: Thirteen healthy control subjects were investigated on two separate occasions in a placebo controlled, randomized, dose-response study of the effect of intravenous infusion of prostacyclin (PGI2, Flolan, 2, 4 and 8 ng kg(-1) min(-1)). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the use of constant infusion of [51Cr]-EDTA and [125I]-hippurane. Urinary output, urinary sodium excretion, fractional sodium excretion, fractional lithium excretion were measured and hormones were measured using radioimmunoassay. RESULTS: During prostacyclin (PGI2) infusion we observed a significant increase in RPF (PGI2: 4.8%; 6.1% and 5.2% vs Plac: -1.5%; -1.9% and -5.8% for 2, 4 and 8 ng kg(-1) min(-1) respectively; P < or = 0.05 for 4 and 8 ng kg(-1) min(-1)) in Ang II (PGI2: 20.0%; 42.9% and 88.9% vs Plac: 0.1%; 8.0% and 0.0%, P < or = 0.01 for 4 and 8 ng kg(-1) min(-1)) in ANP (PGI2: 13.6%; 12.7% and 37.5% vs Plac: -10.2%; -6.6% and -2.4%, P < or = 0.05 for 2 ng kg(-1) min(-1) and P < or = 0.01 for 4 and 8 ng kg(-1) min(-1)), and in HR (PGI2: 8.8%; 17.6% and 32.7% vs Plac: 0.8%; 4.1% and 3.5%, P < or = 0.05 for 2 and P < or = 0.01 for 4 and 8 ng kg(-1) min(-1)). A significant decrease was observed in MBP (MBP:PGI2: -1.7%; -1.9% and -5.6% vs Plac: -0.4%; -1.6% and +2.1%, P < or = 0.01 for 8 ng kg(-1) min(-1)). No significant changes were seen in the other effect variables. CONCLUSIONS: Infusion of prostacyclin in healthy control subjects increases renal plasma flow, angiotensin II, atrial natriuretic peptide, and heart rate and decreases mean blood pressure. Furthermore prostacyclin infusion does not change net sodium excretion in healthy controls.

A comparison of the effects of etodolac and ibuprofen on renal haemodynamics, tubular function, renin, vasopressin and urinary excretion of albumin and alpha-glutathione-S-transferase in healthy subjects: a placebo-controlled cross-over study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be potentially nephrotoxic agents. NSAIDs inhibit the enzyme cyclo-oxygenase and thereby block the prostaglandin synthesis in the kidneys. Cyclo-oxygenase exists in two isoforms (COX-1 and COX-2). It has been proposed that NSAIDs with preferential COX-2 selectivity have fewer renal side effects than drugs with preferential COX-1 selectivity. Etodolac is a relative selective inhibitor of COX-2, while ibuprofen has a higher potency against COX-1 than COX-2. OBJECTIVE: In this study, we compared the effects of etodolac and ibuprofen on renal function, plasma renin, plasma arginine vasopressin and the urinary excretion of albumin and alpha-glutathione-S-transferase (alpha-GST). METHODS: In a randomised, double-blind, three-way crossover study with placebo, we compared the effects of 2 weeks of treatment with ibuprofen and etodolac on renal haemodynamics [glomerular filtration rate (GFR), renal plasma flow (RPF) and filtration fraction (FF)], tubular function and plasma concentrations of the hormones renin (PRC) and arginine vasopressin (AVP) in 18 healthy subjects. In addition, we examined the effects on the urinary excretion of albumin and alpha-GST as markers of renal injury. RESULTS: No differences were found between the three treatments, placebo, ibuprofen and etodolac, in the effects on GFR, RPF, FF, free water clearance, urinary output or fractional excretion of potassium and sodium. However, ibuprofen, in contrast to etodolac, caused a significant decrease in both lithium clearance (-16% versus placebo) and the fractional excretion of lithium (-17% versus placebo), suggesting an increase in the reabsorption in the proximal tubuli. PRC was reduced significantly by ibuprofen (-32% versus placebo) but not etodolac. None of the drugs changed AVP. Fourteen days of treatment with ibuprofen caused a significant decrease (-47% versus placebo) in the urinary excretion of alpha-GST, while no changes were seen after etodolac. None of the drugs changed the urinary excretion of albumin. CONCLUSION: In conclusion, a 14-day administration of etodolac or ibuprofen in therapeutic doses did not affect the renal haemodynamics, the net excretion of electrolytes or the urinary excretion of albumin in healthy subjects. However, ibuprofen, in contrast to etodolac, caused a reduction in PRC, suggesting that COX-1 is involved in basal renin release in humans. Furthermore, ibuprofen decreased lithium excretion suggesting that COX-1 is involved in the re-absorption of sodium and/or water in the proximal tubuli. The reduction in the urinary excretion of alpha-GST by ibuprofen may be caused by an inhibition of the detoxification enzyme by ibuprofen. Overall the study indicates that only small differences in the effects of the two drugs on renal function in healthy subjects exist during a treatment period of 2 weeks.

Urinary aquaporin-2 in healthy humans and patients with liver cirrhosis and chronic heart failure during baseline conditions and after acute water load.

BACKGROUND: Patients with liver cirrhosis and chronic heart failure (CHF) have a reduced capacity to excrete water. Studies in healthy humans have shown that an acute water load reduces the excretion of aquaporin-2 in urine (u-AQP-2). We wanted to test the hypothesis that an acute water load reduces u-AQP-2 less in patients with liver cirrhosis or CHF than in healthy humans. METHODS: Fourteen healthy subjects, 14 patients with liver cirrhosis, and 14 patients with CHF were given an oral water load of 20 mL/kg. Urine was collected every 30 minutes for 4 hours for analysis of u-AQP-2. Blood samples were drawn at the beginning and at the end of the study for analysis of arginine vasopressin (AVP). u-AQP-2 was determined by radioimmunoassay. RESULTS: During the study period, urinary output was 22.8% higher than water intake in the healthy controls and increased 14-fold from baseline, but in patients with liver cirrhosis and CHF urinary output was 14% and 24% less than the intake, while urinary output increased 7- and 19-fold from baseline, respectively. u-AQP2 decreased significantly more in patients with CHF (39%) than in healthy controls (17%) but it was unchanged in those with liver cirrhosis. AVP decreased 46% in patients with CHF, but was unchanged in healthy controls and those with liver cirrhosis. A 24-hour urinary excretion of AQP-2 was significantly elevated in patients with CHF (median, 25.7 nmol/mol creatinine) compared to healthy controls (15.7 nmol/mol creatinine) and those with liver cirrhosis (17 nmol/mol creatinine). CONCLUSION: The excretion of AQP-2 in urine is abnormal both in liver cirrhosis in which we find less suppression of u-AQP2 by an acute water load and in CHF in which we find a high baseline level and an exaggerated suppression of u-AQP2 by an acute water load.

The systemic and renal response to NO inhibition is not modified by angiotensin-II-receptor blockade in healthy humans.

BACKGROUND: The role of angiotensin II (Ang II) in the systemic and renal responses to acute nitric oxide (NO) synthesis inhibition has not been studied in detail in healthy humans. The purpose of the present study was to investigate the effects of Ang II receptor blockade on the systemic and renal response to acute treat ment with Ng-monomethyl-L-arginine (L-NMMA) in healthy subjects. METHODS: Mean arterial blood pressure (MAP), renal plasma flow (RPF), glomerular filtration rate (GFR), sodium excretion (UNa*V), and plasma levels of renin, Ang II, ANP, BNP, and cGMP were assessed in 15 healthy sodium replete humans before and after acute L-NMMA treatment (3 mg/kg) on two occasions, i.e. after pretreatment with the Ang II type 1 receptor (AT-1) antagonist candesartan cilexetil (CAND; 8 mg) or placebo in a double blind, randomized fashion. Renal haemodynamics were measured during water diuresis using renal clearances of [125I]hippuran and [51Cr]EDTA. Plasma hormones were measured by radioimmunoassays. RESULTS: On both study days L-NMMA treatment induced a significant increase in MAP and a significant decrease in GFR, RPF, and UNa*V. These effects of L-NMMA were not affected significantly by pretreatment with CAND. The effects of L-NMMA on hormones were roughly similar on both occasions with a drop in P-cGMP and U-cGMP. However, a fall in renin was observed only during CAND pretreatment. CONCLUSIONS: We conclude that Ang II is not a major mediator of acute vasoconstriction and sodium retention during acute lowering of NO activity in healthy man.