Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine.

BACKGROUND: Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. METHODS: Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. RESULTS: Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. CONCLUSIONS: In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.

Relaxin-mediated renal vasodilation in the rat is associated with falls in glomerular blood pressure.

Relaxin (RLX) is a pleiotropic peptide hormone with marked renal vasodilatory actions that are physiologically important during pregnancy. RLX also has potent antifibrotic actions and is being tested therapeutically in various fibrotic diseases, including chronic kidney disease (CKD). Since renal vasodilation may expose the glomerulus to increased blood pressure [glomerular capillary pressure (PGC)], which exacerbates progression of CKD, we assessed the glomerular hemodynamic actions of acute (0.89 µg·100 g body wt-1·h-1 iv over 75 min) and chronic (1.5 µg·100 g body wt-1·h-1 sc) administration of RLX. Both acute and chronic RLX produced marked renal vasodilation and increased renal plasma flow (RPF) in euvolemic, anesthetized male rats. Glomerular filtration rate also increased with RLX, but the magnitude of the rise was much less than the increase in RPF due to concomitant decreases in filtration fraction. The fall in filtration fraction was the result of significant decreases in PGC, despite a slight increase in mean arterial blood pressure (MAP) with acute RLX and no net change in MAP with chronic RLX. This fall in PGC occurred because of the "in-series" arrangement of the afferent and efferent arteriolar resistance vessels, which can regulate PGC independently of MAP. With both acute and chronic RLX, efferent arteriolar resistance vessels relaxed to a greater extent than afferent arteriolar resistance vessels, thus producing falls in PGC. Based on this finding, RLX has a beneficial hemodynamic impact on the kidney, which, together with the antifibrotic actions of RLX, suggests a strong therapeutic potential for use in CKD.

Carbon Monoxide Releasing Molecules Blunt Placental Ischemia-Induced Hypertension.

BACKGROUND: Preeclampsia is a pregnancy complication which manifests as new-onset hypertension, proteinuria, and a spectrum of other symptoms. While the underlying causes are still a subject of much debate, it is commonly believed that placental ischemia is a central cause. The ischemic placenta secretes factors which are believed to be responsible for the maternal syndrome; most notably the anti-angiogenic protein soluble fms-like tyrosine kinase 1 (sFlt-1). We have reported that induction of the carbon monoxide (CO) producing protein heme oxygenase-1 restored angiogenic imbalance and reduced blood pressure in a rat model of placental ischemia, and that CO blocks hypoxia-induced sFlt-1 production from placental tissue in vitro. We therefore hypothesized that direct administration of CO by a CO-releasing molecule (CORM) would blunt the placental ischemia-induced increase in sFlt-1 and thus the hypertension characteristic of this model. METHODS: We administered a soluble CO donor molecule (CORM-3) daily i.v. in control animals or those undergoing placental ischemia from GD14. Blood pressure and renal function were measured on GD19, and angiogenic markers measured by ELISA. RESULTS: Interestingly, though we found that CORM administration significantly blunted the hypertensive response to placental ischemia, there was no concomitant normalization of sFlt-1 in either the placenta or maternal circulation. We did find, however, that CORM administration caused a significant increase in glomerular filtration rate, presumably by vasodilation of the renal arteries and increased renal plasma flow. CONCLUSIONS: All in all these data suggest that administration of CO by CORMs do lower blood pressure during placental ischemia mechanisms independent of changes in angiogenic balance.

Concerted regulation of renal plasma flow and glomerular filtration rate by renal dopamine and NOS I in rats on high salt intake.

Under high sodium intake renal dopamine (DA) increases while NOS I expression in macula densa cells (MD) decreases. To explore whether renal DA and NOS I, linked to natriuresis and to the stability of the tubuloglomerular feedback, respectively, act in concert to regulate renal plasma flow (RPF) and glomerular filtration rate (GFR). Male Wistar rats were studied under a normal sodium intake (NS, NaCl 0.24%) or a high sodium intake (HS, NaCl 1% in drinking water) during the 5 days of the study. For the last two days, the specific D1-like receptor antagonist SCH 23390 (1 mg kg bwt-1 day-1, sc) or a vehicle was administered. HS intake increased natriuresis, diuresis, and urinary DA while it decreased cortical NOS I expression (P < 0.05 vs. NS), Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in MD (P < 0.001 vs. NS) and cortical nitrates+nitrites (NOx) production (NS 2.04 ± 0.22 vs. HS 1.28 ± 0.10 nmol mg protein-1, P < 0.01). Treatment with SCH 23390 to rats on HS sharply decreased hydroelectrolyte excretion (P < 0.001 vs. HS) while NOS I expression, NADPH-d activity and NOx production increased (P < 0.05 vs. HS for NOS I and P < 0.001 vs. HS for NADPH-d and NOx). SCH 23390 increased RPF and GFR in HS rats (P < 0.01 HS+SCH vs. HS). It did not cause variations in NS rats. Results indicate that when NS intake is shifted to a prolonged high sodium intake, renal DA through the D1R, and NOS I in MD cells act in concert to regulate RPF and GFR to stabilize the delivery of NaCl to the distal nephron.

Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy.

During acute administration of native glucagon-like peptide-1 (GLP-1), we previously demonstrated central hemodynamic effects in healthy males, whereas renal hemodynamics, despite renal uptake of GLP-1 in excess of glomerular filtration, was unaffected. In the present study, we studied hemodynamic effects of GLP-1 in patients with type 2 diabetes under fixed sodium intake. During a 3-h infusion of GLP-1 (1.5 pmol·kg(-1)·min(-1)) or saline, intra-arterial blood pressure and heart rate were measured continuously, concomitantly with cardiac output estimated by pulse contour analysis. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured using Fick's Principle after catheterization of a renal vein. Urine collection was conducted throughout the experiments at voluntary voiding, and patients remained supine during the experiments. During the GLP-1 infusion, systolic and diastolic blood pressure and cardiac output remained unchanged, whereas heart rate increased significantly. Arterio-venous gradients for GLP-1 exceeded glomerular filtrations significantly, but renal plasma flow and glomerular filtration rate as well as renal sodium and lithium excretion were not affected. In conclusion, acute administration of GLP-1 in patients with type 2 diabetes leads to a positive chronotropic effect, but in contrast to healthy individuals, cardiac output does not increase in patients with type 2 diabetes. Renal hemodynamics and sodium excretion are not affected.

Chronic Nicotine Exposure Abolishes Maternal Systemic and Renal Adaptations to Pregnancy in Rats.

Pregnancy is characterized by maternal systemic and intrarenal vasodilation, leading to increases in the renal plasma flow (RPF) and glomerular filtration rate (GFR). These responses are mainly mediated by nitric oxide (NO) and relaxin. The impact of cigarette smoking on the maternal adaptations to pregnancy is unclear. Here we evaluated the effects of chronic exposure to nicotine on systemic and intrarenal parameters in virgin (V) and 14-day pregnant (P) Wistar rats. V and P groups received saline or nicotine (6 mg·kg(-1)·day(-1)) respectively, via osmotic minipumps for 28 days, starting 14 days before pregnancy induction. Nicotine induced a 10% increase in blood pressure in the V group and minimized the characteristic pregnancy-induced hypotension. Renal sympathetic nerve activity (rSNA) and baroreflex sensitivity were impaired by nicotine mainly in the P group, indicating that the effect of nicotine on blood pressure was not mediated by nervous system stimulation. Nicotine had no effect on GFR in the V rats but reduced GFR of the P group by 30%. Renal expression of sodium and water transporters was downregulated by nicotine, resulting in increased fractional sodium excretion mainly in the P group, suggesting that nicotine compromised the sodium and water retention required for normal gestation. There was a reduction in the expression of inducible NO synthase (iNOS) in both the kidney tissue and renal artery, as well as in the expression of the relaxin receptor (LGR7). These results clearly show that nicotine induced deleterious effects in both virgin and pregnant animals, and abolished the maternal capacity to adapt to pregnancy.

Hemodynamic and metabolic effects of estrogen plus progestin therapy in hypertensive postmenopausal women treated with an ACE-inhibitor or a diuretic.

OBJECTIVES: The aim of the study was to assess the hemodynamic and metabolic actions of estrogen plus progestin therapy (EPT) in hypertensive, postmenopausal women treated with perindopril (ACEI) or hydrochlorothiazide (HCTZ). A group of normotensive postmenopausal women was also studied. METHODS: 100 hypertensive and 40 normotensive postmenopausal women were recruited for the study. The hypertensive females were randomly assigned to receive ACEI or HCTZ for 12 months. The patients of the ACEI group and the patients of the HCTZ group, as well as normotensives, were further subdivided into two subgroups each. One subgroup received estrogen plus progestin therapy (EPT+), the other subgroup received no hormone replacement (EPT-). Combined hormone replacement with transdermal patches releasing 17ß-estradiol and norethisterone was used. Office and 24-hour ambulatory blood pressure was measured at baseline and during follow-up. Renal plasma flow (RPF) was measured using the clearance of [125I]-iodohippuran. Pulse wave velocity (PWV) was determined with an automatic device. RESULTS: In normotensive postmenopausal women, transdermal estrogen plus progestin therapy increases RPF and insulin sensitivity, decreases PWV, decreases total and LDL cholesterol, and decreases uric acid serum levels. Perindopril (4 mg/day) and hydrochlorothiazide (25 mg/day) were equally effective in reducing blood pressure in postmenopausal, hypertensive subjects. In these females, perindopril increased RPF and decreased PWV and plasma insulin levels. These effects of the ACEI were not altered by estrogen plus progestin therapy. Hydrochlorothiazide decreased RPF and increased plasma insulin and uric acid concentrations in hypertensive subjects whom were not receiving estrogen plus progestin therapy. CONCLUSIONS: The unfavorable metabolic and hemodynamic actions of the diuretic were counteracted by estrogen plus progestin therapy. Concomitant estrogen plus progestin therapy may be a method to avoid unfavorable hemodynamic and metabolic effects of thiazide diuretics in hypertensive, postmenopausal women.

Differential effect of T-type voltage-gated Ca2+ channel disruption on renal plasma flow and glomerular filtration rate in vivo.

Voltage-gated Ca(2+) (Cav) channels play an essential role in the regulation of renal blood flow and glomerular filtration rate (GFR). Because T-type Cav channels are differentially expressed in pre- and postglomerular vessels, it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed with the use of two T-type Cav knockout (Cav3.1(-/-) and Cav3.2(-/-)) mouse strains. Continuous recordings of blood pressure and heart rate, para-aminohippurate clearance (renal plasma flow), and inulin clearance (GFR) were performed in conscious, chronically catheterized, wild-type (WT) and Cav3.1(-/-) and Cav3.2(-/-) mice. The contractility of afferent and efferent arterioles was determined in isolated perfused blood vessels. Efferent arterioles from Cav3.2(-/-) mice constricted significantly more in response to a depolarization compared with WT mice. GFR was increased in Cav3.2(-/-) mice with no significant changes in renal plasma flow, heart rate, and blood pressure. Cav3.1(-/-) mice had a higher renal plasma flow compared with WT mice, whereas GFR was indistinguishable from WT mice. No difference in the concentration response to K(+) was observed in isolated afferent and efferent arterioles from Cav3.1(-/-) mice compared with WT mice. Heart rate was significantly lower in Cav3.1(-/-) mice compared with WT mice with no difference in blood pressure. T-type antagonists significantly inhibited the constriction of human intrarenal arteries in response to a small depolarization. In conclusion, Cav3.2 channels support dilatation of efferent arterioles and affect GFR, whereas Cav3.1 channels in vivo contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav3.2 and Cav3.1, respectively, may account for the observed effects.

Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (ß=-4.60; P<0.0001) and higher SASSI (ß=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

Renal effects of NO-inhibition in patients with cirrhosis vs. healthy controls: a randomized placebo-controlled crossover study.

BACKGROUND: Nitric oxide (NO) is an important regulator of renal hemodynamics and sodium excretion. Systemic and splanchnic NO-synthesis is increased in liver cirrhosis contributing to the characteristic hyperdynamic circulation. The significance of renal NO in human cirrhosis is not clear. AIMS: In order to clarify the role of NO in the regulation of renal hemodynamics and sodium excretion in human cirrhosis, we studied the effects of N(G)-monomethyl-L-arginine (L-NMMA) - a nonselective NO-inhibitor - on blood pressure (MAP), heart rate (HR), GFR, RPF, UNa × V, FENa, FELi and plasma levels of renin, angII, aldo, ANP, BNP and cGMP in 13 patients with cirrhosis (Child gr.A: 8; Child gr.B+C: 5) and 13 healthy controls. METHODS: The study was randomized and placebo-controlled. Renal hemodynamics were assessed by measuring renal clearance of (51) Cr-EDTA and (125) I-Hippuran for GFR and RPF, respectively. RESULTS: L-NMMA induced a similar, significant increase in MAP in both groups and a more pronounced relative decrease in HR in the CIR group (P = 0.0209, anova). L-NMMA did not change GFR in any group, but RPF decreased significantly in both groups, but most pronouncedly in CIR (P = 0.0478, anova). FENa decreased significantly in both groups after l-NMMA, but the response was again most pronounced in the CIR group (P = 0.0270, anova). All parameters remained stable after placebo. No significant differences were observed between the effects of L-NMMA in Child gr.A vs. Child gr. B+C patients. CONCLUSION: The data supports the hypothesis that renal NO is enhanced in human cirrhosis.

Chronic consumption of three forms of palm oil diets alters glomerular filtration rate and renal plasma flow.

The effects of chronic consumption of three types of palm oil diets on glomerular filtration rate (GFR), renal plasma flow (RPF) and blood pressure were studied. Wistar rats were randomly assigned into four groups of ten rats each, respectively: control, fresh (FPO), photoxidized (PPO), thermoxidized (TPO) palm oil diet-fed rats. The control group was fed rat chow only, while experimental groups had different palm oil diets at 15% wt/wt for twelve weeks and tap water ad libitum. After the feeding period, GFR, RPF, systolic and diastolic blood pressures were measured. GFR and RPF of the TPO (0.07 ± 0.01 ml/min and 1.50 ± 0.24 ml/min) and PPO (0.14 ± 0.01 and 2.54 ± 0.11) groups were significantly (p < 0.001) reduced compared with control (0.77 ± 0.04 and 5.3 ± 0.30) and FPO (0.81 ± 0.02 and 4.8 ± 0.13) groups. The GFR and RPF of the TPO group was significantly (p < 0.05) higher than that of the PPO group. Systolic and diastolic blood pressures of the TPO group (140 ± 3 mmHg and 106 ± 4 mmHg) were significantly (p < 0.01) increased when compared with the control (112 ± 6.4 and 78 ± 5), FPO (118 ± 5 and 81 ± 6) and PPO (122 ± 5 and 89 ± 5) groups. These results suggest that chronic consumption of TPO and PPO caused a decrease in GFR and RPF, but increased blood pressure in rats, while FPO did not adversely affect blood pressure, GFR and RPF.

A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects.

AIM: Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr ) was evaluated in 34 healthy volunteers. METHODS: Subjects received DTG 50 mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para-aminohippurate plasma clearance and CLcr was measured by 24 h urine collection. RESULTS: All treatments were generally well tolerated. A modest decrease (10-14%) in CLcr was observed, consistent with clinical study observations. DTG 50 mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects. CONCLUSIONS: These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.

Phosphodiesterase 5 inhibition protects against increased intra-abdominal pressure-induced renal dysfunction in experimental congestive heart failure.

AIMS: Congestive heart failure (CHF) is associated with impaired renal function. Previously, we have demonstrated that rats with decompensated CHF exhibited exaggerated sensitivity to the adverse renal effects of increased increased intra-abdominal pressure (IAP) as compared with normal controls. This study tested whether phosphodiesterase 5 (PDE5) inhibition protects against the adverse renal effects of increased IAP in rats with CHF. METHODS AND RESULTS: Following baseline periods, rats with compensated and decompensated CHF induced by the placement of an aorto-caval fistula (ACF), rats with myocardial infarction (MI) induced by left anterior descending (LAD) artery ligation, and sham controls were subjected to consecutive IAPs: 7, 10, or 14 mmHg. Urine flow (V), Na(+) excretion (U(Na)V), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pre-treatment with tadalafil on the adverse renal effects of IAP were examined in rats with decompensated CHF and MI. Elevation of IAP to 10 and 14 mmHg produced linear reductions in these parameters. Basal renal function and haemodynamics were lower in CHF rats. Decompensated CHF rats and MI rats that were subjected to 10 and 14 mmHg exhibited exaggerated declines in V, U(Na)V, GFR, and RPF. In contrast, no adverse renal effects were observed in rats with compensated CHF subjected to IAP. Pre-treatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSION: Decompensated CHF and MI rats are vulnerable to the adverse renal effects of IAP. Tadalafil abolishes IAP-induced renal dysfunction, supporting a therapeutic role for PDE5 inhibition in CHF associated with ascites.

Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study.

CONTEXT: Vitamin D deficiency and obesity are associated with increased tissue renin-angiotensin system (RAS) activity. OBJECTIVE: The objective of the study was to evaluate whether vitamin D(3) therapy in obesity reduces tissue-RAS activity, as indicated by an increase in tissue sensitivity to angiotensin II (AngII). PARTICIPANTS: Participants included obese subjects with hypertension and 25-hydroxyvitamin D less than 25 ng/ml. DESIGN: Subjects were studied before and after 1 month of vitamin D(3) 15,000 IU/d, while in dietary sodium balance, and off all interfering medications. Fourteen subjects successfully completed all study procedures. SETTING: The study was conducted at a clinical research center. OUTCOME MEASURES: At each study visit, tissue sensitivity to AngII was assessed by measuring renal plasma flow (RPF), mean arterial pressure (MAP), and adrenal secretion of aldosterone during an infusion of AngII. Subjects were then given captopril, and a second AngII infusion to evaluate the effect of captopril on tissue-RAS activity. RESULTS: Vitamin D(3) therapy increased 25-hydroxyvitamin D (18 to 52 ng/ml) and basal RPF (+5%) and lowered supine MAP (-3%) (all P < 0.01). There was a greater decline in RPF and higher stimulation of aldosterone with AngII infusion after vitamin D(3) therapy (both P < 0.05). As anticipated, captopril increased the renal-vascular, MAP, and adrenal sensitivity to AngII, but this effect was much smaller after vitamin D(3) therapy, indicating that vitamin D(3) therapy corrected the tissue sensitivity to AngII akin to captopril. CONCLUSIONS: Vitamin D(3) therapy in obese hypertensives modified RPF, MAP, and tissue sensitivity to AngII similar to converting enzyme inhibition. Whether chronic vitamin D(3) therapy abrogates the development of diseases associated with excess RAS activity warrants investigation.

Exaggerated natriuresis during clamping of systemic NO supply in healthy young men.

NO (nitric oxide) may be involved in fluid homoeostasis. We hypothesized that increases in NO synthesis contribute to acute, saline-induced natriuresis, which, therefore, should be blunted when NO availability is stabilized. Young men were studied during simultaneous infusions of L-NAME [NG-nitro-L-arginine methyl ester; bolus of 750 µg·kg⁻¹ of body weight and 8.3 µg·min⁻¹·kg⁻¹ of body weight] and SNP (sodium nitroprusside), the latter at a rate preventing L-NAME from increasing total peripheral resistance ('NO-clamping'). Slow volume expansion (saline, 20 µmol of NaCl·min⁻¹·kg⁻¹ of body weight for 3 h) was performed with and without concomitant NO-clamping. NO-clamping itself decreased RPF (renal plasma flow; P~0.02) and tended to decrease arterial blood pressure [MABP (mean arterial blood pressure)]. Volume expansion markedly decreased the plasma levels of renin, AngII (angiotensin II) and aldosterone (all P<0.001), while MABP (oscillometry), heart rate, cardiac output (impedance cardiography), RPF (by p-aminohippurate), GFR [glomerular filtration rate; by using 51Cr-labelled EDTA] and plasma [Na+] and [K+] remained constant. Volume expansion increased sodium excretion (P<0.02) at constant filtered load, but more so during NO-clamping than during control (+184% compared with 52%; P<0.0001). Urinary nitrate/nitrite excretion increased during volume expansion; plasma cGMP and plasma vasopressin were unchanged. The results demonstrate that NO-clamping augments sodium excretion in response to volume expansion at constant MABP and GFR, reduced RPF and decreased renin system activity, a response termed hypernatriuresis. The results indicate that mediator(s) other than MABP, RPF, GFR and renin system activity contribute significantly to the homoeostatic response to saline loading, but the specific mechanisms of hypernatriuresis remain obscure.

Acute effect of a soy protein-rich meal-replacement application on renal parameters in patients with the metabolic syndrome.

BACKGROUND: Soy protein is used for meal replacement therapy in obesity, however the influence on renal function parameters is not adequately investigated. This study evaluates glomerular filtration rate (GFR) and renal plasma flow (RPF) in patients with the metabolic syndrome and healthy controls after ingestion of different amounts of soy protein. METHODS: 10 patients with the metabolic syndrome but no signs of kidney disease and 10 healthy controls ingested 1 g protein/kg body weight of a commercial soy-yoghurt-honeypreparation. The patient group was also given a protein challenge of 0.3 g/kg body weight. RESULTS: Baseline GFR and RPF both were significantly higher in the patient group (147 ± 34.8 vs. 116 ± 21.1 ml/min, p=0.01 and 848 ± 217 vs. 637 ± 121 ml/min, p=0.02) and were strongly correlated with body weight. Use of different algorithms to estimate GFR resulted in underestimation of GFR, particularly in the patients with the metabolic syndrome. The challenge with an acute protein load of 1g protein per kilogram body weight induced a significant increase in GFR and RPF in healthy controls (GFR: +12.6 ± 11.0 % (p=0.01), RPF: +13.6 ± 15.6 % (p=0.04)) and even more in patients with the metabolic syndrome (GFR: +31.5 ± 32.2 % (p=0.01); RPF: +19.4 ± 22.7 % (p=0.02)). The ingestion of 0.3 g protein/ kg body weight did not induce significant changes. CONCLUSIONS: Basic renal function is changed in patients with the metabolic syndrome, even without microalbuminuria. In addition, there is an elevated susceptibility for protein load. However, the protein amount recommended for use in soy-protein based meal replacement therapy induced no significant changes.

Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension.

In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 µmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

Renal resistive index--a valid tool to assess renal endothelial function in humans?

BACKGROUND: In humans, renal endothelial function is assessed by the vasoconstrictive response to L-NG-monomethyl arginine (L-NMMA). We hypothesized that Doppler sonographic measurements of the renal resistive index in response to inhibition of nitric oxide synthase offer a new methodological approach for testing renal endothelial function. METHODS: Forty-one patients without nephropathy were included. Para-aminohippurate and inulin clearance were performed under basal conditions and during L-NMMA infusion. In parallel, renal resistive index was assessed by Doppler sonography, and central blood pressure was determined. RESULTS: Following nitric oxide synthase inhibition, renal resistive index increased significantly, and 29% of our patients developed Doppler sonographic diastolic zero flow. Renal plasma flow decreased in response to L-NMMA, and conversely, renal vascular resistance increased. There was no correlation of renal vascular resistance and renal resistive index at baseline and during nitric oxide synthase inhibition. Changes in renal resistive index were not related to changes in renal perfusion or renal vascular resistance. Renal resistive index correlated with central pulse pressure at baseline and during L-NMMA infusion, whereas renal vascular resistance did not correlate with central pulse pressure. CONCLUSION: Our data do not support the hypothesis that renal resistive index is a tool to test renal endothelial function in humans and should not be used interchangeably with renal vascular resistance.

Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome.

BACKGROUND: Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL. METHODS: Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner. RESULTS: Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025). CONCLUSIONS: Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.

Gender is related to alterations of renal endothelial function in type 2 diabetes.

BACKGROUND: Gender has been shown to affect endothelial function of the forearm circulation in patients with type 2 diabetes, but data on the renal circulation are lacking. We hypothesized that renal vascular nitric oxide (NO) availability is higher, and oxidative stress lower, in female compared to male patients with type 2 diabetes. METHODS: In 41 male and 39 female patients with type 2 diabetes, renal plasma flow (RPF) was determined by constant infusion input clearance at baseline and following infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4.25 mg/kg) to assess basal renal vascular NO availability. After a subsequent infusion of L-arginine (100 mg/kg) to restore baseline conditions, vitamin C (45 mg/kg) was co-infused to determine levels of oxidative stress in the renal circulation. RESULTS: Baseline renal haemodynamics were similar between genders. L-NMMA-induced renal vasoconstriction was more pronounced in females compared to males (-89 +/- 69 versus -60 +/- 52 ml/min/1.73 m(2), P = 0.03). After administration of L-arginine to restore baseline perfusion, the co-infusion of vitamin C led to a lesser increase of RPF in females than in males (+37 +/- 86 versus +60 +/- 52 ml/min/1.73 m(2), P = 0.05). CONCLUSIONS: Our data demonstrate that NO availability in the renal circulation is greater in female than in male patients with type 2 diabetes that is associated with reduced levels of oxidative stress in females. The role of this gender-related difference in renal endothelial function for the initiation and progression of diabetic nephropathy should be addressed in future studies.