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.

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.

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.

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 aquaporin-2 after furosemide and felodipine in healthy humans.

OBJECTIVE: Furosemide inhibits renal sodium and chloride reabsorption in the loop of Henle. A compensatory increased reabsorption of sodium and water takes place in the collecting duct. It is not known whether aquaporin-2 (AQP2) renal water channels are involved in this compensatory reabsorption. In animals, dihydropyridine derivatives of calcium channel blockers down-regulate AQP2 in the collecting duct, but the effect has not been studied in humans. We sought to test the hypotheses that urinary excretion of aquaporin-2 (U-AQP2) increases after a single intravenous dose of furosemide, and that U-AQP2 decreases after a single oral dose of felodipine. MATERIAL AND METHODS: In two randomized, single-blind, placebo-controlled, cross-over studies, we measured the effect of furosemide and felodipine on U-AQP2, urine volume, free water clearance (CH2O), and fractional excretion of sodium (FENa) in 13 healthy subjects in each study. 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. Glomerular filtration rate (GFR) was measured by constant infusion technique. U-AQP2 and hormones were determined by radioimmunoassay. RESULTS: Furosemide treatment increased U-AQP2 (202%), urine volume (214%), and FENa by a factor of 11, (p < 0.001 for all), whereas CH2O and GFR were unchanged. After treatment with placebo, no differences were seen. Furosemide treatment increased AVP (18%), PRC (60%), ang II (100%), and aldo (98%) (p < 0.032); ANP was decreased by 29% (p < 0.001), whereas there was no change in BNP. The hormones were unchanged after placebo except for a minor decrease in ANP after placebo. Felodipine tended to increase U-AQP2, to decrease CH2O and urine volume and GFR, and to increase FENa, but the effect was not significantly different from placebo. Felodipine increased PRC (82%) (p < 0.003) and ang II, but decreased aldo, and increased AVP. After placebo, PRC was unchanged, whereas ang II, aldo and AVP were changed as after felodipine. CONCLUSIONS: Furosemide treatment increased U-AQP2, AVP, and the activity of the renin-angiotensin-aldosterone system. These changes are most likely compensatory phenomena, which prevent an excess loss of sodium and water. Felodipine tended to increase U-AQP2.

Hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors in diagnosing iron-deficient erythropoiesis.

BACKGROUND: The purpose of this study was to test the hypothesis that hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors are sensitive variables in detecting iron-deficient erythropoiesis in healthy subjects and hemodialysis patients. METHODS: Study 1: Twenty-one blood donors donated 450 mL blood. During the following 2 weeks blood samples were analyzed for the variables mentioned above. Study 2: Twenty-eight blood donors received 10,000 U recombinant human erythropoietin (rHuEPO) twice in the first week or placebo, after they had donated 450 mL blood. During the following 3 weeks the blood samples were analyzed for the variables mentioned in Study 1. Study 3: Eighteen hemodialysis patients receiving rHuEPO and iron treatment had either iron treatment discontinued for 4 weeks, after which iron was resumed, or received unchanged treatment. During 8 weeks blood samples were analyzed for the variables mentioned in Study 1. RESULTS: Study 1: Blood donation induced an increase in hypochromic reticulocytes of 178%, in hypochromic erythrocytes the increase was 267%, and in p-transferrin receptors 32%. Study 2: Treatment with rHuEPO induced a more pronounced increase than placebo in hypochromic reticulocytes (232% vs. 158%) and hypochromic erythrocytes (1240% vs. 300%), but not in p-transferrin receptors. Study 3: Discontinuation of iron treatment did not cause any significant differences in the variables mentioned above between the two groups, but caused a 25% decrease in p-ferritin. When iron treatment was resumed, p-ferritin increased by 19%. We found no significant changes in the control group. CONCLUSIONS: Hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors are sensitive variables in the early detection of iron-deficient erythropoiesis in healthy subjects, but in this study the iron withdrawal period was too short to show the value of these variables in the detection of iron-deficient erythropoiesis in hemodialysis patients.