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The effects of leukotriene D4 (LTD4) on guanosine 3',5'-cyclic monophosphate (cGMP) production induced by atrial natriuretic factor (ANF) or sodium nitroprusside (SNP) were investigated in isolated rat glomeruli. First, the isolated glomeruli were preincubated in Krebs-Ringer buffer containing 3-isobutyl-1-methylxanthine for 10 min, then incubated with varying concentrations of ANF, SNP, and LTD4 for 3 min. cGMP content was determined by radioimmunoassay. cGMP production (fmol.glomerulus-1.3 min-1) was not increased by LTD4. cGMP accumulation was increased by ANF (1 microM) and SNP (100 microM) remarkably from 0.19 +/- 0.09 to 3.24 +/- 0.21 (n = 7, mean +/- SE), and from 0.19 +/- 0.09 to 3.67 +/- 0.47 (n = 4), respectively. The increase in cGMP production by ANF was significantly and dose-dependently inhibited by LTD4 (P less than 0.05). Maximum suppression was observed at the concentration of 100 nM (from 3.06 +/- 0.33 to 1.43 +/- 0.09; P less than 0.05). However, LTD4 caused no significant change in the level of cGMP production induced by SNP. Second, particulate or soluble guanylate cyclase from glomeruli were similarly investigated. ANF selectively activated particulate guanylate cyclase and the response was selectively inhibited by LTD4 from 9.07 +/- 1.79 fmol.micrograms-1.3 min-1 (n = 6) to 4.70 +/- 0.70 (n = 6, P less than 0.05). These results suggest the site where LTD4 has effect on cGMP production induced by ANF was the particulate guanylate cyclase system, but not the soluble guanylate cyclase system.

Vasopressin (V) causes a sustained increase in Na reabsorption and K secretion in isolated cortical collecting ducts (CCD) from rats. Because increased Na reabsorption may be associated with increased Na+-K+-ATPase activity, we investigated effects of V, given either in vivo or in vitro, on Na+-K+-ATPase activity in isolated nephron segments of rats. Na+-K+-ATPase activities were measured by coupling the hydrolysis of ATP to the production of a fluorescent nucleotide. In addition to CCD, other microdissected structures were medullary thick ascending limbs of Henle's loop, cortical thick ascending limbs of Henle's loop, and outer medullary collecting duct. To determine the time course of the response, Na+-K+-ATPase activities were measured in CCD 1 h, 3 h, 1 day, 3 days, and 7 days after intramuscular administrations of V. There was a significant increase in Na+-K+-ATPase activity in CCD after in vivo V administration for 7 days but not in any other segment. The activities increased after 3 days of administration of V. For in vitro experiments, CCD were incubated with 10(-6) M V for 1-3 h. Na+-K+-ATPase activities did not change after 1- or 3-h exposure of V in CCD in vitro. We conclude that prolonged V administration in vivo increases Na+-K+-ATPase activity in CCD. Because, in vitro exposure to V does not increase Na+-K+-ATPase activity, we conclude that rapid V-dependent increases in Na and K transport previously demonstrated in isolated perfused tubules are not dependent on a change in maximal Na+-K+-ATPase activity.

A 65-year-old woman with mild renal insufficiency had persistent hyperkalemia and hyperchloremic acidosis. Her plasma aldosterone level was relatively low for her hyperkalemia, and her urine pH was low. Fludrocortisone acetate administration corrected both hyperkalemia and acidosis by increasing urinary excretion of potassium and net acid, implicating deficient mineralocorticoid activity in the distal renal tubule in this patient. During this medication urinary ammonium excretion increased, but urine pH remained low, so that urinary titratable acid excretion did not decrease. On the other hand, correction of hyperkalemia by administration of a potassium-calcium exchange resin alone also resolved the acidosis by increasing urinary ammonium excretion. This increment exceeded the decrement of urinary titratable acid excretion, which was caused by raised urine pH secondary to increased urinary ammonium excretion, and resulted in increase of net acid excretion. Thus, in this patient, hyperkalemia appears to be a decisive causative factor in the acidosis, with deficient mineralocorticoid effect only contributing in part to the reduction of net acid excretion and the acidosis.

The role of the kallikrein system in the natriuresis of SIADH was studied in 3 patients. Following free water intake, serum Na decreased. Urinary Na excretion, urinary aldosterone excretion and urinary kallikrein-like activity (UKaV) increased. Significant relationships were observed between UKaV and urinary aldosterone excretion during the study. Further, there were significant relationships between serum Na and UKaV, and between uric acid clearance and UKaV. In 1 patient, who was observed for a longer period, a significant relationship was observed between Na clearance and UKaV. We conclude that UKaV is increased during hyponatremia in SIADH by volume expansion. This increase in UKaV may play a role in the natriuresis in SIADH.

Aims: The existence of low-responders to angiotensin II receptor blockers (ARBs) in terms of the preservation of renal function is reported here. We investigated the relationship between the responsiveness to ARBs and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Methods: The effects of ARBs on proteinuria and the progression of chronic renal failure were examined in 113 patients with chronic kidney disease for 34 months before and 27 months after the addition of ARBs. Results: Although a decrease in blood pressure was seen in the II, DI and DD patient subgroups of the ACE gene, the decrease in proteinuria and the amelioration of loss of renal function were observed in the II and DI but not in the DD patients. Kaplan-Meier analysis was employed with a decrease of the reciprocal of serum creatinine of more than 0.2, the induction of renal replacement therapy or death as endpoints. The analysis comparing the periods before and after the addition of ARBs revealed the extension of time to an end-point by the addition of ARBs in all groups together (II + DI + DD), in Group II, and Group DI but not in the DD patient Group. Conclusions: These data suggest that DD patients with ACE gene demonstrate diminished response to ARBs in terms of renoprotection and that ACE gene polymorphism needs to be taken into account when using ARBs as a means of renoprotective therapy.

Short-term effects of alacepril, an angiotensin-converting enzyme inhibitor (ACEI), on renal function and hemodynamics were investigated in 10 hypertensive subjects (aged 55.7 +/- 9.5 years, mean +/- SD). Renal plasma flow (RPF) and glomerular filtration rate (GFR) were examined before and after 12-week administration of alacepril, by [131I]hippuran and [99mTc]DTPA, respectively. Alacepril (50 mg/day) caused a significant decrease in both systolic and diastolic blood pressure (SBP and DBP, from 161 +/- 8 to 140 +/- 10 mm Hg and from 100 +/- 3 to 90 +/- 5 mm Hg, respectively). Alacepril increased GFR (from 63.4 +/- 22.2 to 69.1 +/- 22.1 ml/min/1.73 m2, p less than 0.05) without changing RPF (from 438 +/- 194 to 432 +/- 148 ml/min/1.73 m2, p greater than 0.05). Serum creatinine and electrolytes were not changed by alacepril administration. These data show that short-term alacepril administration improves renal function, probably owing to relaxation of renal vasoconstriction.

Serum uric acid concentrations have been associated with mortality in patients receiving hemodialysis. Treatment options are sometimes limited because of the accumulation of a drug and/or its metabolites. The aim of the present study is to investigate the efficacy, safety, and plasma levels of topiroxostat, a selective xanthine oxidase inhibitor, and its metabolites in patients receiving hemodialysis. This was a 52-week open study. The plasma concentrations of topiroxostat and its metabolites were measured. The endpoints selected were effects on serum uric acid concentrations and the safety and tolerability of topiroxostat. A statistical analysis was performed using a paired t test with Bonferroni corrections. Nineteen participants were followed for 52 weeks without significant adverse effects. Serum uric acid concentrations decreased from 527 ± 49 to 325 ± 62, 297 ± 99, 297 ± 68, and 296 ± 83 μmol/L (weeks 4, 12, 26, and 52; p

Nouvelle technique pour le diagnostic rapide et clair grâce a un «autoanalyseur» donnant une courbe de distribution des hematies de differentes morphologies