Vasotocin analogues with selective natriuretic, kaliuretic and antidiuretic effects in rats.

The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa(1)-vasotocin (dAVT), Mpa(1)-Arg(4)-vasotocin (dAAVT) and Mpa(1)-DArg(8)-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V1a agonist (Phe(2)-Ile(3)-Orn(8)-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V2 agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V1a antagonist (Pmp(1)-Tyr(Me)(2)-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V2 antagonist (Pmp(1)-DIle(2)-Ile(4)-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V1a or V1a-like receptor for natriuretic effect and V2 or V2-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones.

Physiological mechanisms for the increase in renal solute-free water clearance by a glucagon-like peptide-1 mimetic.

The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats. The GLP-1 mimetic exenatide (0.05-5.0 nmol/kg, i.m.), alone and in combination with either a vasopressin V2 receptor antagonist (15 nmol/kg, i.p.) or vasopressin (0.01 nmol/kg, i.m.), was injected into control and water-loaded (water 10-50 mL/kg, p.o., or 50 mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E2 excretion and the effects of diclofenac (5 mg/kg, i.m.) and GLP-1 receptor antagonist (0.15 µmol/kg, i.p.) on exenatide action were assessed. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V2 receptor antagonist administration in water-loaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE2 excretion increased following water loading (47 ± 6 vs 24 ± 4 ng/kg over a 30 min period) and was enhanced as a result of additional exenatide injection (69 ± 10 ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct.

Mechanism of 1-deamino-arginine vasotocin induced natriuresis in rats.

1-Deamino-arginine vasotocin (1dAVT) induced diuresis and a considerable increase in urinary sodium excretion in female Wistar rats. Sodium fractional excretion rose up to 19.3 ± 1.1%. An increase in urine flow rate after 1dAVT (0.5 nmol/kg body-weight [bw]) injection was accompanied by a significant rise of the solute-free water reabsorption. The 1dAVT-induced natriuresis was as high as natriuresis produced by injection of a maximal dose of furosemide (10mg/kg bw). V(1)-receptor antagonists (ОРС-21268, [ß-mercapto-ß,ß-cyclopentamethylenepropionyl(1),O-Me-Tyr(2),Arg(8)]-vasopressin) blocked the increase in urinary sodium excretion after the 1dAVT injection. The 1dAVT-induced natriuresis was strongly correlated with an increase in the urinary cGMP and prostaglandin E(2) excretion. The natriuretic effect of 1dAVT did not depend on the formation of nitric oxide (NO) or atrial natriuretic peptide of which concentration in the rat blood serum remained stable. The above results indicate that the 1dAVT has unique effects on rat kidney compared to all other known diuretics - it induces extremely high natriuresis and stimulates solute-free water reabsorption. Mechanism of the natriuretic effect of 1dAVT includes decrease in tubular sodium reabsorption due to activation of V(1)-like receptors and formation of cGMP and PGЕ(2).

Urinary aquaporin-2 in children with acute pyelonephritis.

Children with acute pyelonephritis develop polyuria and have reduced maximum urinary concentration capacity. We studied whether these abnormalities are associated with altered urinary excretion of the water channel aquaporin-2 (AQP2) in the renal collecting duct. AQP2 is the main target for antidiuretic action of arginine vasopressin (AVP), and the urinary excretion of this protein is believed to be an index of AVP signaling activity in the kidney. Children with acute pyelonephritis, aged 5-14 years, were examined for urinary flow rate, creatinine clearance, unchallenged urine osmolality, and urinary ion excretion. Urinary excretion of AQP2 was measured by dot immunoblotting technique. Studies were performed in the acute phase of pyelonephritis, in the same children after treatment, and in control patients. At the onset of pyelonephritis, urinary flow rate and solute excretion were increased, but the urinary osmolality was unchanged. The urinary level and urinary excretion of AQP2 was increased in acute pyelonephritis and decreased after treatment. Excretion of aquaporin-3 was unchanged, suggesting that the increase in AQP2 urinary excretion was not due to a shedding of collecting duct cells. The results suggest that a mechanism proximal to the collecting duct may be responsible for the polyuria observed in children with acute pyelonephritis. Increased urinary AQP2 levels suggest that a compensatory activation of apical plasma membrane targeting of AQP2 may occur in pyelonephritis.