Search

Indomethacin is used to pharmacologically occlude patent ductus arteriosus in preterm infants. It induces renal untoward effects and furosemide is administered simultaneously to counteract them. The effect of furosemide is blunted by indomethacin. We analyzed comparatively the interactions of furosemide and indomethacin at the organic anion transport system in adult and newborn individuals. Adult and 5-day-old Wistar rats were allocated into three groups: (1) indomethacin (10 mg/kg, ip); (2) furosemide (2 mg/kg, ip); and (3) indomethacin/furosemide, at the same doses. Urinary flow, glomerular filtration rate (GFR), sodium and potassium fractional excretions, and free-water and osmolal clearances were estimated. Para-aminohippuric acid (PAH) uptake was measured in renal cortical slices to study the organic anion's secretory pathway. In adult and newborn rats, furosemide-induced increments in urinary fluxes and excretions of sodium and potassium were blunted by indomethacin administered simultaneously. PAH uptake was decreased to a further extent by indomethacin than by furosemide, suggesting that inhibition of the diuretic effect might be related to competition in the secretion of furosemide. Inhibitory interaction between indomethacin and furosemide was achieved at approximately 10-fold lower concentrations in the newborn than in the adult rats, suggesting that tubular secretion in the neonate is more sensitive to the action of these drugs than in the adult individual.

In mammals, neonatal positive calcium balance is required for adequate growth. Parathyroid hormone (PTH) plays a central role in this process mainly through its action on the distal nephron. We studied the effect of PTH on cytosolic calcium in distal segments from neonatal rat kidney. PTH elicited a concentration-dependent increase in cytosolic calcium in neonatal distal nephron (EC(50)=0.5 nM) but not in proximal tubules. At similar PTH concentrations the response was higher in the neonatal than in the adult tubules. The response was associated with protein kinase C (PKC), since phorbol myristate acetate (100 nM) increased [Ca(2+)]i, and staurosporin, an inhibitor of PKC, decreased (10 nM) or suppressed (100 nM) the PTH effect. cAMP analogues did not change [Ca(2+)]i. The response was diminished in low external calcium (0.1 mM) and absent at zero calcium, indicating dependency on external calcium. Resting calcium decreased from 80+/-10.8 to 28.6+/-2.6 nM at zero [Ca(2+)]e. PTH and nifedipine increased cytosolic calcium in an additive fashion. We show for the first time that PTH increased cytosolic calcium in the distal nephron of neonatal kidney, in a concentration-dependent pattern and in association with PKC activation. Higher sensitivity of the neonatal tubule might facilitate absorption of this cation during the neonatal period, when growth requires a positive balance of calcium.

The effects of cyclosporin A (CyA, 50 mg/kg body weight) or its commercial vehicle (cremophor) on the acid-base regulation of uninephrectomized rats were assessed for 7 days and in non-nephrectomized rats for 15 days. CyA induced a marked systemic acidosis, accompanied by decreases in blood PCO(2) and plasma bicarbonate. Untreated uninephrectomized rats did not show the acidosis. In CyA-treated rats the urine pH decreased (control 6. 65+/-0.06 vs. CyA 6.18+/-0.08; P<0.01) as well as urinary bicarbonate (non-nephrectomized rats 7.50+/-1.88 mM vs. uninephrectomy plus CyA 0.75+/- 0.06 mM; P<0.01), suggesting partial renal compensation of systemic acidosis. Titratable acidity increased in CyA-treated rats (control 21.6+/-1.2 vs. CyA 63.3+/-12.0 microEq/l; P<0.001). Phosphate, glucose, and osmolar clearances were not significantly altered in non-nephrectomized rats treated with CyA for 15 days. There was a striking decrease in body weight in CyA-treated rats (control 274.0+/-3.8 vs. CyA 225.0+/-5.1 g; P<0. 01), but compensatory growth of the remaining kidney was not prevented by this drug or by its vehicle. In summary, CyA induced a severe metabolic acidosis in uninephrectomized rats that was not compensated by the remaining kidney, in spite of the well-preserved compensatory weight gain of this organ. Loss of body weight was significant in CyA-treated animals.

The role of eicosanoids, arachidonic acid (AA) metabolites, in blood pressure regulation under physiological and pathological conditions during the perinatal period is still under investigation. This review focuses on the synthesis and catabolism of some vasoactive AA metabolites by fetal, neonatal and placental cells, and on the vascular responses of the fetus and neonate to prostanoids and to the inhibitors of their synthesis. Vasodilator prostaglandins, PGE2 and prostacyclin (PGI2), increase steadily during pregnancy, while thromboxane A2 (TXA2), a potent vasoconstrictor, remains low during pregnancy, increasing only shortly before delivery. TXA2 participates in the closure of umbilical vessels and ductus arteriosus. In pregnancy-induced hypertension, increase in the synthesis of TXA2 occurs early during pregnancy. Decrease in the catabolism of AA precedes the onset of hypertension in the developing spontaneously hypertensive rat. In newborn piglets, platelet-activating factor, vasoconstrictor porstaglandins and leukotriene D4 have a marked constrictor effect on the pulmonary circulation and induce pulmonary hypertension, without affecting the systemic blood pressure. Although the role of AA metabolites in the regulation of haemodynamics during the perinatal period is not fully understood, it is apparent that several eicosanoids modulate the action of hormones and vasoactive agents.

Experimental and clinical evidence support the assumption that eicosanoids affect the morphological development and the functional behaviour of the kidney during the intra-uterine and newborn periods. Inhibition of prostaglandin (PG) synthesis in the pregnant rhesus monkey resulted in renal hypoplasia in the offspring. The plasma levels of PGs are high in the newborn. Production of PGE2 by the cortical collecting duct was found to be similar in newborn and adult rabbit but the affinity of the renal tissue of the newborn for this eicosanoid was higher than that of the renal tissue of the adult rat. Based on findings in adult animals this would be expected to blunt the effect of antidiuretic hormone and account, in part, for the limited ability of the newborn to concentrate the urine. Yet, administration to unanaesthetized newborn rats of acetaminophen, a drug that inhibits the synthesis of PGE2 and thromboxane B2, blocked, rather than enhanced, the increment in urine osmolality produced by 1 h of water deprivation. The effect was absent in weaning and adult rats. A similar experimental manoeuvre increased sodium excretion in newborn but not in weaning or adult rats. Age-related differences are also evident with regard to side effects of PG synthesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)