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Newborn rat distal cells express an apical Ca2+ channel activated by dihydropyridine drugs. Similarly, in Madin-Darby canine kidney (MDCK) cells, nifedipine increased Ca2+i in a concentration-dependent manner (IC50=4 μM) in fura-2-loaded cells. Response to nifedipine was abolished by EGTA, suggesting that it depends on extracellular calcium. Ca2+ channel antagonist isradipine and agonist BayK8644 increased Ca2+i indicating that this effect is related to the dihydropyridine group. Diltiazem (20 μM) and gadolinium (200 μM) decreased the nifedipine effect (62 and 43%, respectively). Lanthanum (100 μM) did not change the response. Valinomycin clamping of the membrane potential did not modify nifedipine-induced increment, indicating that it was unrelated to potassium fluxes. We performed whole cell clamp experiments in MDCK cells maintained at -50 mV with perfusion solution containing 10 mM CaCl2. Nifedipine (20 μM) induced an increase in current (1.2±0.3 nA), which was partially inhibited by Gd3+. No significant current was induced by nifedipine in the presence of 0.5 mM EGTA. To determine the effects of nifedipine on the membrane potential, we performed oxonol fluorescence experiments. The addition of nifedipine or Bay K8644 induced depolarization, highly dependent on external sodium. Nifedipine (20 μM) induced depolarization of 6.9±0.8 mV (n=21). EC50 to nifedipine was in the 10 μM range. We conclude that MDCK cells exhibit a dihydropyridine-activated cationic channel., (Copyright © 2011 S. Karger AG, Basel.)

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 neonates pharmacokinetics of furosemide is very slow, as compared to adult individuals, because it is eliminated through glomerular filtration and tubular secretion, mechanisms that are not fully developed in the newborn mammal. In addition, Henle's loop, the main site of action of this diuretic, is shorter in the neonate than in the adult animal. The aim of this study was to measure the response to furosemide in the unanesthetized newborn rat and to compare it with that of the adult. Furosemide (0.5, 1, 1.5, 2, 5 or 10 mg/kg body weight, i.p.) or vehicle were administered to newborn and adult rats and the effects on sodium, potassium and water balance were assessed. Despite the physiological characteristics of the neonatal kidney, furosemide induced a more marked sodium excretion and decrease in free water clearance in the newborn than in the adult rat. In contrast, urinary potassium losses elicited by furosemide were higher in the adult than in the newborn rat at similar doses. At both ages, the effects of the diuretic were dose-dependent. Plasma sodium decreased, whereas plasma potassium and hematocrit increased in the newborn rats, after the highest doses of furosemide. In the adult rat changes were less marked. Our results suggest that the neonatal kidney is more sensitive to equivalent doses of furosemide than the adult kidney.

The uptake of prostaglandin E2, one of the main renal prostaglandins and of p-aminohippurate, an indicator of the anion organic transport, by slices of kidney cortex from adult female rats was studied in the presence and in the absence of indomethacin. The drug's inhibitory effect on the uptake of prostaglandin E2 was observed both after in vivo administration as well as when it was present in the bathing media. The effect was more pronounced when the drug was given in vivo and in addition, was present in the bath. [14C] PAH uptake was inhibited by indomethacin in a dose-related pattern and the kinetic analysis of this effect is indicative of a competitive inhibition. As expected, uptake of PAH by medullary slices was not affected by the presence of either indomethacin of PGE2. Indomethacin was more potent in inhibiting PGE2 uptake than PAH uptake.