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PubMed1978

Effect of different drugs on a cytochrome c--phospholipid bilayer membrane.

Liposomes were prepared from dipalmitoyl phosphatidylcholine and dicetylphosphate and their interaction with the extrinsic membrane protein cytochrome c examined in terms of changes in 22Na permeability, electrophoretic mobility, protein binding, and motion of an incorporated spin label. The amount of cytochrome c bound displays no significant temperature dependence over the temperature range studied (from 30 to 55 degrees C) whereas cytochrome c causes an increase in 22Na efflux only above the phospholipid phase transition temperature. Interaction of the protein with the lipid vesicles causes no significant disturbance in the bilayer interior as monitored by the motion of the incorporated spin probe. The drugs 2,4-dinitrophenol and ethacrynic acid, both of which increase the magnitude of the vesicle negative charge, enhance both cytochrome c binding and its effect on 22Na permeability. In contrast, the local anesthetic dibucaine, which induces a positive surface charge on these liposomes, reduces both protein binding and the protein-induced increase in 22Na efflux. Finally, the chemicals butylated hydroxytoluene, 2-tert-butylphenol, and tert-butylbenzene, all of which cause early 'melting' of the phospholipid fatty acyl chains, block the capacity of cytochrome c to enhance 22Na permeability while having no effect on its binding to the vesicles.

Cytochrome c Group↗
PubMed1975

Electrolyte excretion and free-water production during onset of acute diuresis.

The concentration of major urinary solutes was studied in ureteral urine collected at 15- to 30-s intervals at the onset of acute diuresis induced in anesthetized dogs either by high-ceiling diuretics (mainly ethacrynic acid) or by osmotic diuretics. Phosphate/inulin clearance ratios remained unchanged; potassium/inulin clearance ratios rose rapidly. Principal attention is given to the mechanisms underlying a transient rise in urinary sodium and chloride concentrations during the onset of diuresis. When the data are corrected for washout artifacts from the pelvis and ureter, it can be shown that the initial collection periods are associated with a transient increase in free-water production and by the simultaneous secretion of urea from the interstitium into the tubular fluid. The former coincides in time with the rise in urinary chloride concentration and represents an augmentation of water reabsorbed in the collecting duct, which is relatively impermeable to chloride. Both responses are quantitatively consistent with the transition from a hyperosmotic to isosmotic medullary interstitium.

Animals↗
PubMed1976

Renal tubular reabsorptive response to hypernatremia.

Renal tubular reabsorptive response to rapid infusions of isotonic saline and 5% NaCl solutions were measured during brisk ethacrynic acid diuresis in anesthetized dogs. When adjustments were made for effects of variations in volume expansion, as indexed by plasma protein concentration ([Pprot]), tubular reabsorption of sodium per unit filtrate volume (TNa/GFR) was found to be significantly and positively correlated with plasma sodium concentration ([PNa]) despite hypernatremia and total body surfeit of sodium. The proportions of sodium and water reabsorbed were also homeostatically inappropriate, since the sodium concentration in the reabsorbate was somewhat in excess of that in contemporary plasma ultrafiltrate. These findings signify that glomerulotubular balance holds when the filtered load of sodium is increased by an increment in [pNa] as well as GFR. It is proposed that the moiety of tubular reabsorption (some 75% of GFR) studied here is more closely related to regulation of volume than of osmolality of sodium concentration, and the primary regulation exerted is on tubular volume reabsorption (bulk fluid reabsorption) rather than on the amount of sodium reabsorbed.

Animals↗
PubMed1980

Oxygen requirement of bicarbonate-dependent sodium reabsorption in the dog kidney.

The ratio between changes in sodium reabsorption and renal oxygen consumption (Na/O2) was measured in anesthetized dogs at high plasma bicarbonate concentration (32 +/- 1 mM); ethacrynic acid was infused continuously to prevent variations in transcellular NaCl reabsorption when sodium reabsorption was altered by varying plasma PCO2 and glomerular filtration rate (GFR). At high plasma PCO2 (110 mmHg) sodium reabsorption varied in proportion to GRF between 50 and 125% of control GFR (glomerulotubular balance). By reducing PCO2 to 20 mmHg, sodium reabsorption was reduced by 50-60% at constant GFR. The Na/O2 ratio was not significantly different during the two procedures and averaged 48 +/- 2. The ratio between changes in NaHCO3 reabsorption and oxygen consumption averaged 17 +/- 1, which is not significantly different from the Na/O2 ratio of Na-K-ATPase-dependent sodium transport. We propose that NaHCO3 is admitted to the cell by Na+/H+ exchange and that sodium is actively transported by Na-K-ATPase across the peritubular cell membrane; NaHCO3 provides the osmotic force for paracellular reabsorption of water and NaCl (bicarbonate-dependent reabsorption) without additional energy requirement.

Absorption↗
PubMed1980

Chloride concentration gradient in newborn dogs in the presence of distal nephron blockade.

Renal tubular Na+, Cl-, and H2O reabsorption was determined in 14 newborn dogs, 3--29 days of age, and in three adult dogs. In all animals NaCl reabsorption beyond the proximal tubule was blocked with ethacrynic acid (2 mg/kg) and amiloride (2.4 mg/kg). During distal blockade, fractional reabsorption of NaCl and water in both newborns and adults was approximately 70%, and there was a urine-to-plasma chloride gradient equal to 1.34 +/- 0.01, indicating that the proximal tubules of the newborn as well as those of the adult can generate a transtubular Cl- gradient. Upon administration of acetazolamide (50 mg/kg), there was a dramatic increase in excretion of Na+, Cl-, HCO3-, and water, and a decrease in the transtubular chloride gradient. After acetazolamide, the degree of inhibition of HCO3 reabsorption was well correlated with that of Na+, (r = 0.77) or Cl- (r = 0.74), and Na+ or Cl- inhibition exceeded that of HCO3-. In the newborn animal, the ratio of inner-to outer cortical nephron function is high at birth and declines rapidly during the first few weeks of life. However, there was no correlation between age and changes in either electrolyte excretion or in the transtubular chloride gradient. Therefore, the newborn dog possesses Cl- permselective tubules in the inner cortex that, in the presence of intact HCO3- reabsorption, are capable of establishing a functional transtubular Cl- gradient contributing to NaCl reabsorption.

Aging↗
PubMed1980

Natriuretic effect of oxytocin on saline-expanded neonatal dogs.

The natriuretic effect of oxytocin was studied in 40 anesthetized newborn dogs 2-33 days of age. After saline expansion, puppies excreted only 2.86% of the filtered sodium (adult dogs undergoing similar volume expansion excrete about 65-8% of the filtered sodium). After oxytocin was infused in these saline-expanded puppies at 8 mU x kg-1 x h-1, fractional sodium excretion increased to 7.51%. Oxytocin had no natriuretic effect in nonexpanded puppies. In nonexpanded animals, when distal nephron function was blocked by a combination of ethacrynic acid, chlorothiazide, and amiloride, fractional sodium excretion averaged 31%. In contrast, distal nephron blockade in saline-expanded animals resulted in fractional sodium excretion of 55%. When oxytocin was infused in either saline-expanded or nonexpanded puppies undergoing distal nephron blockade, there was no increase in sodium excretion. These results support the following conclusions. In the newborn dog 1) the attenuated natriuretic response to saline expansion is related to increased reabsorption of sodium in the distal nephron; 2) an adult type of natriuretic response to saline expansion can be induced in puppies by infusion of oxytocin; and 3) oxytocin inhibits sodium reabsorption in the distal nephron.

Animals↗
PubMed1981

Effect of furosemide on calcium and magnesium transport in the rat nephron.

Superficial tubules were perfused in vivo to determine the effect of intraluminal furosemide on electrolyte transport in the loop of Henle and distal tubule of the rat with special reference to calcium and magnesium reabsorption. in vivo perfusion of single tubules allowed us the opportunity to investigate separate electrolyte transfers with altering the corticomedullary concentration gradient within the kidney. Intraluminal furosemide (3 X 10(-6) and 3 X 10(-5) M) resulted in proportionately greater calcium and magnesium inhibition relative to sodium and chloride in Henle's loop. Furosemide had little effect on transport function within the perfused superficial distal tubule. Distal calcium and magnesium reabsorption was dependent on their respective deliveries to this segment. Parathyroid hormone increased fractional calcium and magnesium reabsorption in Henle's loop and the distal tubule in the presence of intraluminal furosemide. These results are consistent with a luminal effect of furosemide in the loop of Henle that inhibits calcium and magnesium transport to a greater degree than sodium chloride. Intraluminal ethacrynic acid (10(-4) M) or its cysteine complex had no effect on electrolyte transport in the perfused rat nephron.

Animals↗
PubMed1984

Pressure natriuresis during saline expansion in newborn and adult dogs.

Pressure natriuresis was studied in anesthetized saline-expanded adult (n = 10) and neonatal (n = 23) dogs. One group (protocol B) received ethacrynic acid and amiloride to block distal nephron function. Studies in the other group (protocol A) were done without diuretics. Renal arterial blood pressure was raised by bilateral carotid artery occlusion. Renal perfusion pressure was then lowered in steps by partially occluding the aorta proximal to the renal arteries. In protocol B carotid occlusion was associated with an increase in both absolute and fractional sodium excretion by adult and newborn dogs. Moreover, there was significant negative correlation (P less than 0.01) between absolute change in renal arterial pressure and change in tubular reabsorption of sodium per milliliter glomerular filtrate for both age groups. For each mmHg increase in blood pressure there was greater inhibition of sodium reabsorption in the puppy (0.55 mueq/ml glomerular filtrate) than in the adult (0.18 mueq/ml, P less than 0.05). In protocol A puppies, the inhibition of sodium reabsorption due to increases in renal perfusion pressure was less than that occurring in protocol B, indicating that some of the sodium escaping proximal nephron reabsorption was reabsorbed distally. Results of these studies indicate that during saline expansion pressure natriuresis is primarily a proximal tubular event, and the sensitivity of the proximal tubule to changes in renal arterial blood pressure is greater in the newborn than the adult kidney.

Aging↗
PubMed1984

Renal osmotic effect of mannitol in the neonatal and adult dog.

The renal response to mannitol loading was studied in 21 newborn dogs aged 1-19 days and in 12 adult dogs. One group of animals (protocol B) underwent distal nephron blockade with ethacrynic acid and amiloride prior to and during infusion of mannitol to estimate proximal tubule function. The other group of animals (protocol A) received mannitol without the diuretics. Mannitol was infused at progressively increasing dosages, resulting in progressively increasing mannitol excretion rates. For all groups of animals, as mannitol excretion rates increased, urine flow and sodium, potassium, and chloride excretion rates increased. However, there was no correlation between mannitol excretion and bicarbonate excretion. The osmotic effect of mannitol was quantitated from the slope of the plot of mannitol excretion vs. sodium excretion (dNa/dMan). In both pups and adults dNa/dMan was greater in protocol B (1.47 for pups, 0.70 for adults) than in protocol A (0.18 for pups, 0.07 for adults). In addition, in protocol B dNa/dMan was greater in the newborn than in the adult and decreased logarithmically with age in pups. In protocol B, as mannitol excretion increased, the urine-to-plasma sodium ratio declined in adults but did not change in pups. Urine-to-plasma osmolality ratio remained at unity throughout the experiment in both age groups in protocol B. These results indicate that 1) the osmotic effect of mannitol is greater in the immature than in the mature kidney, and 2) the greater osmotic effect in the neonatal kidney is related to inability of the immature proximal tubule to generate and sustain a transtubular sodium gradient.

Animals↗
PubMed1979

PGA1 and PGF2 alpha metabolism by pig pulmonary endothelium, smooth muscle, and fibroblasts.

To determine the cellular site for uptake and degradation of circulating prostaglandins (PGs) by the lung, the metabolism of PGA1 and PGF2 alpha was studied in pig lung slices, smooth muscle preparations, and pulmonary valves, as well as in isolated and cultured endothelial cells and cultured fibroblasts. Formation of 15-keto metabolites of both PGA1 and PGF2 alpha by lung slices was confirmed. No evidence of PGF2 alpha degradation could be found in any of the remaining preparations. For PGA1, however, 15-hydroxyprostaglandin dehydrogenase activity was detected in the three smooth muscle preparations studied (trachea, aorta, pulmonary artery) and found to be similar to that measured in lung slices. But the inhibitory effect of diphloretin phosphate and bromcresol green was much more marked in smooth muscle tissues than in lung slices, which suggested that PGA1 metabolism by the lung was not due to smooth muscle cells. Endothelial cells, freshly isolated and cultured, originating from the pulmonary artery and from the aorta, formed a PGA1-glutathione adduct, poorly extractable in ethyl acetate. This reaction, also present in cultured fibroblasts, was inhibited by ethacrynic acid. The cellular site responsible for the pulmonary degradation of circulating PGs remains undetermined.

Animals↗
PubMed1996

Loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa.

The purpose of this study was to determine whether loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa in situ and, if so, to start to determine the mechanisms that mediated these responses. By using intravital microscopy, we found that bradykinin induced a significant concentration-dependent increase in fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) leaky site formation in the hamster cheek pouch. These responses were significantly attenuated by topical application of two structurally distinct loop diuretics, furosemide and ethacrynic acid, onto the cheek pouch (P < 0.05). Hydrochlorothiazide, a nonloop diuretic, had no significant effects on bradykinin-induced responses. Furosemide had no significant effects on adenosine-induced leaky site formation. Application of bradykinin after furosemide, but not after hydrochlorothiazide, was associated with a significant concentration-dependent decrease in bradykinin-like immunoreactivity in the cheek pouch suffusate (P < 0.05). Prostaglandins and changes in vasomotor tone did not modulate the effects of furosemide on bradykinin-induced responses. These data indicate that loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa in a specific fashion, probably by amplifying local bradykinin catabolism. We suggest that topical loop diuretics could be useful in the treatment of oral mucosa inflammation elicited by bradykinin.

Adenosine↗
PubMed1998

Pseudoporphyria cutanea tarda induced by furosemide in a patient undergoing peritoneal dialysis.

We report on a 32-year-old female patient undergoing peritoneal dialysis for diabetic nephropathy who developed blisters and cutaneous fragility on the dorsa of the hands. Histopathology of an early lesion showed a subepidermal cleft under a regular epidermis with single necrotic keratinocytes and normal dermal structures. In an advanced lesion, a subepidermal bulla and caterpillar bodies were found in the epidermis. Dermal vessel walls were normal and surrounded by a discrete lymphocytic infiltrate. Direct immunofluorescence revealed perivascular deposits of C3. Uroporphyrin and coproporphyrin levels of serum, urine and dialysate were repeatedly normal, confirming pseudoporphyria. The patient took furosemide (500 mg daily). Replacement of furosemide by ethacrynic acid led to spontaneous healing of the blisters. The patient was free of further lesions at the 1-year follow-up.

Adult↗
PubMedDate not supplied

Several different ion channel modulators abrogate contact hypersensitivity in mice.

A major obstacle in transdermal delivery of drugs is the development of adverse skin sensitization reactions. We tested the concept that ion channel modulators as a class of agents suppress contact hypersensitivity in a mouse model. Mice were sensitized to several contact sensitizing chemicals including dinitrochlorobenzene (DNCB) and a sensitizing drug, nadolol. We report our successful use of several ion channel modulators in suppressing contact hypersensitivity, including amiloride, ethacrynic acid (ECA), nifedipine and verapamil. For this purpose, Balb/c female mice were sensitized with DNCB, and abrogation of induction of contact hypersensitivity reaction (CHR) was examined by topical pretreatment of the target-sensitized skin with amiloride, nifedipine and pairwise combinations of these agents with ECA, a potassium ion channel blocker. Abrogation of induction of CHR was observed in all cases. In addition, suppression of contact hypersensitivity was observed in nadolol-sensitized mice pretreated with either verapamil or nifedipine. The results indicate that ion channel inhibitors are broadly effective inhibitors of allergic contact dermatitis and may be useful for facilitating the transdermal delivery of therapeutic drugs that have sensitization potential.

Amiloride↗
PubMed1983

Chloride- and bicarbonate-stimulated ATPase activity in bovine lens epithelium.

An anion-stimulated, ouabain-insensitive Mg2+ATPase activity has been found in fresh homogenates prepared from capsules and epithelia of bovine lenses. Approximately equal activity was observed in the presence of HCO3- or of Cl-. The stimulation of each anion obeys saturation kinetics, with an optimum at approximately 20 mM Cl- or HCO3-. Whereas SCN- inhibits anion-activated ATPase in most other tissues, it failed to inhibit Cl- - or HCO3--stimulated ATPase activity in the bovine lens. On the contrary, SCN- proved a potent activator of the enzyme. However, in keeping with other tissues, OCN- and the diuretic drugs, furosemide and ethacrynic acid are inhibitory. ATP is the primary substrate for the enzyme, which also shows some activity on GTP, ITP, and even ADP. Little Na+/K+-dependent ATPase activity was observed in the fresh homogenate, but it increased in lyophilized preparations. In contrast, the lyophilized preparations showed no anion-dependent ATPase activity. It is postulated that active bicarbonate ion transport in the lens may be mediated by this anion-dependent ATPase.

Adenosine Triphosphatases↗
PubMed1990

Sex differences in the subunits of glutathione-S-transferase isoenzyme from rat and human kidney.

Glutathione-S-transferase (GST) isoenzymes were purified from cytosolic preparations from kidneys of male and female rats and kidney cortical specimens from 2 male and 1 female human subjects. GST isoenzyme expression was analyzed by SDS-PAGE, measurement of catalytic activities with specific substrates and determination of their subunits by ELISA and Western blotting using specific antibodies. GST from female rat kidneys showed a preponderance of subunits 3 and 4; levels of these isoenzymes were 3-4 times greater in females than in males. Levels of subunits 1 and 2 were 1.5-2 times greater in the male rat kidneys. Additional minor bands at 24 and 22 kD were observed in GST preparations from both male and female rat kidneys while a band at 25.3 kD was observed only in the male rat kidney. These bands did not react with antibodies to GST 1-1, GST 2-2 or GST 3-4. Both male and female human kidney samples contained GST isoenzymes comparable to the near-neutral (25-5 kD) and basic forms (25 kD) of GSTs found in human liver. In addition a 28-kD band was present in GST preparations from both male and female human kidneys. Additional bands at 29 and 25.2 kD were present only in male human kidneys. Both the kidney cytosol and the total GSTs prepared from female rats shared 2- to 4-fold greater activity with 1,2-dichloro-4-nitrobenzene, ethacrynic acid and trans-4-phenyl-3-buten-2-one than those from males. The measurement of specific subunit amounts by ELISA were in agreement with these results.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1968

Correction of metabolic alkalosis by the kidney after isomertric expansion of extracellular fluid.

Metabolic alkalosis was induced in dogs by administering ethacrynic acid and sustained by feeding a chloride-deficient diet. At the height of the alkalosis extracellular fluid was expanded "isometrically," i.e., with an infusion that duplicated plasma sodium, chloride, and bicarbonate concentrations. Correction of metabolic alkalosis promptly followed such expansion and was attributed to the selective retention by the kidneys of chloride from the administered solution. Since plasma chloride concentration was not increased as an immediate consequence of the infusion, it is concluded that the change in renal tubular function that led to the selective retention of chloride must have been mediated by factors independent of filtrate chloride concentration.A decrease in circulating mineralocorticoid level, as a consequence of volume expansion, does not seem to account for this change in tubular function since identical studies in dogs receiving excessive amounts of 11-deoxycorticosterone acetate during the day of infusion yielded similar findings. Moreover, no other consequence of volume expansion appears to be sufficient to cause this change in tubular function in the absence of metabolic alkalosis; when the alkalosis was corrected with hydrochloric acid before infusion, isometric expansion of extracellular volume did not induce selective chloride retention. We suggest that isometric expansion during metabolic alkalosis causes a decrease in proximal sodium reabsorption that relinquishes filtrate to a more distal site in the nephron and that this site may retain chloride preferentially when hypochloremia or chloride deficiency is present.

Acid-Base Equilibrium↗
PubMed1997

Study of oxidative-stress in rifampicin-induced hepatic injury in growing rats with and without protein-energy malnutrition.

1. Rifampicin (RMP) induced hepatic injury was investigated in growing rats. The interaction of moderate and severe protein-energy malnutrition (PEM) was also investigated. 2. Status of oxidative/antioxidative profile was studied by the mechanistic approach, to enumerate the nature of injury. 3. Successful hepatic injury in rats was produced by giving intraperitoneal injection of RMP (50 mg/kg/day). 4. Hepatic lipid peroxidation was significantly increased in all the RMP treated rats. 5. Superoxide dismutase, catalase and glutathione peroxidase activities in the hepatic tissue decreased with RMP treatment. 6. Hepatic thiols represented as total and protein-bound thiols, showed significant elevation, whereas the non protein thiols remain unchanged with RMP treatment. 7. Glutathione-S-transferases also showed significant elevation against 1,2-dichloro-4 nitrobenzene (DCNB) and ethacrynic acid (EA) as substrates. 8. The oxidative/antioxidative profile was observed to be more severely affected with coexistence of malnutrition. 9. Histopathological correlation showed an additional fatty infiltration of hepatocytes with coexistence of malnutrition. 10. Thus, in conclusion, it can be speculated that an altered oxidative/antioxidative profile is the closely associated with production of RMP induced hepatic injury.

Alanine Transaminase↗