Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice.

The expression of NHE2 and NHE3 on intestinal-brush border membranes suggests that both Na(+)/H(+) exchangers serve absorptive functions. Studies with knockout mice showed that the loss of NHE3, but not NHE2, causes diarrhea, demonstrating that NHE3 is the major absorptive exchanger and indicating that any remaining absorptive capacity contributed by NHE2 is not sufficient to compensate fully for the loss of NHE3. To test the hypothesis that NHE2 provides partial compensation for the diarrheal state of NHE3-deficient mice, we crossed doubly heterozygous mice carrying null mutations in the Nhe2 and Nhe3 genes and analyzed the phenotypes of their offspring. The additional loss of NHE2 in NHE3-deficient mice caused no apparent reduction in viability, no further impairment of systemic acid-base status or increase in aldosterone levels, and no apparent worsening of the diarrheal state. These in vivo phenotypic correlates of the absorptive defect suggest that the NaCl, HCO, and fluid absorption that is dependent on apical Na(+)/H(+) exchange is due overwhelmingly to the activity of NHE3, with little contribution from NHE2.

Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2.

To study the role of Na+/H+ exchanger isoform 2 (NHE2) and isoform 3 (NHE3) in sodium-fluid volume homeostasis and renal Na+ conservation, mice with Nhe2 (Nhe2-/-) and/or Nhe3 (Nhe3-/-) null mutations were fed a Na+-restricted diet, and urinary Na+ excretion, blood pressure, systemic acid-base and electrolyte status, and renal function were analyzed. Na+ -restricted Nhe2-/- mice, on either a wild-type or Nhe3 heterozygous mutant (Nhe3+/-) background, did not exhibit excess urinary Na+ excretion. After 15 days of Na+ restriction, blood pressure, fractional excretion of Na+, and the glomerular filtration rate (GFR) of Nhe2-/-Nhe3+/- mice were similar to those of Nhe2+/+ and Nhe3+/- mice, and no metabolic disturbances were observed. Nhe3-/- mice maintained on a Na+-restricted diet for 3 days exhibited hyperkalemia, urinary salt wasting, acidosis, sharply reduced blood pressure and GFR, and evidence of hypovolemic shock. These results negate the hypothesis that NHE2 plays an important renal function in sodium-fluid volume homeostasis; however, they demonstrate that NHE3 is critical for systemic electrolyte, acid-base, and fluid volume homeostasis during dietary Na+ restriction and that its absence leads to renal salt wasting.

Pharmacological properties of a new fluoroquinolone on the central nervous system in rodents.

The pharmacological effects of the novel fluoroquinolone 7-(1R,4R-2,5-diazebicyclo[2.2.1]heptan-2-yl)-1-(1,1-dimethyl )ethyl-6-fluoro - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (BMY-40062, CAS 116143-32-9) on central nervous system were investigated in mice and rats, in comparison in some cases with those of reference quinolones. BMY-40062 showed no effect on general behavior, spontaneous activity, body temperature and neuromuscular coordination in rats at the doses of 1000 and 250 mg/kg. None of the quinolones tested including BMY-40062 modified the seizures induced by bicuculline, a specific GABA A antagonist. BMY-40062 and ciprofloxacin did not consistently influence the pentetrazol-induced convulsions. On the contrary, pefloxacin exhibited a marked convulsivant activity. In the fenbufen (non-steroidal anti-inflammatory drug)-induced seizure model, BMY-40062 showed no effect. Enoxacin, norfloxacin followed by ciprofloxacin elicited a convulsivant effect in presence of fenbufen. Under these experimental conditions, BMY-40062 had no effect on the central nervous system compared to the other tested quinolones in rodents.

A radiotelemetry system for chronic measurement of blood pressure and heart rate in the unrestrained rat validation of the method.

Chronic measurements of systemic arterial blood pressure and heart rate via a chronically implanted telemetric transmitter in unrestrained rats, was validated in a three-phase study. In the first part, week-to-week variability of systolic, diastolic, and mean arterial pressures, and heart rate was found to be minimal over the course of nine weeks. In the second part, the reproducibility of cardiovascular response to three successive administration of sotalol, an antihypertensive agent, was studied. In the last part, cardiovascular parameters determined by telemetry were compared to those obtained by direct arterial catheterization and showed a good linear correlation between those two methods.