Tissue oxygen tension in the stria vascularis.

Tissue oxygen tension in the stria vascularis was successfully measured in cats using the polarographic technique. A correlation study using the differential coefficient between oxygen tension in the stria vascularis and systemic blood pressure proved that vascular autoregulation is present in the mean systemic blood pressure range between 40 and 80 mmHg. The anatomical findings and the response patterns to different gas inhalations indicated that the type of vascular regulation present is more closely related to chemical control than to auto-regulation.

Nephrotoxicity and renal cell carcinoma after use of iron- and aluminum-nitrilotriacetate complexes in rats.

Wistar male rats were tested for nephrotoxicity and carcinogenicity after administration of ferric nitrilotriacetate [(NTA) CAS: 139-13-9] (Fe-NTA) [No. of rats (n) = 24] and Al-NTA (n = 24). The control rats were given AlCl3 (n = 10), NTA (n = 10), and saline (n = 10). Sublethal doses of Fe-NTA [5-7 mg Fe/kg (body wt)] and Al-NTA [1.5-2.0 mg Al/kg (body wt)] were chosen and injected ip for 3 months. AlCl3 and NTA were given in equivalent doses and saline was given in equivalent volumes. All the rats given Fe-NTA or Al-NTA had a depressed weight gain, polyuria, and glucosuria from the 1st week. Histologically, acute tubular necrosis and regenerating epithelial cells were observed. Regenerative atypical epithelial cells in the renal cortex were seen at the termination of Fe-NTA or Al-NTA administration. Control rats had no remarkable changes. After 1 year, primary renal cell carcinoma and metastases to liver, lung, and peritoneum were observed only in Fe-NTA-treated rats (14 of 18 surviving rats). On the contrary, there were no tumors in Al-NTA-treated rats (none of 12 surviving rats). The results suggest that nephrotoxicity and renal cell carcinoma are two independent phenomena from Al-NTA treatment and that a long-term sublethal dose of Al-NTA is not related to renal carcinogenicity.

Oxygenation through the round window membrane and the inner ear function.

The effect of oxygenation through the round window membrane was estimated using polarographic technique and the combined action potential of the inner ear. The calculated amount of oxygen permeable through the round window membrane (14% in room air and 80% in pure oxygen) revealed to have very limited effect in maintaining the inner ear potential. Carbogen inflation in maintaining the N1 potential during asphyxia was significantly effective only at 8 kHz. Oxygen supply by this route, however, may enable the inner ear tissue alive even in misery perfusion and recover the high tone potential as a therapy of otitis media with effusion.

Acute toxicity study of KB-944, a new calcium antagonist.

The acute toxicity of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) was studied in mice, rats and dogs: In mice and rats, toxic symptoms such as deceleration of spontaneous movement, ataxic gait, disappearance of righting reflex, reduction in body temperature and suppression of breathing appeared following administration of a single dose of KB-944. The symptoms developed in dogs were depression, bradycardia and labored breathing. The LD50 values determined in male and female rats were 1622 and 1555 mg/kg, respectively, for oral administration, 2216 and 2820 mg/kg for subcutaneous injection, and 762 and 479 mg/kg for intraperitoneal injection. The LD50 values determined in male and female mice were 2807 and 3856 mg/kg, respectively, for oral administration, greater than 4000 mg/kg for subcutaneous injection, and 815 and 777 mg/kg for intraperitoneal injection. As shown above, there was no evident difference in LD50 between sexes in either species of animals. Since many of the dogs given an oral dose larger than 1000 mg/kg vomited the drug, oral LD50 value could not be determined.

1-month subacute oral toxicity study of KB-944, a new calcium antagonist, in rats.

Diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944), a new Ca-antagonist, in the dose range of 25--200 mg/kg/day, was orally administered to Jcl:SD rats for five consecutive weeks and the following results were obtained. Neither death nor inhibition of body weight gain nor any toxic symptoms of the drug were noted in rats but an increase in water intake was found in the rats treated with over 100 mg/kg/day of KB-944. In plasma there was a decrease in alkaline phosphatase activity, creatinine level and cholinesterase activity and an increase in GPT activity and total cholesterol level in rats given a higher dosage of the drug. Weight gain of the liver, kidneys, heart, adrenals and ovaries, and degeneration in the epithelium of the renal proximal tubule were observed. However, none of these changes were serious and the maximum non-toxic dose of KB-944 was 25 mg/kg/day.

1-month subacute oral toxicity study of KB-944, a new calcium antagonist, in beagles.

Using male and female Beagles, we studied the subacute toxicity of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) administered orally and the following results were obtained. No dogs died during the administration period. Both male and female dogs given 200 mg/kg and those given 100 mg/kg underwent body weight decrease and inhibition of body weight increase, respectively. Enlargement of liver cells occurred in male dogs given 200 mg/kg and female dogs given 100 or 200 mg/kg. There were no further findings, even histopathologically, which showed any toxic effect of the drug. The maximum non-toxic dose of this drug was considered to be 30 mg/kg.