The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats.

We investigated whether lack of the canalicular multispecific organic anion transporter in transport-deficient (TR-) rats would result in plasma and urinary accumulation of troglitazone or its major metabolites and whether any accumulation would be associated with increased levels of bilirubin or bile acids. Administration of a single oral dose of troglitazone (200 mg/kg) to TR- rats resulted in 2- and 50-fold increases in plasma levels and 30- and 500-fold increases in urinary amounts of troglitazone sulfate and troglitazone glucuronide, respectively, compared with normal rats. No changes were found in the plasma concentrations and urinary amounts of troglitazone or troglitazone-quinone. Accumulation of troglitazone metabolites in plasma was accompanied by a 2-fold increase in the serum level of conjugated bilirubin in TR- rats, whereas no changes were observed in normal animals. Bile acids were detected in the urine of both TR- and normal rats, with an average 3-fold greater level found in the urine of TR- animals. Biliary metabolic profiles revealed a delay in the secretion of troglitazone sulfate and troglitazone glucuronide in TR- rats over the first 2- and 4-h periods, respectively. These results demonstrate the role of multidrug resistant associated protein-2 in biliary secretion of troglitazone glucuronide and troglitazone sulfate and suggest the presence of compensatory mechanisms responsible for transport of troglitazone metabolites and bilirubin-glucuronide at the basolateral and canalicular sites of hepatocytes.

Spontaneous hyperthyroidism in an aged male and female Macaca mulatta.

A 31-year-old male and a 31-year-old female rhesus monkey developed clinical signs consistent with hyperthryoidism. These included a ravenous appetite, hyperactivity, and accentuated ratchet movement and hand tremors while performing fine motor tasks. Bilaterally enlarged thyroid glands were palpated in both monkeys. A unique clinical finding of the female as the hypertrophic cardiomyopathy. The T3 and T4 levels in the male rhesus were 3.79 ng/ml and 28.20 microg/dl, respectively. T3 and T4 levels in the female were 4.33 ng/ml and 22.2 microg/dl, respectively. A biopsy of the enlarged thyroids demonstrated a typical multinodular goiter with cystic hyperplasia. The female rhesus was successfully treated with methimazole, but the hypertrophic cardiomyopathy did not resolve. The relationship between erythrocytosis and T4 levels common to humans and cats is also evident in the rhesus monkey.

Arrhythmia prevalence during ambulatory electrocardiographic monitoring of beagles.

Ambulatory ECG, approximately 18 to 24 hours in duration, were obtained from 113 male and 115 female clinically normal, purpose-bred Beagles. The ECG analyzed semi-automatically (44 males, 46 females) were evaluated for heart rate, ventricular ectopic complexes (VEC), bradycardia, and sinus pause; those analyzed by visual inspection (69 males, 69 females) were evaluated for VEC, second-degree atrioventricular block, and supraventricular escape complexes. Mean heart rate was highest at times of maximal human contact (eg, feeding, cleaning) and lowest at periods of no human contact. Bradycardia was observed in 27 of 44 males (61.4%) and 18 of 46 females (39.1%). Sinus pause was identified in 33 of 44 males (75%) and 30 of 46 females (65.2%). Frequency of bradycardia and sinus pause tended to vary inversely with mean heart rate. Ventricular ectopic complexes were detected in 18.8 to 26.1% of the ECG analyzed by use of either method. Although VEC runs and bigeminy were observed, most VEC were single and occurred sporadically. Second-degree atrioventricular block was observed in 6 of 69 males (8.7%) and 14 of 69 females (20.3%); episodes often were single and occurred sporadically. Supraventricular escape complex occurred in 2 of 69 females (2.9%). Multiple types of abnormal complexes were observed in 2 of 69 males (2.9%) and 6 of 69 females (8.7%). Among clinically normal Beagles, ambulatory electrocardiography detects a higher percentage of dogs with VEC, second-degree atrioventricular block, and supraventricular ectopic complexes than does resting electrocardiography.

Gastric acid secretion in the cynomolgus monkey.

Gastric acid secretion was measured in male and female cynomolgus monkeys under basal conditions and in response to intravenous administration of pentagastrin (PG). There were no statistically significant differences between males and females in either basal or PG-stimulated gastric acid output. Neither were differences between males and females statistically significant when adjusted according to body weight. For both sexes combined, basal acid output was 17 +/- 20 muEq/h. Intravenous infusion of PG stimulated gastric acid secretion at dose rates of 1 micrograms/kg/h and greater. Maximal stimulation occurred at dose rates of 10 and 100 micrograms/kg/h, indicating gastric acid secretion plateaus above PG doses of 10 micrograms/kg. Acid secretion values in response to 100 micrograms of PG/kg/h for both sexes combined were 571 +/- 132 and 400 +/- 135 muEq/kg/h for peak acid output and maximum acid output, respectively. These data suggest that the cynomolgus monkey may be a useful model for gastric physiology studies of relevance to human beings.

Neural catecholamine deficiencies in the porcine stress syndrome.

A study was conducted to compare catecholamine concentrations in nervous tissues of stress-susceptible (SS) and stress-resistant (SR) pigs that were physically stressed. Ten pigs were included in each group on the basis of results of halothane screening tests, blood typing analysis, and examination for serum creatine kinase (CK) activities at 6 weeks of age. The nervous tissues analyzed included the substantia nigra (SN) and the caudate nucleus (CN) which were taken from pigs as soon as possible after death and frozen in liquid nitrogen. Tissues were radioenzymatically assayed for dopamine, norepinephrine, and epinephrine concentrations. The SS pigs exhibited significantly greater (P less than 0.001) CK activity concentrations than did those SR pigs before and after physical stress. Concentrations of dopamine, norepinephrine, and epinephrine in the CN of SS pigs were significantly lower (P less than 0.05) than those in the CN of SR pigs. Similarly, the SN of SS pigs had lower dopamine, norepinephrine, and epinephrine concentrations than did the SN of SR pigs. The catecholamine deficiencies observed in the porcine stress syndrome seem to have similarities with certain human extrapyramidal diseases.

Urinary and caudate nuclei catecholamine levels in stress-susceptible and normal swine.

Eight stress-susceptible and eight normal pigs were used in the first portion of the study. Urine samples were collected for 24 hr over 4 consecutive days while the pigs were kept in metabolism cages. Each 24-hr sample was assayed for epinephrine, norepinephrine and dopamine. Urinary levels of dopamine were lower (P < .01) in the stress-susceptible pigs. No significant differences in urinary epinephrine or norepinephrine were observed. The second portion of the study evaluated the catecholamines in the caudate nucleus of the brain. Six stress-susceptible and six control pigs were examined. Immediately after exsanguination, caudate nuclei were excised and frozen in liquid nitrogen. The caudate nuclei were assayed for catecholamines within 2 to 3 days of freezing. Caudate nuclei dopamine levels were lower (P < .01) in stress-susceptible pigs (5,961 ng/g) than in control pigs (10,878 ng/g). No significant differences in norepinephrine levels of the caudate nuclei were observed between the two groups.