Long-term hypoxia changes myometrial responsiveness and oxytocin receptors in the pregnant ewe: differential effects on longitudinal versus circular smooth muscle.

Previous studies from our laboratory demonstrated that long-term hypoxia (LTH) altered in vitro contractile responses to oxytocin in full-thickness myometrial strips from pregnant sheep. The present study was designed to determine, first, if the reduced contractile response to oxytocin following LTH is the result of combined effects on longitudinal and circular smooth muscle or if the effect is specific to a single muscle layer and, second, if the reduced contractile response to oxytocin following LTH is caused by changes in oxytocin-receptor protein. Pregnant ewes were maintained at high altitude (3820 m) from Day 30 to Days 137-142 of gestation, when the ewes were killed for collection of myometrial tissue. Tissue was also collected from age-matched, normoxic controls. Longitudinal and circular layers were separated, length-tension curves generated to determine optimal resting tension, and all strips exposed to increasing half-log doses of oxytocin ranging from 10-12 to 10-6.5 M. The expression of oxytocin-receptor protein was measured using Western blot analysis. We found that LTH did not affect KCl-induced contraction of either smooth muscle layer, whereas the sensitivity of both myometrial layers to oxytocin was altered. A decreased maximum contractile response of the circular layer to oxytocin was also observed. Additionally, LTH decreased expression of oxytocin-receptor protein in the circular layer and increased levels in the longitudinal layer. Results from the present study indicate that LTH alters contractile responses and oxytocin-receptor protein expression in a layer-specific manner in the pregnant sheep myometrium.

Fetectomy alters maternal pituitary-adrenal function in pregnant rhesus macaques.

The interplay between the fetus and mother may play a key role in the regulation of primate pregnancy and parturition. This study was designed to test the hypothesis that fetectomy alters maternal pituitary-adrenal function. Between 117 and 122 days of gestation (term = 167 days), six rhesus macaques underwent surgery for catheter implantation. At surgery the fetuses were removed while the membranes and placenta were left in situ. Six additional intact catheterized pregnant animals served as controls. Animals were maintained under a 12L:12D cycle with lights-on from 0700 to 1900 h. Beginning at least 1 wk after surgery, maternal arterial blood samples were collected at 3-h intervals for 24 h for hormone and catecholamine analysis. This sampling protocol was repeated at weekly intervals until cesarean delivery at 151-157 days of gestation. Following fetectomy, plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were significantly lower (36%, 35%, and 44%, respectively) compared with control animals (P;lt 0.05). Despite a significant reduction in overall levels, the rhythm in maternal plasma cortisol was maintained following fetectomy. Plasma dopamine and norepinephrine were also depressed (P;lt 0.05), whereas epinephrine remained unaffected. Our data clearly demonstrate the role of the fetus in the regulation of the maternal pituitary-adrenal axis during gestation. This interaction plays a significant role in the regulation of maternal endocrine function that may influence the initiation of labor.

Pharmacokinetic and fetal cardiovascular effects of enalaprilat administration to maternal rhesus macaques.

OBJECTIVE: The purpose of this study was to determine the extent of placental transfer of the angiotensin-converting enzyme inhibitor enalaprilat and the effects on maternal and fetal cardiovascular parameters. STUDY DESIGN: Between gestational days 122 and 126 (term 167 days) five rhesus macaques underwent surgery for implantation of maternal and fetal vascular catheters. At least 4 days after surgery maternal and fetal blood pressures and heart rates were recorded for 1 hour. This was followed by a 5-minute maternal venous infusion of saline solution vehicle and recording for an additional hour. Enalaprilat was then infused over 5 minutes through the maternal femoral artery at doses of 0.05, 0.1, or 0.2 mg/kg. Maternal and fetal arterial blood samples were collected for determination of blood gas status and plasma enalaprilat concentrations. RESULTS: Enalaprilat rapidly crossed the placenta, and fetal values for areas under the concentration time curve were 50% to 65% of maternal values across dose groups. Drug was retained in the fetal plasma approximately threefold to fourfold longer than in maternal plasma. Maternal heart rate, blood pressure, arterial Po2 and pH were unchanged after enalaprilat infusion, as were fetal heart rate and blood gases. In contrast, fetal arterial pressure decreased significantly (19% to 23%, p < 0.01) after maternal treatment with 0.1 and 0.2 mg/kg and remained depressed throughout the 6-hour study interval. At 0.05 mg/kg fetal arterial pressure was decreased by 13% from baseline; differences were not significantly different (p > 0.05). CONCLUSIONS: Results from this study indicate that enalaprilat rapidly crosses the primate placenta with a single intravenous administration to the mother, resulting in significant and prolonged reduction of fetal arterial pressure. Because maternal cardiovascular parameters were unaffected, enalaprilat appears to have a direct effect on fetal arterial pressure.

Fetectomy alters maternal endocrine and uterine activity rhythms in rhesus macaques during late gestation.

OBJECTIVE: The current study was designed to test the hypothesis that fetectomy will eliminate or substantially alter rhythms in maternal estradiol concentrations and subsequently reduce or eliminate uterine activity rhythms. STUDY DESIGN: Six rhesus macaques underwent surgery for catheter implantation between days 117 and 122 of gestation (term = 167 days). At surgery the fetuses were removed and the membranes and placenta remained intact. Thirteen additional catheterized pregnant animals served as controls. Maternal arterial blood samples were collected for hormone analysis at 3-hour intervals for 24 hours, starting at 9 AM. This sampling protocol was performed four times at weekly intervals until 151 to 157 days' gestation. RESULTS: A significant rhythm (p < 0.01) in estradiol was determined in the control animals with peak concentrations observed in the morning hours whereas the progesterone peak was observed at night. In the fetectomy group mean plasma estradiol concentrations decreased significantly from 312 +/- 34 to 110 +/- 8 pg/ml throughout the study (p < 0.01). Despite a trend toward elevated morning levels, the estradiol rhythm was ablated. The uterine contractile rhythm observed in the control animals with peak activity between 10 PM and midnight (p < 0.01) was also ablated after fetectomy. Basal concentrations of progesterone were significantly lower than control values. CONCLUSIONS: (1) Fetectomy resulted in the elimination of the maternal estradiol rhythm. (2) The uterine activity rhythm was lost after fetectomy. These data suggest that the fetus, by supplying precursors of estrogen, may play an indirect role in the regulation of maternal estradiol rhythms, which in turn appear to play a key role in regulating uterine activity rhythms.

Acute encephalopathy with hepatic steatosis induced by pantothenic acid antagonist, calcium hopantenate, in dogs.

In Japan, acute encephalopathy with hepatic steatosis resembling Reye's syndrome has been reported to occur after treatment with the pantothenic acid antagonist, calcium hopantenate. We studied the causal relationship and the pathogenesis in dogs. The agent was administered to seven dogs at increasing doses over a period of 8 weeks. Anorexia, vomiting, and diarrhea were common clinical findings. In four dogs, coma suddenly developed after the appearance of gastrointestinal signs. Three animals died during periods when they were not under direct observation. The effects of the agent appear to be related to dose. Laboratory findings representing significant changes at the time of coma included hypoglycemia, leukocytosis, hyperammonemia, hyperlactatemia, and elevated levels of serum transaminases. Microvesicular hepatic steatosis and mitochondrial abnormalities were consistent pathological findings. The hepatic mitochondria were enlarged and characterized by an increased number of cristae and the presence of crystalloid inclusions. In a second group of four dogs, pantothenic acid was given in addition to and in the same amount as calcium hopantenate at increasing doses over a period of 8 weeks. All four dogs survived the 8 weeks and only one developed mild anorexia. No significant biochemical changes were found and neither hepatic steatosis nor mitochondrial abnormalities were observed. The addition of pantothenic acid prevented the development of the disorder in the four animals. These results show that calcium hopantenate produces acute encephalopathy with hepatic steatosis in dogs, by inducing a deficiency of pantothenic acid. The hepatic mitochondrial changes of this reaction differ from those of Reye's syndrome.

[A case of involuntary movements probably produced by low doses of phenytoin intoxication].

A 49-year-old woman, who presented gait disturbance, orofacial dyskinesia, choreoathetosis and slightly cloudy consciousness, was admitted to our hospital on February 7, 1986. She had a slight fever and sore throat for the previous ten days. She had been treated for hypothyroidism as well as migraine with abnormal electroencephalogram since age 47, and was given a daily dosage of 70 mg phenytoin, 80 mg phenobal, and 125 mg dried thyroid. On admission, she was somnolent, and her speech was slurred. There were choreoathetosis of all extremities, orofacial dyskinesia, horizontal nystagmus, and dysdiadochokinesis with impaired heel-knee and finger-nose test. She could not only walk but also stand by herself. The plasma level of phenytoin was above 40 micrograms/ml (normal: 10 to 20 micrograms/ml). The plasma level of phenobal was normal. T3 was 0.76 ng/dl (normal: 0.96-1.92). T4 was 3.3 micrograms/dl (normal: 5.1-12.8). Biochemical screening, liver and kidney function tests were normal. Cerebrospinal fluid, ECG, chest X-rays and brain CT were normal. Electroencephalogram showed 5 to 6 Hz moderate voltage theta waves with artifacts of electromygram due to orofacial dyskinesia. After phenytoin was discontinued, the dyskinetic movement and gait disturbance disappeared, and her consciousness became alert in parall with reduction of plasma level of phenytoin. We suggested that acute phenytoin intoxication due to low dosages of phenytoin might be precipitated by upper respiratory infection and that involuntary movements in this case might be related to hypothyroidism.

[An autopsy case of carcinomatous sensory neuropathy associated with gastric adenosquamous carcinoma].

A 61-year-old man was admitted on May 1986 with complaints of hypesthesia and pain in the both legs, and of progressive difficulty in walking. Physical examination was unremarkable. On neurological examination, deep tendon reflexes were decreased in all extremities without pathological reflexes. Vibration sense was decreased severely at the medial malleolus and moderately at the anterior superior iliac spine. Joint sensation of the toes was moderately decreased. Light touch, temperature discrimination, and pinprick sensation were slightly decreased on fingers bilaterally and distal to the middle part of both legs. Muscle strength was normal. His gait was unsteady and Romberg's sign was positive. Finger to nose test and heel to knee test were mildly disturbed bilaterally. The sural nerve action potential was not elicited on electrical stimulation. Laboratory studies for malignancy showed gastric cancer. Only July 4, he underwent subtotal gastrectomy. Histologically it showed adenosquamous carcinoma. Postoperatively gait disturbance and pain in both legs improved slightly. Peak latencies of P2 of SEP following right and left posterior tibial nerve stimulation were 47. 9 msec and 48.8 msec on February 14, and 44.5 msec and 43.9 msec on October 6, 1986, respectively, and their postoperative shortening was evident. He died of multiple liver and lung metastasis of the gastric cancer in November 28, 1986. At autopsy, tumor metastasis were noted in liver, lung and perigastroduodenal and retroperitoneal lymph nodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Reye-like syndrome following treatment with the pantothenic acid antagonist, calcium hopantenate.

Three senile patients developed fatal acute encephalopathy while receiving calcium hopantenate. The clinical, biochemical, and pathological picture was similar to Reye's syndrome. Calcium hopantenate is a pantothenic acid antagonist. The serum levels of calcium hopantenate were high in coma, and that of pantothenic acid examined in one patient was lowered. Evidence obtained indicated that the Reye-like syndrome might be caused by calcium hopantenate possibly due to the induction of pantothenic acid deficiency.

Familial spinocerebellar degeneration as an expression of adrenoleukodystrophy.

A family with adrenoleukodystrophy and clinical manifestations of spinocerebellar degeneration was studied. Two adult male first cousins showed progressive limb and truncal ataxia, slurred speech and spasticity of the extremities. Brain CT scans demonstrated atrophy of the pons and cerebellum, in both cases. Very long chain fatty acids in plasma and erythrocyte membranes were elevated in the affected patients and intermediately increased in an aunt and the mother of one patient, thereby indicating homozygotes and carriers of adrenoleukodystrophy, respectively. This unusual type of adrenoleukodystrophy seems to be transmitted as an X-linked recessive trait.