Increase in blood pressure with enhanced Na+, K+ -ATPase activity in stroke-prone spontaneously hypertensive rats after 4-weeks intake of rapeseed oil as the sole dietary fat.

Twenty stroke-prone spontaneously hypertensive rats were divided into 2 groups of 10 animals each, and fed a defatted diet and orally administered rapeseed (canola) oil or soybean oil at 10 (w/w)% of the consumed diet once a day for 4 weeks. At the 4th week of administration, the systolic blood pressure in the canola oil group was higher (235 +/- 2 mmHg, mean +/- S.E.M., N=10) than that in the soybean oil group (225 +/- 4 mmHg, N=10, P<0.05). In isolated, perfused mesenteric bed from these rats, the increase in perfusion pressure by norepinephrine, ATP, arachidonic acid, endothelin-1, angiotensin II or serotonin showed no between-group differences. There were also no between-group differences in the production of thromboxane A2 and prostaglandin 12 in the outflow by arachidonic acid injection. On the other hand, in the isolated aortic ring from the canola oil group, developed tension in potassium-free solution was enhanced with activation of Na+, K+ -ATPase. These results suggest that canola oil intake as the sole dietary fat increases systolic blood pressure of stroke-prone spontaneously hypertensive rats. The changes in vascular responsiveness to vasoconstrictors and production of prostanoids are unlikely to have relevance to the elevation of blood pressure. However, altered Na+, K+ -ATPase activity may play a role in the promotion of blood pressure elevation.

The influence of total body hyperthermia on brain haemodynamics and blood-brain barrier in dogs.

This study was designed to examine the influence of total body hyperthermia (TBHT) using an extracorporeal circuit with a heat exchanger on the cerebral blood flow (CBF), intracranial pressure (ICP), brain tissue pH, cerebral autoregulation and blood-brain barrier (BBB) permeability in dogs. The rectal temperature of the dow was raised to 41.5 degrees C, maintained at 41.5-42.0 degrees C for 2 hours (HT period) and then reduced to normothermia by cooling. Regional CBF was measured by the hydrogen clearance method before heating, during the HT period and after cooling. ICP and brain tissue pH were monitored during the TBHT treatment. Autoregulation of the CBF during the HT period was assessed by measuring the regional CBF and the ICP in a state of induced hypo- or hypertension. The influence of TBHT on BBB permeability was examined using an immunohistochemical technique. The regional CBF increased from 38.1 +/- 6.5 (mean +/- SD) to 49.1 +/- 9.8 ml/100 g/min and the ICP from 10.3 +/- 4.2 to 16.8 +/- 3.4 mmHg when TBHT was raised. These returned to normal values after cooling. The regional CBF and the ICP changed in parallel with drug-induced changes of mean arterial blood pressure during the HT period. These changes suggest that autoregulation of the CBF is paralysed during the HT period. Brain tissue pH decreased rapidly when the rectal temperature exceeded 41.0 degrees C. The pH was 7.18 +/- 0.05 during the HT period and was relatively stable. The pH returned to a normal value after cooling. Immunopositive stain for albumin was not observed in heated brain tissue except for the normally leaky pineal gland and the choroid plexus, indicating preservation of BBB during TBHT. These results suggest that brain oedema may occur easily due to paralysed cerebral autoregulation when the arterial blood pressure fluctuates excessively, so arterial blood pressure must be controlled strictly during TBHT.

Effect of whole-body hyperthermia on the development of peritumoral brain oedema.

The effect of whole-body hyperthermia on the development of peritumoral brain oedema and intracranial pressure was studied in cats with intracerebral transplanted tumour. Whole-body hyperthermia was achieved by means of extracorporeal circulation. The temperature within the brain tumour tissue was increased to 41.8 +/- 0.15 degrees C (mean +/- SD) for 2 h. Measurements of brain water content revealed that hyperthermia worsened the degree of peritumoral brain oedema. Microscopical observation demonstrated that extravasation of horseradish peroxidase, indicating disruption of the blood-brain barrier in the oedematous region, was more severe in animals exposed to hyperthermia than in non-treated animals. Intracranial pressure significantly increased from 13.5 +/- 5.26 mmHg to 25.8 +/- 6.16 mmHg (p < 0.05) during hyperthermia, although it was controlled at 20.7 +/- 2.60 mmHg by continuous infusion of glycerol. The results suggest that whole-body hyperthermia acting on a brain-bearing tumour caused an increase in intracranial pressure due to worsening of the degree of peritumoral vasogenic type of brain oedema. We emphasize that whole-body hyperthermia may be performed with careful monitoring of intracranial pressure for patients who have brain tumour.

Hypotensive effect of a phosphorus-containing novel angiotensin converting enzyme inhibitor, (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl)phosphinyl] oxy]-1-oxohexyl]-L-proline (SQ 29,852) in conscious hypertensive dogs.

The hypotensive efficacy of (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl) phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29,852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI) was examined in conscious two-kidney, one-clip Goldblatt hypertensive dogs. The acute hypotensive effect of SQ 29 852 was compared with that of captopril or enalapril at 3 mg/kg, p.o., for each, and the potencies were ranked as follows, enalapril greater than SQ 29,852 greater than captopril. On the other hand, the hypotension caused by repetitive dosing with SQ 29,852 (3 mg/kg, p.o./d for 7 d followed by another 7-d treatment with 10 mg/kg, p.o./d) was somewhat more marked than that by enalapril at the same dosage. Blood urea nitrogen (BUN) increased in all the animals given enalapril, while that in all of the SQ 29,852-treated animals did not increase. These results indicate that SQ 29,852 is a potent, and long-lasting ACEI with a possible low incidence of side effects.

[A fifty two-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in dogs].

A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a newly developed anti-allergic agent, was carried out in beagles by oral administration of 30, 90, 270 and 810 mg/kg/day for 52 weeks. The recovery study was carried out by the withdrawal for 5 weeks using control and the 810 mg/kg groups. The results are as follows: 1. Observation of general conditions revealed soft feces, mucous feces, and diarrhea in both sexes of the 270 and 810 mg/kg groups during the administration period, and these findings disappeared during the withdrawal period. One female of the 810 mg/kg group exhibited tremors in the legs and neck, staggering, a decrease of spontaneous motor activity, and clonic convulsions in Week 17 of administration and died on Day 118. One male of the same group exhibited whole body tremors and staggering from Week 32 to Week 52. 2. Body weight gain tended to be inhibited in males of the 810 mg/kg group during the administration period. The body weight of the female that died decreased rapidly after the appearance of neurological symptoms. The body weight of the male that exhibited neurological symptoms decreased after their appearance but later increased. 3. There were no abnormal changes in food consumption in all of the sacrificed dogs. The female that died did not eat at all after the appearance of neurological symptoms. The male that exhibited neurological symptoms did not eat at all for 1 week after their appearance, but the food consumption returned to normal thereafter. 4. Prothrombin times were prolonged in males of the 270 and 810 mg/kg groups at Week 26, and activated partial thromboplastin times were prolonged in males of the 810 mg/kg group at Week 52. 5. Plasma levels of alkaline phosphatase, GPT and LDH were elevated in some males and females of the 810 mg/kg groups. 6. No abnormalities due to IPD-1151T administration were found in urinalysis, opthalmological examination, electrocardiography, and fecal occult blood examination, or organ weights. 7. Autopsies including histopathological and electron microscopic examinations on the sacrificed dogs revealed no abnormalities. Subserosal hemorrhage in the base of the heart, congestion in the lungs, congestion and vacuolation in the liver and slight cell infiltration around vessels of the brain were found in the female that died.(ABSTRACT TRUNCATED AT 400 WORDS)

[Inventions for preservation of hormonal function in long-term culture of human functioning pituitary adenoma].

This study was designed to establish in vitro model systems in human hormone-producing pituitary adenomas that are analogous to the in vivo cellular environment. Mechanically dispersed cells composed of single cells and aggregates from 6 pituitary adenomas (3 GH producing adenomas and 3 prolactinomas) were cultured on microporous membrane cell culture inserts (Millicell-CM) coated with Basement Membrane Matrigel for up to 6 months. Growth hormone or prolactin in the medium was measured during the culture, and morphological feature in vitro was also compared with that of the original tumor at intervals. Not only single cells but also large aggregated cells which usually float in the medium when seeded on conventional plastic, were flattened and firmly attached to coated microporous membrane under the control of medium volume in culture. In both type adenomas, especially prolactinomas, surviving aggregated adenoma cells revealed preserved hormone activity and no dedifferentiation of cell characteristics after 6 months in culture. Particularly during the first 2 months in culture, close similarity existed between in vivo and in vitro conditions with regard to cell morphology and hormone release. These results indicate that this new culture method may further aid the investigation of in vitro cellular structure and function in human pituitary adenomas under conditions which closely mimic the in vivo cellular environment.

[Effect of calcium channel antagonist (nicardipine) on growth hormone and prolactin secretion in pituitary adenomas].

This study was designed to investigate the effect of calcium channel antagonist (nicardipine) on basal and bromocriptine-inhibited GH or PRL secretion in eight patients with pituitary adenomas (six GH producing adenomas and two prolactinomas). GH or PRL was measured in blood collected at intervals for 12 hours after oral administration of nicardipine (Nc) (40 mg) and/or bromocriptine (Br) (2.5 mg) in each case. In vitro, pituitary adenoma cells were incubated in media containing Nc (200 ng/ml) and/or Br (200 ng/ml) over a 72-h period, and then in drugs-free media for three days. Media were collected at 24-h intervals and assayed for GH or PRL. In three of six GH producing pituitary adenomas, GH secretion was inhibited by Nc both in vivo and in vitro. In prolactinomas, PRL secretion was inhibited by Nc in vitro, but in vivo, an increase of plasma PRL levels was observed after Nc administration in one of two cases. In two acromegalic patients and one patient with prolactinoma, Nc reduced the suppression of GH or PRL secretion induced by Br. These findings indicate that influx of extracellular calcium plays an important part in both GH and PRL secretion in functioning pituitary adenomas, and that Nc effects on GH and PRL secretion in pituitary adenomas by blocking of influx of calcium and/or antidopaminergic action. It is considered that the combined administration of calcium channel antagonist (Nc) and Br for acromegalic patients and administration of Nc for patients with prolactinomas should be avoided.

[Influence of total body hyperthermia on normal brain tissue].

The influence of total body hyperthermia (TBHT) on normal brain tissue was studied in 40 dogs. The dogs were anesthetized with sodium thiopental (10 mg/kg/hr) intravenously, and were ventilated by artificial respirator. The TBHT was induced by extracorporeal circuit in cooperating a heat exchanger. Rectal temperature was raised to 41.5 degrees C and maintained at 41. 5 -42.0 degrees C for 2 hr (HT period) and was then fallen to normothermia by cooling, Regional cerebral blood flow (CBF) was measured by hydrogen clearance method before heating, during and after TBHT treatment. Brain temperature, rectal temperature, intracranial pressure (ICP), brain tissue pH and electroencephalography (EEG) were monitored continuously during TBHT. Histopathological changes of the brain tissue were studied in dogs killed just after TBHT and 2 weeks after TBHT. Autoregulation of the CBF during HT period was assessed by measuring the regional CBF and the ICP at a state of induced hypo- or hypertension. The brain temperature (at the depth of 5mm under the brain surface) was usually 0.6 degrees C lower than the rectal temperature during HT period. The regional CBF increased from 38.1 +/- 6.5 (mean +/- SD) to 49.1 +/- 9.8ml/100 g/min by raising rectal temperature, and it recovered to a normal value after cooling. The ICP increased from 10.3 +/- 4.2 to 16.8 +/- 3.4 mmHg by raising rectal temperature, and it returned to a normal value after cooling. Brain tissue pH decreased from 7.33 +/- 0.02 to 7.17 +/- 0.09 rapidly when the rectal temperature reached 41.0 degrees C, and then returned to a normal value gradually after the start of cooling.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive action of the novel angiotensin converting enzyme inhibitor benazepril hydrochloride in hypertensive rat models.

Single or repeated administration of benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4), a novel angiotensin I converting enzyme inhibitor, (0.3-10 mg/kg p.o.) caused significant antihypertensive effects in renal and spontaneously hypertensive rats (SHR). The antihypertensive effects of benazepril hydrochloride was about 3 times as potent as that of captopril in these models. Single administration (0.3-3 mg/kg p.o.) of benazepril hydrochloride and enalapril maleate showed an equipotent antihypertensive effect in SHR. Benazepril hydrochloride (3-30 mg/kg p.o.), however, showed no clear effect on the blood pressure and heart rate in normotensive or DOCA/salt hypertensive rats.

[Experimental brain tumor in adult mongrel cat].

Small animal models such as the rat have serious limitations for multiple human scale instrumentation, surgical manipulations, and computerized tomographic (CT) evaluations, so that large animal models are required for the study using them. Although brain tumors induced with Rous sarcoma virus in neonatal beagle or adult monkey had been reported, these animals are very expensive ones for tumor research. A major drawback of virally induced brain tumor model is, moreover, the need for specialized viral facilities and safety precautions for laboratory personnel. In this paper, a cat glioma model implanted with C6 glioma cells derived from rats injected with N-nitrosomethylurea is reported. For an implantation dose of 5 x 10(5) cells/50 microliters, C6 glioma cells were suspended in modified Eagle medium supplemented with 10% fetal bovine serum and 0.5% agar. Twenty adult mongrel cats were injected with 5 x 10(5) C6 glioma cells intracerebrally. Implanted cats had brain tumors of about 10 mm in diameter with a yield of 80%. The mean survival was about 3 weeks after implantation. Tumors developed as spheroidal, hemorrhagic masses with central areas of necrosis and peripheral edema. They were located within the parenchyma of the implanted region. This tumor possessed many of the histological and radiological characteristics of human glioblastoma such as the following: Areas of hemorrhage and necrosis surrounded by pseudopallisading were observed within the tumor consisting of spindle-shaped cells with pleomorphic nuclei. A mass lesion with ring or garland-like enhancement surrounded by brain edema was shown on the CT scans.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of Maffucci's syndrome with brain-stem tumor].

A case of Maffucci's syndrome with brain-stem tumor is reported. A 17-year-old man with a history of diplopia and unsteady gait for 5 months was admitted to our hospital on May 6, 1987. Neurological findings on admission disclosed left VIIth cranial nerve and bilateral VIIth nerve palsies and mild quadriplegia with a bilateral Babinski sign. His left limbs were deformed and disproportionally shortened since birth, and there were multiple enchondroma of the phalanges. Several bluish subcutaneous soft tumors were present on his left hand. Histological examination of a skin lesion confirmed the cavernous hemangioma. A CT scan showed diffuse symmetrical low density area in the brain-stem. No contrast enhancement was noted. Sagittal magnetic resonance imaging (MRI) demonstrated swelling of the brain stem especially in the pons and medulla oblongata. Left vertebral angiogram showed an avascular mass in the region brain stem. Brain-stem glioma being strongly suspected, both radiation therapy and chemotherapy were performed. After 66 Gy irradiation and ACNU administration, his neurological deficits gradually improved. The patient was discharged from the hospital on foot on August 7, 1987. The sagittal MRI taken on January 24, 1988 disclosed that the brain-stem swelling was apparently diminished. Maffucci's syndrome is a congenital, non-hereditary mesodermal dysplasia associated with multiple enchondromas and subcutaneous hemangioma. Although numerous tumors of the central nervous system have been described in association with Maffucci's syndrome, to our knowledge, no mention has been made of lesions in the brain-stem. The present case is an extremely rare instance of this syndrome complicated by the occurrence of a brain-stem tumor.