Search PubMed⌕ Search

Biomedical subjects

M Shibata

Publications and source records attributed to M Shibata.

At least 379 records · Page 21Linked to original sources
PubMed1994

Actinomycin D blocks interleukin-1 alpha-induced pial arteriolar dilation and increased prostanoid production in newborn pigs.

Effects of protein synthesis and cyclooxygenase inhibitors on interleukin-1 alpha (IL-1 alpha)- and histamine-induced pial arteriolar dilation and cerebrospinal fluid (CSF) prostanoid increases were examined in anesthetized piglets using closed cranial windows. Topical IL-1 alpha (10.8 micrograms) increased pial arteriolar diameter from 15 to 30 min after its infusion, and enhanced CSF prostanoids. Topical protein synthesis inhibitor, actinomycin D, at a concentration of 10(-8) M attenuated and 10(-6) M completely blocked both IL-1 alpha-induced vasodilation and CSF prostanoid increase. Inhibition of prostaglandin H synthases with indomethacin blocked both vasodilation and CSF prostanoid increase by IL-1 alpha. Topical histamine (10(-6) M) also increased pial arteriolar diameter and CSF prostanoids but without the delay seen between IL-1 alpha infusion and responses. These histamine effects were not modified by coinfusion of actinomycin D but blocked by indomethacin. These results suggest that, although IL-1 alpha and histamine do share the same mechanism insofar as activation of prostaglandin synthesis is concerned, an additional step appears to be involved for IL-1 alpha, likely involving de novo protein synthesis.

Animals↗
PubMed1994

Different pial arteriolar responses to acetylcholine in the newborn and juvenile pig.

Using the closed cranial window technique, the present study was designed to test the hypothesis that the pial arteriolar response to acetylcholine is age dependent. In newborn pigs (1-5 days old) pretreated with the phosphodiesterase inhibitor isobutyl methyl xanthine (IBMX), acetylcholine (10(-5) M) produced pial arteriolar constriction with no change in CSF cyclic GMP (cGMP) that was blocked by indomethacin (5 mg/kg i.v.). In contrast, in indomethacin- and IBMX-treated juvenile pigs (3-4 weeks old), acetylcholine (10(-) M) increased the pial arteriolar diameter by 17 +/- 1% and increased CSF cGMP by 2.1 +/- 0.3-fold. Similar vascular and biochemical changes for acetylcholine were observed in juvenile pigs pretreated with only IBMX. In the absence of IBMX, acetylcholine produced modest pial constriction in juvenile pigs. In the IBMX-pretreated juvenile pigs, L-nitroarginine (LNA; 10(-6) M) decreased pial arteriolar diameter by 15 +/- 2% and blocked acetylcholine-induced dilation and associated changes in CSF cGMP. A23187, a calcium ionophore, and sodium nitroprusside (SNP) elicited similar dilation and changes in CSF cGMP in both age groups. LNA blocked A23187 dilation, but SNP dilation was unchanged. L-Arginine (10(-3) M) partially restored acetylcholine- and A23187-induced dilation to indomethacin- and LNA-pretreated juvenile pigs. These data show that acetylcholine produces dilation in the juvenile pig through the production of the putative endothelium-derived relaxing factor (EDRF) nitric oxide but does not do so in the new born period. We speculate that contributions of EDRF to the acetylcholine-induced changes in pial arteriolar diameter develop with age.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]- pyridine-7-acetate (Y-23023), a new prodrug type of anti-inflammatory agent, and indomethacin after oral administrations in rats.

N,N-Dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]- benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M1) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M1 and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean Cmax (1.13 micrograms mL-1) of M1 after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean Cmax (3.38 micrograms mL-1) after 3 h in plasma. The mean AUC of M1 and indomethacin in plasma were 5.45 micrograms h mL-1 and 22.49 micrograms h mL-1, respectively. The mean tmax, Cmax and AUC of M1 in PMNs were 1 h, 11.1 ng (41 pmol)/10(8) cells and 58.6 ng (164 pmol) h/10(8) cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15.4 ng (57 pmol)/10(8) cells and 95.2 ng (266 pmol) h/10(8) cells, respectively. The PMNs/plasma ratio of M1 was about 2.8 times that of indomethacin. These results indicate that the association of M1, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.

Absorption↗
PubMed1994

Light/dye microvascular injury selectively eliminates hypercapnia-induced pial arteriolar dilation in newborn pigs.

Cerebral vasodilation in response to hypercapnia involves prostanoids in newborn pigs. This study examines the hypothesis that endothelial injury in vivo inhibits cerebral vasodilation and prostacyclin synthesis in response to hypercapnia, thus suggesting prostacyclin is a primary endothelium-derived vasodilating factor in newborn pig cerebral circulation. Anesthetized piglets with closed cranial windows were studied before and after injury caused by light/dye or before and after dye-only sham control. Light/dye injury was produced by injecting sodium fluorescein intravenously and passing filtered light from a mercury arc lamp through the cranial window. Ultrastructural changes to endothelium of pial vessels were produced that were characterized by surface pits, vacuolar cytoplasmic inclusions, and mitochondrial injury. After the light/dye injury, dilation to hypercapnia was absent while dilations to iloprost, isoproterenol, and sodium nitroprusside and constrictions to norepinephrine and acetylcholine were retained. Before light/dye treatment, hypercapnia increased cortical periarachnoid 6-keto prostaglandin F1 alpha concentration approximately threefold. However, after treatment, 6-keto-prostaglandin F1 alpha was not increased significantly in response to hypercapnia. These findings are consistent with the hypothesis that endothelial prostacyclin synthesis induced by hypercapnia participates in dilation of adjacent smooth muscle.

Animals↗
PubMed1994

CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation.

The role of cyclic nucleotides and prostanoids in cerebrovascular reactivity to increased carbon dioxide was investigated in anesthetized and artificially ventilated newborn pigs equipped with closed cranial windows. Pial arteriolar diameter was measured, and cortical periarachnoid cerebrospinal fluid (CSF) was collected from beneath the cranial window for determination of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and prostanoids. Progressively increasing arterial PCO2 (PaCO2) from normocapnia (33 +/- 1 mmHg) to hypercapnia (final PaCO2, 83 +/- 2 mmHg) resulted in dose-dependent pial arteriolar dilation and concomitant increases in cAMP, cGMP, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical CSF. N omega-methyl-L-arginine, N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, methylene blue, and LY 83583 did not inhibit cerebral vasodilation or the increases in cortical cAMP/cGMP induced by hypercapnia. Indomethacin abolished the vasodilatory response to hypercapnia and attenuated the hypercapnia-induced increases in cAMP and cGMP. Prostacyclin analogues increased both cAMP and cGMP levels in cortical CSF and induced pial arteriolar dilation (iloprost > carbaprostacyclin). The present data suggest that in newborn pigs cyclic nucleotides are involved in cerebral vasodilation in response to hypercapnia via a prostanoid-dependent mechanism.

Amino Acid Oxidoreductases↗
PubMed1994

Indomethacin reduces ischemia-induced alteration of blood-brain barrier transport in piglets.

Cerebral ischemia-reperfusion (Isc-Rep) alters blood-brain barrier (BBB) transport properties in piglets. Pretreatment with superoxide dismutase and catalase partially attenuates these effects. Activated O2 species produced with Isc-Rep in piglets are generated via prostaglandin (PG) H synthase. This experiment determines if products of PGH synthase alter BBB transport of sodium and albumin. Piglets anesthetized with nitrous oxide and halothane were divided into four groups: 1) control, 2) indomethacin (5 mg/kg iv) with no Isc-Rep, 3) Isc-Rep alone, and 4) Isc-Rep after pretreatment with indomethacin (Indo). Regional transfer coefficients (Kin) and regional cerebral blood flow (microspheres) were measured at 2 h reperfusion after 20 min total global cerebral ischemia. Kin values are represented as absolute values and also relative to blood flow to account for any changes in perfusion caused by ischemia and/or Indo. Indo alone did not alter sodium or albumin transfer compared with control animals. Isc-Rep alone caused a significant increase in sodium and albumin transport compared with all other groups (control cerebral sodium Kin was 18.2 +/- 2.7 cm3.g-1.s-1.10(6) vs. 32.9 +/- 3.1 for Isc-Rep, P < 0.05). In contrast, there was no significant difference in sodium or albumin transfer with Isc-Rep after Indo pretreatment (e.g., cerebral sodium Kin was 22.0 +/- 2.0 for Isc-Rep after Indo) compared with the control or Indo alone groups. Indo pretreatment effectively attenuates increased BBB transport of both sodium and albumin following cerebral ischemia. We conclude that products of PGH synthase are involved in BBB alterations of protein and cation transport that follow the early stages of cerebral reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Permissive role of prostacyclin in cerebral vasodilation to hypercapnia in newborn pigs.

Hypercapnic cerebral vasodilation in piglets is accompanied by increased cerebral prostanoid synthesis. Interventions that prevent the increased prostanoids also interfere with the vasodilation. However, the increased prostanoids may not produce vasodilation directly; instead, they may allow or enhance function of another mechanism. The present experiments examined the hypothesis that prostacyclin can allow, but may not directly produce, cerebral vasodilation to hypercapnia. Chloralose-anesthetized piglets were equipped with closed cranial windows for measurements of pial arteriolar diameters. Hypercapnia (arterial CO2 partial pressure approximately 70 mmHg) was administered before and after indomethacin (5 mg/kg iv) in all animals. Then artificial cerebrospinal fluid (aCSF) under the cranial window was replaced for the remainder of the experiment with aCSF containing vehicle, carbaprostacyclin (60 pM), iloprost (1 pM), prostaglandin E2 (PGE2; 1.7 and 3.3 nM), isoproterenol (10 and 100 nM), or sodium nitroprusside (1 microM), and hypercapnia was repeated. The two prostacyclin receptor agonists restored cerebral vasodilation to hypercapnia that had been blocked by indomethacin (to 92 +/- 31% and 76 +/- 11% of the before-indomethacin dilation for carbaprostacyclin and iloprost, respectively.) The highest dose of PGE2 partially restored the dilation (43 +/- 7% of the pre-indomethacin response). In contrast, neither isoproterenol nor sodium nitroprusside permitted significant dilation to hypercapnia following indomethacin treatment. These data indicate that prostacyclin can allow hypercapnic vasodilation to occur, but increasing levels do not appear to be necessary to cause the dilation directly. The short half-life of prostacyclin may explain why active prostanoid synthesis appears to be necessary for hypercapnia-induced cerebral vasodilation in newborn pigs.

Animals↗
PubMed1994

Inhibition of nitric oxide synthesis suppresses sleep in rabbits.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, on spontaneous and interleukin-1 (IL-1)-induced sleep were examined in rabbits. Animals were injected intracerebroventricularly or intravenously during the light phase with vehicle, L-NAME, IL-1, or the combination of L-NAME and IL-1. Injection of L-NAME (5 mg icv and 100 mg/kg iv) suppressed both non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) for 4-6 h. The sleep-suppressive effects are unlikely due to pressor responses to L-NAME because administration of L-NAME (5 mg icv) produced only a transient (3-4 min) slight increase in systemic blood pressure. Injection of IL-1 (20 ng icv) elicited fever, suppressed REMS, and increased NREMS for 6 h. NREMS was suppressed for 3 h after the combined intracerebroventricular injections of 5 mg L-NAME and 20 ng IL-1 and was elevated during postinjection hours 4-6. Administration of IL-1 (30 ng/kg iv) increased NREMS and brain temperature for 2 h. After the combined injection of IL-1 and L-NAME (100 mg/kg), NREMS was significantly suppressed during postinjection hours 1-5. It is not known whether the interactions between the sleep-suppressive effects of L-NAME and the NREMS-promoting effects of IL-1 are specific, being mediated via a common mechanism, or whether they are additive, being mediated via independent mechanisms. The pyrogenic and REMS-suppressive actions of either intracerebroventricularly or intravenously injected IL-1 were not affected by L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Evaluation of pulmonary arterial pressure in acute pulmonary embolism.

Twenty-six patients with acute pulmonary embolism underwent hemodynamic examination. Twenty-three of the patients were free of prior cardiopulmonary diseases. The other 3 patients had prior history of cardiac disease. In the 23 patients, the mean pulmonary arterial pressure (PAm) ranged from normal range to 35 mmHg at the time of the embolic event and generally declined within ten days after the embolic event. However, in the 3 patients with a history of disease, reelevation of PAm was observed during the pressure monitoring. PAm was positively correlated with the extent of pulmonary vascular obstruction (r = 0.863, p < 0.01) and also with mean right atrial pressure (RAm, r = 0.830, p < 0.01). In the presence of prior cardiac disease, PAm in patients with normal preembolic PAm increased proportionally to the extent of obstruction. Continuous hemodynamic monitoring is valuable for estimating the degree of embolic obstruction and the speed of embolus resolution and for detecting new embolic episodes in some cases.

Acute Disease↗
PubMed1994

Subarachnoid hematoma attenuates vasodilation and potentiates vasoconstriction induced by vasoactive agents in newborn pigs.

The effects of perivascular blood on pial arteriolar vasoreactivity to selected vasodilators and vasoconstrictors were examined in vivo in a newborn pig model. alpha-Chloralose-anesthetized newborn pigs were fitted with closed cranial windows 4 d after cortical subarachnoid injections of autologous blood. The responsiveness of pial arterioles to topical application of dilator agents [iloprost, prostaglandin E2 (PGE2), histamine, and sodium nitroprusside (SNP)] and vasoconstrictor agents [leukotriene C4 and endothelin-1 (ET-1) in artificial cerebrospinal fluid was studied in control and blood-injected piglets. Pial arterioles dilated dose dependently in response to topical application of iloprost, PGE2, histamine, and SNP in the control group, with increases in diameter of 54, 44, 67, and 50% at 10(-8) M, 10(-5) M, 10(-5) M, and 10(-5) M, respectively. These dilations in response to iloprost, PGE2, and histamine in the blood-injected piglets were significantly attenuated to 23, 18, and 34%, respectively, whereas the dilation in response to SNP was not changed (64%). Constrictions in response to 10(-8) M leukotriene C4 and ET-1 were 16 and 26% and were potentiated by hematoma to 36 and 43%, respectively. The lowest dose of ET-1 (10(-12) M) significantly dilated pial arterioles in the control but not in the blood-treated group. We conclude that prolonged exposure of pial arterioles to perivascular blood attenuates cerebrovascular dilation in response to selected vasoactive agents (iloprost, PGE2, and histamine) but not to SNP, suggesting that blood-induced attenuation of vasodilation and the generalized vasoconstriction may involve inhibiting the prostanoid/cAMP signaling pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Gastrointestinal physiology-regulated dogs: utilization of a bioavailability study of a new thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine, an antagonist of platelet-activating factor, and its preparations.

The gastrointestinal (GI) physiology of beagle dogs was effectively regulated with a combined treatment using intramuscular pentagastrin (10 micrograms/kg x 2) and intravenous atropine sulfate (0.02 mg/kg x 1). The superiority of the GI physiology regulated-dogs over the intact dogs was confirmed by comparative bioavailability studies using two classes of preparations of poorly water-soluble 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180). Both the fine granules and the tablets of Y-24180 exhibited similar absorption profiles in the intact dogs, whereas the latter preparations revealed a delayed plasma curve of the drug in the regulated-dogs. The absorption profiles of the two classes of Y-24180 preparations in the regulated-dogs simulated those in healthy volunteers. The combined-treatment of beagle dogs with pentagastrin and atropine sulfate was suggested to supply a useful animal model for predicting the absorption characteristics of poorly water-soluble drugs and their preparations in humans.

Administration, Oral↗
PubMed1994

Sustained release of phenytoin following the oral administration of phenytoin sodium/ethylcellulose microcapsules in human subjects and rabbits.

Phenytoin sodium was microencapsulated with ethylcellulose (EC) by a coacervation-phase separation method from ethyl acetate solution to develop a prolonged release dosage form of phenytoin. Release of phenytoin from the microcapsules (phenytoin sodium/EC) was evaluated by the JP dissolution test in JP disintegration media No. 1 and No. 2. The release rates of phenytoin from phenytoin sodium powders were extremely rapid in both media, however, the release rates from the microcapsules were much more retarded. Following the oral administration of microcapsules to rabbits, prolonged plasma concentrations of phenytoin were obtained, while microcapsules orally administered to human subjects showed prolonged urinary excretion of phenytoin metabolites.

Administration, Oral↗
PubMed1994

Utility of gastrointestinal physiology regulated-dogs: bioavailability study of a commercial sustained-release dosage form of theophylline.

The utility of gastrointestinal physiology regulated-dogs (regulated-dogs) was evaluated in a bioavailability study. The gastrointestinal physiology of beagle dogs was regulated with a combined-treatment of intramuscular pentagastrin and intravenous atropine sulfate. Theophylline has been regarded as a drug that is absorbed completely in the entire gastrointestinal tract but slowly in the colon for humans. A commercial sustained-release tablet (SR tablet) of theophylline and a commercial conventional tablet of aminophylline (theophylline hemiethilenediamine salt) were chosen as model preparations in this study. In the regulated-dogs, the drug absorption was almost complete for the conventional tablet. The bioavailability of the SR tablet accounted for 76% in the regulated-dogs and 71% in intact dogs relative to that of the conventional tablet in the regulated-dogs, respectively, but no significant difference was detectable between these values. An advantage of the regulated-dogs over the intact dogs was, however, revealed in the time-profiles of the cumulative percentage of theophylline absorbed from the SR tablet, suggesting a modification of drug absorption by the prolonged arrival of the tablet to the colon.

Animals↗
PubMed1994

Pathologic observations of pigs intranasally inoculated with serovar 1, 4 and 5 of Haemophilus parasuis using immunoperoxidase method.

Nineteen, 7- to 13-week-old pigs were inoculated intranasally with different strains of Haemophilus parasuis (serovar 1, 4 and 5), and the pathological lesions induced by each strain were compared. Eleven of thirteen pigs inoculated with either strain Nagasaki (serovar 5) or No. 4 (serovar 1) died between days 1 to 6 after inoculation, and had septicemic lesions, meningitis, or polyserositis. One of six pigs inoculated with strain SW124 (serovar 4) died with polyserositis, another one recovered after illness, and the remaining four pigs remained in good health. Five of the septicemic pigs had thrombi at many organs. Endotoxin was detected in the plasma of 10 pigs in the acute stage of infection. Using the immunoperoxidase technique, H. parasuis antigen was detected in lesions of infected pigs. In the serosal lesions the bacterial antigen was found mainly in the cytoplasm of infiltrating neutrophils and macrophages and appeared as degenerated bacteria and/or lytic bacterial material in dilated phagosomes. Many of the bacteria in the blood vessels of pigs with septicemic lesions were also degenerated. Although H. parasuis was reisolated from nasal secretions of infected pigs, the bacterial antigen could not be detected in the nasal cavities of these pigs. No lesions were observed in the parenchyma of the lung. However, H. parasuis antigen was detected in the tonsil of infected pigs.

Administration, Intranasal↗
PubMed1994

A full-coordinate model of the polymerase domain of HIV-1 reverse transcriptase and its interaction with a nucleic acid substrate.

We present a full-coordinate model of residues 1-319 of the polymerase domain of HIV-I reverse transcriptase. This model was constructed from the x-ray crystallographic structure of Jacobo-Molina et al. (Jacobo-Molina et al., P.N.A.S. USA 90, 6320-6324 (1993)) which is currently available to the degree of C-coordinates. The backbone and side-chain atoms were constructed using the MAXSPROUT suite of programs (L. Holm and C. Sander, J. Mol. Biol. 218, 183-194 (1991)) and refined through molecular modeling. A seven base pair A-form dsDNA was positioned in the nucleic acid binding cleft to represent the template-primer complex. The orientation of the template-primer complex in the nucleic acid binding cleft was guided by the positions of phosphorus atoms in the crystal structure.

Amino Acid Sequence↗
PubMed1994

[201Tl scintigraphic evaluation of tumor mass and viability of bone and soft-tissue tumors].

To characterize 201Tl uptake in patients with bone and soft-tissue tumor, we studied 49 patients with surgically proven tumors and one patient with a tumor diagnosed arteriographically. In 37 of our 50 patients, the tumor was evaluated with 201Tl and arteriography. Moreover, in 14 of patients with pre-operative chemotherapy, pathologic changes were graded on the basis of percent tumor necrosis as defined histologically. The percent tumor necrosis histologically was compared with changes in the scintigraphic and conventional angiographic studies. Radiologic comparisons demonstrated a high degree of correlation with images of 201Tl and both arterial and blood pool phase of 99mTc-HMDP. Ninety-six percent of 28 malignant tumors had positive 201Tl uptake. None of the patients showed any thallium accumulation in the soft tissues or skeleton adjacent to the lesion. Activity of 201Tl was mainly dependent upon a tumor blood flow and a vascular density. In of 14 cases with the preoperative chemotherapeutic treatment, 201Tl scintigraphic changes showed concordance with % tumor necrosis. Thallium-201 was superior to 99mTc-HMDP in predicting tumor response to chemotherapy. Interestingly, delayed images of 99mTc-HMDP of 5 responders with > 90% tumor necrosis showed decreased uptake in the adjacent bone to the tumor mass lesions. It seems to be quite all right to consider that a major determinant of 201Tl uptake is intratumoral angiogenecity, which is closely connected with tumor viability. Therefore, 201Tl is a sensitive radiopharmaceutical for detection of vascular rich bone and soft-tissue tumors, and appears to be a simple and an accurate test for evaluating the response to specific therapeutic regimens of malignant bone and soft-tissue tumors.

Adolescent↗