Biomedical subjects

M Majima

Publications and source records attributed to M Majima.

At least 19 recordsLinked to original sources

PubMed2005

Regulatory expression of lipoxin A4 receptor in physiologically estrus cycle and pathologically endometriosis.

Expression of receptors for prostaglandin (PG) and leukotriene (LT) has been reported to detect in endometrium and smooth muscle of uterus, suggesting involvement of these arachidonic metabolites in endometrial pathology and reproductive biology. Lipoxin (LX), which is produced by lipoxygenases from arachidonic acid, has been characterized as an anti-inflammatory lipid mediator. Biological actions of Lipoxin A4 (LXA4) are mediated through the specific receptor. In order to know roles of LXA4 in female genitalia, expression of LXA4 receptor mRNA was quantified by real-time polymerase chain reaction. Significantly higher expression of the receptor was detected in endometrium and myometrium than ovary in normal rats. Expression of the receptor in endometrium was increased at stage of proestrus cycle under physiological condition. Exogenous administration of progesterone into female rats significantly reduced the expression, while administration of estradiol or pregnant mare serum gonadotropin (PMSG) did not. Both, endometrium in experimental endometriosis induced in rats and the tissues from patients with ectopic endometriosis showed a higher expression of LXA4 receptor compared to the normal tissues. In contrast, expressions of BLT1 and BLT2, receptors for leukotriene B4, did not change in the endometriosis. These observations suggest a possible role of LXA4 and the receptor under physiological estrus cycle and pathological condition as endometriosis.

17-alpha-Hydroxyprogesterone↗

PubMed2005

Effect of MKC-733, a 5-HT receptor partial agonist, on bowel motility and symptoms in subjects with constipation: an exploratory study.

BACKGROUND: MKC-733, a 5-HT(3) receptor partial agonist, is a novel enteroprokinetic compound. OBJECTIVE: The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined. METHODS: The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22-67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0.2 and 0.5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low (n = 6) and high (n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms. RESULTS: Percent elimination increased after treatment with 0.5 mg MKC-733 compared with placebo treatment in the whole group (70.4 +/- 33.5% vs. 47.1 +/- 36.6%, mean +/- SD, P < 0.05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0.5 mg MKC-733 compared with placebo (7.1 +/- 0.9 vs. 5.9 +/- 0.5, P < 0.05; 60.0 +/- 35.8% vs. 13.3 +/- 19.4%, P < 0.05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo (P < 0.05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted. CONCLUSION: Multiple doses of 0.5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population.

Adult↗

PubMed2004

[Long survival with chronic ventricular fibrillation under support of uni-left-ventricular assist system].

Few minutes of suspended malignant ventricular arrhythmia may be permitted for the patient with left ventricular assist system (LVAS). However, longer and continuous ventricular arrhythmia, especially ventricular fibrillation (Vf), may induce the low output of LVAS, which leads circulatory collapse immediately. Our presenting case is a female dilated cardiomyopathy patient who has been supported with LVAS. Four months after the LVAS installation, her electrocardiogram has changed to Vf without any symptoms. Her ventricular function has never recovered, even ventricular tachycardia. She has been a candidate of heart transplantation for more than 19 months with this rare hemodynamic condition (LVAS+Vf), like the Fontan circulation. Her performance status is limited due to deceasing of the LVAS flow, which caused by the change of her position: 2.5-2.9 l/min (lie down) to 2.0 l/min (rise). Her peak VO2/W is 6.9 ml/min/kg measured by the cardio-pulmonary exercise test. However, she has developed her general status by doing rehabilitation program and is able to walk for more than 100-150 meters.

Adult↗

PubMed2003

Amelioration of hyperalgesia by kinin receptor antagonists or kininogen deficiency in chronic constriction nerve injury in rats.

OBJECTIVE: The present study was designed to examine the involvement of bradykinin in thermal and mechanical hyperalgesia induced by chronic constriction nerve injury (CCI) using B1 and B2 receptor antagonists and mutant kininogen-deficient rats. METHODS: Sprague-Dawley (SD) rats and Brown Norway (B/N-) rats given CCI treatment on day 0, were used as a model of neuropathic pain. Either a kinin B1 antagonist des-Arg9-[Leu8]-bradykinin or the receptor B2 antagonist HOE-140 was constantly infused into the left jugular vein of SD rats on days 15 to 22 after CCI. Vehicle-treated rats and sham-operated rats without nerve injury were also prepared as controls. In all rats, we observed pain behavior, and measured the latency period of paw withdrawal from the thermal stimuli and, with von Frey filaments, the mechanical pain threshold, before surgery and on days 14 and 22 after CCI. B/N-Katholiek rats, which congenitally lack plasma kininogen and release no kinin, were also tested for hyperalgesic parameters. Expression of kinin receptor mRNA in the dorsal root ganglia was detected by RT-PCR. RESULTS: Most of the rats (88%) showed some pain behavior, which was reduced to 67% by a B1 antagonist and to 57% by a B2 antagonist infused between days 15 to 22. Thermal hyperalgesia was significantly reduced from 7.25 +/- 0.41 sec (mean +/- SEM) to 8.36 +/- 0.41 sec in paw withdrawal latency on day 22 by a B1 antagonist and from 7.24 +/- 0.19 sec to 8.23 +/- 0.21 sec by a B2 antagonist (P < 0.05). Mechanical hyperalgesia was also ameliorated from 0.02 +/- 0.007 g force to 0.16 +/- 0.08 g force in pain threshold by a B1 antagonist and from 0.03 +/- 0.007 g force to 0.10 +/- 0.003 g force on day 22 by a B2 antagonist. Moreover, deficient B/N-Katholiek rats showed a low incidence of thermal and mechanical hyperalgesia on day 14. Expression of both B1 and B2 receptor mRNAs was detected in the lumbar dorsal ganglia ipsilateral to the site of the nerve injury. CONCLUSION: These data suggests that kinin were at least partly involved in yielding nociceptor hypersensitivity up to day 14 after CCI. Bradykinin and its B1 and B2 receptors were involved in the maintenance of hyperalgesia.

Animals↗

PubMed2003

Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide.

BACKGROUND: We previously reported that endogenous prostaglandin I(2), generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric mucosal protection against ethanol. Administration of capsaicin also inhibited ethanol induced gastric mucosal injury through immediate release of CGRP from primary sensory neurones, which is termed the neural emergency system. In the present study, we tested whether endogenous prostaglandin I(2) also modulates the cytoprotective action of capsaicin using prostaglandin I receptor knockout mice (IP(-/-)). METHODS: The stomachs of IP(-/-) or their wild-type counterparts (IP(+/+)), anaesthetised with urethane (1.225 g/kg), were doubly cannulated from the oesophageal and duodenal sides, and the gastric mucosa was perfused (1 ml/min) with physiological saline. Perfusate was changed to 50% ethanol alone, or 50% ethanol containing capsaicin (16 approximately 1600 micro M). The injured area was estimated at the end of each perfusion experiment. In some animals, CGRP-(8-37), a CGRP antagonist (0.3 mg/kg), or indomethacin (1 mg/kg) was intravenously injected before perfusion of 50% ethanol containing capsaicin. RESULTS: Capsaicin inhibited the injured area in a dose dependent manner. Fifty per cent ethanol containing capsaicin (480 micro M) immediately increased intragastric levels of CGRP although 50% ethanol alone did not. The protective action of capsaicin (480 micro M) against ethanol was completely abolished by intravenous injection of CGRP-(8-37). Indomethacin also inhibited the protective action of capsaicin, and this was accompanied by reduced levels of intragastric CGRP. Intragastric levels of prostaglandin E(2) were not increased by capsaicin treatment but those of 6-keto-prostaglandin F(1alpha), a metabolite of prostaglandin I(2), were markedly increased. No protective action of capsaicin was observed in IP(-/-) which lacked the ability to increase intragastric CGRP levels in response to ethanol containing capsaicin. The CGRP content of the stomach from untreated IP(-/-) did not differ from those in IP(+/+). Capsaicin (160 micro M) together with intragastric perfusion of beraprost sodium (PGI(2) analogue, 2.5 micro g/ml) showed enhanced protection against ethanol induced injury. This enhanced protection was completely blocked by intravenous injection of CGRP-(8-37). CONCLUSIONS: The present results suggest that endogenous prostaglandin I(2) enhances the protective action of the capsaicin mediated neural emergency system against ethanol induced gastric mucosal injury through enhancement of CGRP release.

6-Ketoprostaglandin F1 alpha↗

PubMed2002

Enhanced exudation of fibrinogen into the perivascular space in acute inflammation triggered by neutrophil migration.

OBJECTIVE: The present experiments were performed to ascertain whether or not all plasma components are extravasated when vascular permeability is increased. ANIMALS: Male Sprague-Dawley strain rats (specific pathogen-free) 8 weeks old (for histamine exudation) or 9-10 weeks old (for carrageenin pleurisy) were used. METHODS: Histamine or A-carrageenin was injected into the rat right pleural cavity to induce rat pleurisy. Protein components in the inflammatory exudate and plasma were separated by high performance liquid chromatography. Coagulation time was assessed, and the fibrinogen levels in the pleural exudate were determined by thrombin time. The fibrinogen levels were also visualized by immunoblot analysis. Tumor necrosis factor-alpha (TNF-alpha, 0.4 microg/rat, intrapleurally), anti-rat CD18 monoclonal antibody (anti-CD18 antibody, 1 mg/kg, i. v.) and granulocyte-colony stimulating factor (G-CSF, 100 microg/kg, s.c. twice daily for 4 days) were used. RESULTS: In the histamine-induced extravasation, the level of plasma protein components with large molecules over 900 kD in the exudate was 62% of that in the rat's own plasma. The amount of fibrinogen in the pleural exudate was 1/8 of that in the plasma and was faintly detected in immunoblot analysis, but it was clearly detected after the treatment of rats with TNF-alpha. In rat carrageenin pleurisy, fibrinogen was hardly detected in immunoblot analysis in the exudate collected 0.5 h after carrageenin, when neutrophils did not migrate into the exudate. However, it was clearly present after neutrophil migration started 2 h later The increase in the neutrophil counts in the exudate caused by G-CSF enhanced the fibrinogen level in the exudate, whereas intravenous injection of anti-CD18 antibody suppressed the fibrinogen level in immunoblot analysis. CONCLUSIONS: Venular permeability increase in the rat histamine exudation induced minimal extravasation of plasma proteins with large molecules, such as fibrinogen, while fibrinogen molecule was detected in rat carrageenin-injected pleurisy, when neutrophil diapedesis occurred. Thus, only when neutrophils started to migrate into the perivascular space was fibrinogen clearly detected in the exudate.

Albumins↗

PubMed2001

Effect of neutral endopeptidase inhibitor on bradykinin-induced bronchoconstriction.

To evaluate whether neutral endopeptidase (NEP) inhibitors have adverse respiratory effects, the influence of a NEP inhibitor on bradykinin (BK)-induced bronchoconstriction was investigated. In anesthetized and artificially ventilated guinea pigs, changes in airway opening pressure (Pao) were measured as an index of bronchoconstriction. An infusion of phosphoramidon (3 mg kg(-1) h(-1)), a NEP inhibitor, significantly enhanced the bronchoconstriction induced by high-dose BK (30 nmol kg(-1), i.v.). Capsaicin (0.1 mg kg(-1), i.v.) and SR48968 (0.3 mg kg(-1), i.v.), an NK2 receptor antagonist, significantly inhibited the phosphoramidon-induced enhancement of BK-induced bronchoconstriction, although FK888 (3 mg kg(-1), i.v.), an NK1 receptor antagonist, did not. Both neurokinin A (NKA) (0.1-3 nmol kg(-1), i.v.) and substance P (SP) (0.1-3 nmol kg(-1), i.v.) induced dose-dependent bronchoconstriction which was enhanced by phosphoramidon infusion, although these enhancements were more prominent in the NKA series. Phosphoramidon partially inhibited BK degradation in lung homogenate, and both NKA and SP degradation in the lung homogenate were significantly suppressed by phosphoramidon. In bronchoalveolar lavage fluid (BALF), levels of NKA and SP were significantly elevated after a bolus of BK with a phosphoramidon infusion. These results suggest that NEP inhibitors may have adverse respiratory effects resulting from inhibition of the degradation of neurokinins, but mainly of NKA, when a large amount of BK is generated.

Animals↗

PubMed2001

Nitric oxide is generated in smooth muscle layer by neurokinin A and counteracts constriction in guinea pig airway.

It has been reported that several bronchoconstrictors generate nitric oxide (NO), counteracting bronchoconstriction, and removal of bronchial epithelia reduces NO production. However, it has not been elucidated whether neurokinin A (NKA), a potent bronchoconstrictor liberated from nerve terminals, generates NO. Specific questions in this study were (1) does NKA also generate NO, (2) does NO counteract NKA-induced bronchoconstriction, and (3) does the NO generation require bronchial epithelial cells? In an in vivo study exogenous as well as endogenous (capsaicin-induced) NKA increased airway opening pressure (P(ao)) and the exhaled NO level, and both were inhibited by an antagonist selective for NK(2) receptor (a receptor for NKA), SR48968. The exhaled NO level became negligible with an inhibitor of NO synthase (NOS) type 1-3 (N(G)-nitro-L-arginine methyl ester, L-NAME) with increased P(ao), but not with a NOS type 2 inhibitor. In an in vitro study, NKA increased the nitrite/nitrate level in superfused fluid of tracheal segments. Removing smooth muscle reduced nitrite/nitrate in the fluid to negligible levels, while the level was unchanged with removal of the epithelia. Pretreatment with l-NAME enhanced the tension of epithelia-removed tracheal segments. These findings indicate that (1) NKA generates NO, (2) NO counteracts NKA-induced bronchoconstriction, and (3) NKA activates NOS in the muscle layer, independently of bronchial epithelia.

Airway Resistance↗

PubMed2001

Participation of cyclooxygenases in cutaneous thermal nociception under non-inflamed and inflamed conditions.

OBJECTIVE AND DESIGN: Effects of cyclooxygenase inhibitors on noxious thermal stimuli were investigated in non-inflamed and inflamed rats. MATERIALS: Male Sprague-Dawley rats were used in this study. TREATMENT: Cyclooxygenase inhibitors, indomethacin, mofezolac, NS-398, and JTE-522 were administered orally at a dose of 10 mg/kg 1 h prior to and 4 h after the intravenous injection of lipopolysaccharide (1 mg/kg). METHODS: The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. Expression ofcyclooxygenase was examined by reverse transcription-polymerase chain reaction. RESULTS: In normal rat, administration of indomethacin, relatively cyclooxygenase-1-selective inhibitor, mofezolac, or cyclooxygenase-2-selective inhibitors, NS-398 and JTE-522 had no effects on the escape latency against thermal stimuli. Injection of lipopolysaccharide into rat induced the expression of mRNA for cyclooxygenase-2 in the subcutaneous tissue of foot pad. The escape latency at 8 h was significantly shortened by the injection. This hyperalgesia could be reversed by pretreatment of rat with NS-398 or JTE-522, but not with mofezolac. CONCLUSIONS: Cyclooxygenases may have little participation in peripheral skin thermal nociception in non-inflamed condition, although cyclooxygenase-2 could be responsible for the hyperalgesia during inflammation induced by lipopolysaccharide.

Animals↗

PubMed2001

Proinflammatory characteristics of a nonpeptide bradykinin mimic, FR190997, in vivo.

1. Proinflammatory potency of the nonpeptide bradykinin (BK) B(2) receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline) was investigated. 2. Intradermal injection of FR190997 (0.03 - 3 nmol site(-1)) into dorsal skin of rats increased vascular permeability in a dose-dependent manner. The effect was less than that of BK, but it was long-acting and was inhibited by treatment with FR173657 (3 mg kg(-1), p.o.). Captopril (10 mg kg(-1), i.p.) did not enhance the plasma extravasation by FR190997 (0.3 nmol site(-1)) in the presence of soybean trypsin inhibitor (SBTI, 30 microg site(-1)). 3. Subcutaneous injection of FR190997 (3 nmol site(-1)) into the hindpaw of mice markedly induced paw swelling. The oedema lasted up to 3 h after the injection. Administration of indomethacin or NS-398 (10 mg kg(-1), i.p.) significantly reduced it at 3 h after the injection. 4. Simultaneous i.p. injection of prostaglandin (PG) E(2) (1 nmol site(-1)) or beraprost sodium (0.5 nmol site(-1)) with FR190997 (5 nmol site(-1)) greatly enhanced frequency of writhing reactions in mice. 5. FR190997 (0.3 - 30 nmol kg(-1), i.v.) showed less increase in airway opening pressure (Pao) in the guinea-pig after i.v. injection. Furthermore, FR190997 (0.03 - 30 nmol) resulted in a very weak contraction of tracheal ring strips and lung parenchymal sections in vitro. 6. In mice sponge implants, topical application of FR190997 increased angiogenesis and granulation with enhanced expressions of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) mRNAs. 7. These results indicate that FR190997 has proinflammatory long-lasting characteristics and it might be 'a stable tool' for studying the role of BK B(2) receptor in vivo.

Animals↗

PubMed2001

Sciatic neuropathy caused by disorder of a nutrient artery: a case report of thromboembolism secondary to profunda femoral artery aneurysm.

This report describes a case of sciatic neuropathy caused by an obstruction of the nutrient artery of the nerve. The patient was a 76-year-old man who had an aneurysm in his right thigh and suddenly complained of pain and weakness in his right leg. Computed tomography scan and ultrasonography of the right thigh showed an aneurysm with a thrombus in the lumen of the profunda femoral artery. His symptoms did not immediately improve after the aneurysm had been resected, and were consistent with right sciatic neuropathy. Recovery of strength of the right tibialis anterior muscle from 0/5 to 3/5 required 12 months. In this case, thromboemboli from the aneurysm were thought to have obstructed the profunda femoral artery, which supplied the sciatic nerve via perforating arteries.

Aged↗

PubMed2001

Adaptive cytoprotection mediated by prostaglandin I(2) is attributable to sensitization of CRGP-containing sensory nerves.

BACKGROUND & AIMS: The phenomenon by which the gastric mucosa is protected in response to mild irritants has been called adaptive cytoprotection, a mechanism believed to be related to production of endogenous prostaglandins (PGs). We tested whether PGs generated by mild irritant prevent injury through the release of calcitonin gene-related peptide (CGRP) from the sensory nerves using prostanoid receptor-knockout mice. METHODS: The stomach was doubly cannulated and perfused with 1 mol/L NaCl or 50% ethanol. CGRP levels in the perfusate were determined by enzyme immunoassay, and the injured area was estimated at the end of perfusion. RESULTS: Preperfusion with mildly hypertonic saline (1 mol/L NaCl) increased generation of gastric PGE(2) and PGI(2) and reduced ethanol-induced mucosal damage. Exposure of ethanol after 1 mol/L NaCl increased intragastric CGRP levels from 166 +/- 27 to 713 +/- 55 pg/2 min (n = 4, P < 0.05), and the protective action of 1 mol/L NaCl was inhibited by indomethacin treatment. CGRP antagonist blocked 1 mol/L NaCl-induced protective effect. Intragastric perfusion of 50% ethanol after administration of PGI(2), but not of PGE(2), increased CGRP levels. Application of 1 mol/L NaCl to IP receptor-knockout mice (IP(-/-)) did not elicit the protective effects seen in the wild-type on ethanol-induced gastric mucosal lesions. Protective effect of 1 mol/L NaCl was observed in EP3 receptor-knockout mice (EP3(-/-)). CGRP level during ethanol perfusion was not increased in IP(-/-) but was increased in EP3(-/-) and wild-type counterparts after preperfusion of 1 mol/L NaCl. CONCLUSIONS: These results indicate that the endogenous PGI(2) generated by 1 mol/L NaCl may have a protective role in gastric mucosal injury through enhancement of CGRP release from gastric mucosa. This mechanism may explain the adaptive cytoprotection observed after treatment with mild irritants.

6-Ketoprostaglandin F1 alpha↗

PubMed2001

[Endogenous prostaglandins and angiogenesis].

Angiogenesis is a process involved in several physiological events including embryonic development, female reproductive cycle placentation and wound repair. It also plays a part in various pathological conditions such as tumor growth, diabetic retinopathy and rheumatoid arthritis. Angiogenesis is a very complex multistep process involving a variety of biologically active substances, among which are the prostaglandins (PGs), which can induce several growth factors and proliferation of endothelial cells in vitro and in vivo. Angiogenesis is reportedly enhanced by prostaglandins (PGs). We investigated whether or not COX-2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14-day experimental period as granuloma formed. In sponge granuloma, mRNA of COX-1 was constitutively expressed, whereas that of COX-2 was increased with neovascularization in parallel with the increased expression of vascular endothelial growth factor (VEGF). bFGF-stimulated angiogenesis was inhibited by indomethacin or a selective COX-2 inhibitor, NS-398. These results suggested that endogenous PGs generated through COX-2 may enhance the neovascularization in sponge granuloma by increased expression of VEGF and that a COX-2 inhibitor would facilitate the management of conditions involving angiogenesis.

Animals↗

PubMed2001

Transient prevention of ethanol-induced gastric lesion by capsaicin due to release of endogenous calcitonin gene-related peptide in rats.

Pre-exposure of the rat gastric mucosa to capsaicin reduced the mucosal lesion by 50% ethanol to 1/4. Treatment with an antagonist of calcitonin gene-related peptide (CGRP), CGRP (8-37), nullified the effect of capsaicin. During constant perfusion of the gastric lumen with physiological saline + pepstatin, the CGRP level was not increased by 50% ethanol, but it showed a peak (802.5 +/- 145.7 pg/2 min) after 1.6 mM capsaicin. Four minutes after capsaicin, the CGRP level was kept at a high level and the gastric lesion was markedly reduced by re-exposure of the mucosa to 50% ethanol. At 20-30 min after capsaicin, the CGRP levels returned to the resting level and the reddened area by 50% ethanol was not reduced. It was concluded that capsaicin transiently prevented the mucosal lesion through CGRP release.

Animals↗

PubMed2001

Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo.

We previously reported that endogenous prostaglandins (PGs) may increase cAMP facilitated angiogenesis through the induction of vascular endothelial growth factor (VEGF) in rat sponge implantation models. In the present experiment, we tested whether or not adenylate cyclase / protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by 8-bromo-cAMP, forskolin and amrinone. Angiogenesis without topical injections of the above compounds was suppressed by SQ22,536, an inhibitor for AC, or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. PGE2-induced angiogenesis was suppressed with SQ22,536 or H-89. These results suggested that AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.

Adenine↗

PubMed2001

A potential role of bradykinin in angiogenesis and growth of S-180 mouse tumors.

Angiogenesis is an important event in tumor growth. We evaluated the contribution of endogenous bradykinin to tumor-associated angiogenesis and tumor growth using pharmacological approaches in mice bearing sarcoma 180 cells. The weight of implanted tumors increased in parallel with increased hemoglobin contents (a parameter to evaluate angiogenesis) over a 20-day experimental period. Daily administration of bradykinin B2-receptor antagonists, Hoe140 (0.1 and 1 mg/kg per day, local injection) or FR173657 (30 mg/kg per day, p.o.), significantly suppressed the increment in angiogenesis and tumor weight, but a B1-receptor antagonist, desArg10-Hoe140 (1 mg/kgperday), did not. Administration of a plasma kallikrein inhibitor, soybean trypsin inhibitor (3 mg/site per day), significantly suppressed angiogenesis and tumor growth. In contrast, bradykinin-degrading enzyme inhibitors, captopril and phosphoramidon (500 microg/site per day), enhanced angiogenesis and increased tumor weight. Our results suggest that bradykinin, produced by plasma kallikrein or plasma kallikrein-like enzymes, promote tumor-associated angiogenesis and tumor growth in vivo.

Adrenergic beta-2 Receptor Antagonists↗

PubMed2001

Role of the renal kallikrein-kinin system in the development of salt-sensitive hypertension.

The role of the renal kallikrein-kinin system in the development of salt-sensitive hypertension was studied using mutant kininogen-deficient Brown-Norway Katholiek (BN-Ka) rats, which generate no kinin in their urine, and other hypertensive rat models. It was found that ingestion of a low sodium diet or infusion of NaCl in doses slightly above 0.15 M caused hypertension and sodium accumulation in erythrocytes and the cerebrospinal fluid of kininogen-deficient BN-Ka rats. Development of hypertension in the deoxycorticosterone-acetate-salt model was completely prevented by administration of a newly discovered inhibitor, ebelactone B, of carboxypeptidase Y-like exopeptidase (an urinary kininase). The urinary kallikrein excretion of spontaneously hypertensive rats was lower than that of Wistar Kyoto rats at 4 weeks of age and did not increase by administration of furosemide, a diuretic agent, although approximately 50% of the diuretic action of this agent was dependent upon the renal kallikrein-kinin system in normal rats. In conclusion, the renal kallikrein-kinin system works as a safety valve for excess sodium intake.

Animals↗

PubMed2001

FR167653, a cytokine synthesis inhibitor, exhibits anti-inflammatory effects early in rat carrageenin-induced pleurisy but no effect later.

We prepared a pharmacological profile of FR167653 (1-[7- (4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl) pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedion sulfate monohydrate), a cytokine synthesis inhibitor, on early (5 h after irritation) and late (14-24 h after irritation) phases of rat carrageenin-induced pleurisy and on mediator-induced plasma exudation, in comparison with that of dexamethasone. In the early phase, FR167653 (30 mg/kg) and dexamethasone (0.3 mg/kg) equipotently suppressed plasma exudation and leukocyte infiltration. Furthermore, both agents significantly lowered the prostanoid levels in the exudate. Expression of cyclooxygenase-2 protein on leukocytes in the early phase of inflammation was not affected by dexamethasone, but it was suppressed by FR167653. However, FR167653 did not significantly affect the leukocyte mRNA level of cyclooxygenase-2. Both agents significantly suppressed the levels of both tumor necrosis factor-alpha and interleukin-1beta. FR167653 had a different pharmacological profile from dexamethasone in the late phase of this model in that, unlike dexamethasone, it did not affect cyclooxygenase-2 expression in mesothelial cells, the 6-keto-prostaglandin F1alpha level in the exudate or hyperplasia of mesothelium. Furthermore, unlike dexamethasone, FR167653 did not consistently inhibit mediator-induced plasma exudation. These results suggest that FR167653 or one of its analogs may be new candidates for therapy with a spectrum of activity distinct from that of current anti-inflammatory steroids.

Animals↗