Biomedical subjects

M Majima

Publications and source records attributed to M Majima.

At least 73 records · Page 4Linked to original sources

PubMed1996

Induction mechanism of small intestinal lesions caused by intravenous injection of endotoxin in rats.

The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage.

Animals↗

PubMed1996

Determination of bradykinin-(1-5) in inflammatory exudate by a new ELISA as a reliable indicator of bradykinin generation.

We have developed an ELISA for BK-(1-5) (Arg1-Pro2-Pro3-Gly4-Phe5). In rat carrageenin-induced pleurisy, in which a plasma exudation peak was observed 5 h after carrageenin, BK levels in the exudates were negligible (< 60 pg/rat). BK-(1-7) (des-Phe8-Arg9-BK) was detectable (900-400 pg/rat) over the entire course of the inflammation. However, a larger amount of BK-(1-5) was detectable in association with the increase in plasma exudation, showing a peak (8800 +/- 1200 pg/rat) 3 h after carrageenin. Bromelain (10 mg/kg, i.v.) and soy bean trypsin inhibitor (0.3 mg/rat, intra-pleural) significantly reduced BK-(1-5) levels (by 60-93%, 3, 7 and 19 h after carrageenin) and plasma exudation rates (by 61-74%, 3 and 7 h after carrageenin). Dexamethasone (0.3 mg/kg, i.p.) reduced BK-(1-5) levels (by 78%) and decreased plasma exudation (by 70%) 3 h after carrageenin. In nasal allergy patients, antigen challenge of nasal mucosa elevated BK-(1-5) levels and active kallikrein levels in nasal washes. These results verify that BK-(1-5) determined by ELISA is a good indicator for release of kinins in vivo.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Increased migration of neutrophils to granulocyte-colony stimulating factor in rat carrageenin-induced pleurisy: roles of complement, bradykinin, and inducible cyclooxygenase-2.

Administration of human recombinant granulocyte colony-stimulating factor (G-CSF, 100 micrograms/kg/day, s.c) to rats for 4 days significantly increased circulating neutrophil counts (by 1130%), together with an increase in mononuclear leukocyte counts (by 119%). Infiltrated pleural neutrophil counts in G-CSF-treated rats (G-CSF-r) 5 h after the intrapleural injection of zymosan-activated serum were significantly higher (by 155%) than those in control rats (Vehicle-r). In carrageenin-induced pleurisy, counts of infiltrated pleural neutrophils in G-CSF-r 5 and 7 h after carrageenin were significantly higher (by 119% and 116%) than those in Vehicle-r. G-CSF treatment increased the volume of pleural exudate and the plasma exudation rate by 122% and 226%, compared to values in Vehicle-r 5 h after carrageenin. Cobra venom factor (75 micrograms/kg, i.v.) significantly reduced pleural neutrophil migration in G-CSF-r (by 53%) and Vehicle-r (by 49%). Bromelain (10 mg/kg, i.v.) and aspirin (100 mg/kg, p.o.) reduced pleural neutrophil migration and reduced exudate volume and plasma exudation. Intrapleural bradykinin-(1-5) and prostaglandin E2 levels were significantly higher in G-CSF-r than in Vehicle-r. The increased neutrophil migration in G-CSF-r may be attributed to enhanced activation of the complement system facilitated by increased plasma exudation due to bradykinin and prostaglandins.

Animals↗

PubMed1996

Role of tachykinins in enhancement of bradykinin-induced bronchoconstriction by captopril.

In anesthetized, mechanically ventilated guinea pigs, infusion of captopril (1 mg/kg/h), an angiotensin converting enzyme inhibitor, significantly enhanced bronchoconstriction induced by intravenous injection of bradykinin (BK; 0.1-30 nmol/kg). Pretreatment of guinea pigs with capsaicin (100 mu g/kg) slightly suppressed the bronchoconstriction by BK alone and almost all of the enhancement of BK-induced bronchoconstriction by captopril was suppressed. Intravenous injection of substance P (SP; 0.1-100 nmol/kg), neurokinin A (NKA; 0.1-30 nmol/kg) and neurokinin B (NKB; 0.1-30 nmol/kg) also induced dose-dependent bronchoconstriction but captopril treatment enhanced only the bronchoconstriction induced by SP. BK degradation in bronchoalveolar lavage fluid (BALF) in vitro was significantly suppressed by captopril (p < 0.05). Captopril infusion to guinea pigs significantly increased the levels of BK, SP, and NKA in BALF after BK injection (p < 0.05). FK224, an NK1 and NK2 receptor antagonist and SR 48968, an NK2 receptor antagonist, significantly suppressed the bronchoconstriction induced by BK alone (p < 0.01 and p < 0.05, respectively) as well as the enhancement by captopril (p < 0.01). It can be concluded that the enhancement of BK-induced bronchoconstriction by captopril was attributable to inhibition of the degradation of BK itself and thereby enhanced release of NKA and partly of SP from sensory nerves by BK.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Role of endogenous substance P in ethanol-induced mucosal damage in the rat stomach.

To determine the role of endogenous substance P in ethanol-induced mucosal damage, two experiments were performed. In the first experiment, the stomachs of anesthetized rats were doubly cannulated and gastric damage was induced with 5ml of 30% ethanol in the gastric lumen. The damage was ameliorated by pretreatment with capsaicin (0.16 and 1.6 mM) and spantide (100 mg/kg, i.v.). In the second experiment, the gastric mucosa of these rats was perfused with physiological saline containing pepstatin (10 microliters/ml). Endogenous substance P (SP) in the perfusate was measured by enzyme immunoassay (EIA). The peak SP levels were increased by capsaicin (0.16-1.6 mM) in a concentration-dependent manner. Perfusion with 50% ethanol for 5 min increased the SP levels approximately threefold. Perfusion with 1.6 mM capsaicin, followed by 50% ethanol, reduced the injured area to about one-quarter of the original injured area. The peak SP levels during perfusion with 50% ethanol after pretreatment with 1.6 mM capsaicin did not differ from those observed after vehicle pretreatment (control). The area under the curve for SP release during 50% ethanol perfusion after vehicle perfusion was not reduced by previous perfusion with 1.6 mM capsaicin followed by 50% ethanol, indicating that the prevention of ethanol-induced injury by capsaicin may be due to excess amounts of different neuropeptides released simultaneously.

Animals↗

PubMed1996

Role of prostaglandin H synthase-2 in prostaglandin E2 formation in rat carrageenin-induced pleurisy.

Rat carrageenin-induced pleurisy was used to clarify the role of prostaglandin H synthase (PGHS)-2 in acute inflammation. Intrapleural injection of 0.2 ml of 2% lambda-carrageenin induced accumulation of exudate and infiltration of leukocytes into the pleural cavity. When PGHS-1 and -2 proteins in the pleural exudate cells were analyzed by Western blot analysis, PGHS-2 was detectable from 1 hr after carrageenin injection. Its level rose sharply, remained high from 3 to 7 hr after injection, and then fell to near the detection limit. PGHS-1 was also detected, but kept almost the same level throughout the course of the pleurisy. Levels of prostaglandin (PG) E2 and thromboxane (TX) B2 in the exudate increased from hour 3 to hour 7, and then declined. Thus, the changes of the level of PGE2 were closely paralleled those of PGHS-2. The selective PGHS-2 inhibitors NS-398, nimesulide and SC-58125 suppressed the inflammatory reaction and caused a marked decrease in the level of PGE2 but not in those of TXB2 and 6-keto-PGF 1 alpha. These results suggest that the PGHS-2 expressed in the pleural exudate cells may be involved in PGE2 formation at the site of inflammation.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Lack of contribution of circulatory kinin elevated by captopril to induce hypotension in normotensive and hypertensive rats.

Captopril (10 mg/kg, i.p.) increased the arterial bradykinin (BK) level (Art-BK) of non-treated Sprague-Dawley rats (SD), determined by an ELISA, from 10.8 +/- 3.2 pg/ml to 32.9 +/- 5.4 pg/ml significantly (p < 0.05, n = 6). Intravenous infusion of BK (100-3000 ng/kg/min) dose-dependently increased heart rate (HR) and decreased mean blood pressure (MBP), the former at lower doses than the latter, and the hypotensive response became significant at 3000 ng/kg/min. Art-BK determined during infusion of the lowest dose of BK (100 ng/kg/min) was 12 times the endogenous Art-BK after captopril administration. In spontaneously hypertensive rats, Wistar Kyoto rats, and deoxycorticosterone acetate-salt treated hypertensive rats, Art-BK (450-1280 pg/ml) determined during intravenous BK-infusion (1000-3000 ng/kg/min), which induced significant hypotension, was 20 to 100 times the endogenous Art-BK (4.5-64 pg/ml) with captopril treatment. These results suggest that the increased Art-BK due to inhibition of kinin degradation by captopril could not account for the hypotension due to this angiotensin converting enzyme inhibitor in normotensive and hypertensive rats.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Reduction by a kallikrein inhibitor of the increased nasal airway resistance of allergic patients after antigen challenge.

Kallikrein activity in nasal lavage fluid, which was measured with a synthetic substrate, Pro-Phe-Arg-methylcoumarilamide, was increased in accordance with the severity of the symptoms of house-dust-mite allergic rhinitis. Antigen challenge was applied to patients with allergic rhinitis by placing a disk containing allergen on the nasal mucosa of the right inferior turbinate. Kallikrein activities and kinin levels in the nasal lavage fluid had increased significantly 15 min after the antigen challenge. These increases were accompanied by a marked increase in nasal airway resistance 15 min after antigen challenge. Pretreatment of the patients with camostat mesilate (60 mg/kg, p.o), a non-peptide serine proteinase inhibitor clinically used in Japan, inhibited the kallikrein activity in the nasal lavage fluid. The increase in nasal airway resistance after antigen challenge was also markedly reduced by oral administration of the inhibitor, indicating involvement of the kallikrein-kinin system in induction of the nasal symptoms.

Airway Resistance↗

PubMed1996

Release site of TNF alpha after intravenous and intraperitoneal injection of LPS from Escherichia coli in rats.

Lipopolysaccharide (LPS) concentrations in the portal vein after intraperitoneal (i.p.) injection were slightly higher than those in the arteries. The tumor necrosis factor (TNF alpha) levels in arterial serum were higher after i.p. injection than after i.v. injection and rose to a peak at 90 min after some delay. Infusion of LPS into the portal vein increased the TNF alpha levels in the arterial serum. Pretreatment with indomethacin further increased the arterial levels of TNF alpha after portal infusion, but did not after them after i.p. injection, because of the reduction by indomethacin of LPS absorption after i.p. Injection of LPS. TNF alpha was also generated in the peritoneal cavity after i.p. injection of LPS. The TNF alpha concentrations in the arterial serum and in the peritoneal cavity were accelerated by mast cell degradation. In conclusion, TNF alpha was generated mainly in the liver, but also in the peritoneal cavity, after i.p. injection of LPS, and was negatively regulated by prostaglandins.

Animals↗

PubMed1996

Pivotal role of renal kallikrein-kinin system in the development of hypertension and approaches to new drugs based on this relationship.

Renal kallikrein is one of the tissue kallikreins, and the distal nephron is fully equipped as an element of the kallikrein-kinin system. Although a low excretion of urinary kallikrein has been reported in essential hypertension, the results from studies on patients with hypertension are not consistent. Congenitally hypertensive animals also excrete lowered levels of urinary kallikrein, but the effects of this are yet unknown. Extensive genetic and environmental studies on large Utah pedigrees suggest that the causes of hypertension are closely related to the combination of low kallikrein excretion and the potassium intake. Mutant kininogen-deficient Brown Norway-Katholiek rats, which cannot generate kinin in the urine, are very sensitive to salt loading and to sodium retention by aldosterone released by a non-pressor dose of angiotensin II, which results in hypertension. The major function of renal kallikrein-kinin system is to excrete sodium and water when excess sodium is present in the body. Failure of this function causes accumulation of sodium in the cerebrospinal fluid and erythrocytes, and probably in the vascular smooth muscle, which become sensitive to vasoconstrictors. We hypothesize that impaired function of the renal kallikrein-kinin system may play a pivotal role in the early development of hypertension. Inhibitors of kinin degradation in renal tubules and agents, which accelerate the secretion of urinary kallikrein from the connecting tubules and increase the generation of urinary kinin, may be novel drugs against hypertension.

Animals↗

PubMed1996

Failure of the oxytocin-induced increase in secretion of urinary kallikrein in young spontaneously hypertensive rats.

Urinary kallikrein excretion during oxytocin (OT) infusion were studied in anesthetized (sodium pentobarbital, 50 mg/kg, i.p.) young (4-weeks-old) spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). OT-infusion (30 nmol/kg/30 min) to WKY significantly increased urinary excretion of the active kallikrein from the basal levels (25.4 +/- 5.6 10(-2) x AU/15 min, n = 5) to 37.3 +/- 5.0 10(-2) x AU/15 min (P < 0.05, n = 5) and 50.7 +/- 17.1 10(-2) x AU/15 min (P < 0.05, n = 5) 15 and 30 min after the start of OT-infusion, respectively. In SHR, OT-infusion did not increase the urinary excretion of active kallikrein, but did decrease the urine volume and sodium excretion. The concentration of the active kallikrein in the kidney of WKY was not changed by OT-infusion, but that of SHR was slightly increased. The OT-infusion resulted in significantly higher concentrations of the active kallikrein in SHR kidney than in WKY kidney. These results suggest that less excretion of urinary kallikrein in SHR during OT-infusion may be attributable to a lower response in the secretion of kallikrein from the kidney.

Animals↗

PubMed1996

Inhibitory effects of a phosphate diester of alpha-tocopherol and ascorbic acid (EPC-K1) on myocardial infarction in rats.

The inhibitory effect of a phosphate diester of alpha-tocopherol and ascorbic acid (EPC-K1) was examined in myocardial infarction induced in rats, in comparison with a selective 5-lipoxygenase inhibitor, AA-861. EPC-K1 significantly reduced the infarct size at 24 and 48 h after ligation, whereas AA-861 reduced it only at 48 h after ligation. In in-vitro experiments, EPC-K1 inhibited not only superoxide anion generation (IC50 = 4.2 x 10(-5) M), but also acid phosphatase activity (IC50 = 2.4 x 10(-5) M) in rat polymorphonuclear leukocytes in a concentration-dependent manner, while AA-861 showed marginal effects on both actions. These results indicated that EPC-K1 induced cardioprotective effects by affecting neutrophil functions by inhibition of generation of superoxide-anion generation and acid-phosphatase activity. The mechanism of the reduction of the infarct size by EPC-K1 differed from that of AA-861, which latter inhibited 5-lipoxygenase and the formation of leukotriene B4.

Animals↗

PubMed1995

Ebelactone B, an inhibitor of urinary carboxypeptidase Y-like kininase, prevents the development of deoxycorticosterone acetate-salt hypertension in rats.

Kininogen-deficient Brown Norway Katholiek rats (BN-Ka) excrete little urinary kinin, compared with normal rats of the same strain (BN Kitasato rats (BN-Ki)). Deoxycorticosterone acetate-salt treatment increased systolic blood pressure in both rats, but much faster in BN-Ka than in BN-Ki. Daily subcutaneous administration of ebelactone B (15 and 5 mg/kg/day), a rat urinary carboxypeptidase Y-like kininase inhibitor, significantly reduced systolic blood pressure in BN-Ki, but not in BN-Ka. This treatment significantly increased urinary Na+ excretion and reduced Na+ concentration in the erythrocytes in BN-Ki, but not in BN-Ka. An angiotensin-converting enzyme inhibitor, lisinopril (5 mg/kg/day s.c.), did not reduce the systolic blood pressure in either BN-Ki or BN-Ka. These results suggested that ebelactone B has promise as a preventive agent for the development of hypertension acting through the inhibition of urinary kinin degradation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Enzymic reconstruction of glycosaminoglycan oligosaccharide chains using the transglycosylation reaction of bovine testicular hyaluronidase.

The reconstruction of glycosaminoglycan chains using the transglycosylation reaction of testicular hyaluronidase was investigated. First, the optimal conditions for the transglycosylation reaction catalyzed by the enzyme were determined by incubation with the enzyme, using hyaluronic acid (M(r) = 800,000) as a donor and pyridylaminated hyaluronic acid hexasaccharide having glucuronic acid at the nonreducing terminal as an acceptor. The carbohydrate chains as reaction products were determined by high performance liquid chromatography and mass spectrometry. The optimal pH for hydrolysis by the enzyme was found to be about 5.0, whereas that for the transglycosylation reaction was about 7.0. Sodium chloride in the reaction medium inhibited the transglycosylation reaction. Under the optimal conditions, the carbohydrate chains were sequentially transferred along with disaccharide units to the nonreducing terminal of the acceptor and elongated up to docosasaccharide from the acceptor, pyridylaminated hexasaccharide. Using a combination of hyaluronic acid, chondroitin, and chondroitin 4- and 6-sulfate as an acceptor and a donor, it was possible to reconstruct hybrid chains, which were natural or unnatural types of glycosaminoglycan chains. Therefore, it is highly likely that application of the transglycosylation reaction using testicular hyaluronidase would facilitate artificial reconstruction of glycosaminoglycans having some physiological functions.

Animals↗

PubMed1995

A patient with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation: confirmation of a gene mutation in cardiac muscle.

A 44-year-old woman with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation, was reported. She was diagnosed as having diabetes at 33 years of age and was treated with insulin. However, she stopped treatment 6 months later and had no medical care until she developed diabetic ketoacidosis at 41 years of age. She had diabetic foot, diabetic retinopathy, and nephropathy with low insulin secretory capacity, leading to insulin treatment. A point mutation of the mitochondrial tRNA(Leu(UUR)) gene was identified in peripheral leukocytes at 43 years of age, and sensorineural hearing impairment was detected at the same time. Her mother also suffered from diabetes mellitus with deafness and her son, who was not diabetic at age 19, had the same mitochondrial DNA (mtDNA) mutation. At 44 years of age, she developed congestive heart failure due to cardiomyopathy, and the same mtDNA mutation was identified in the cardiac muscle. Thus, it is very likely that in this patient, diabetes and cardiomyopathy was caused by the same abnormality, the point mutation of mitochondrial tRNA(Leu(UUR)) gene.

Adult↗

PubMed1995

Approaches to the development of novel antihypertensive drugs: crucial role of the renal kallikrein-kinin system.

The renal kallikrein-kinin system has been shown to be important in the development of hypertension, but its precise role remains to be determined. The recent use of mutant rats that are deficient in plasma kininogens and hence incapable of generating kinin in the renal tubules has facilitated elucidation of the involvement of kinin in hypertension. In this article, Masataka Majima and Makoto Katori provide evidence that the renal kallikrein-kinin system plays a crucial role in the development of hypertension and discuss a novel rationale for developing effective new antihypertensive drugs.

Animals↗

PubMed1995

Oxytocin-induced natriuresis mediated by the renal kallikrein-kinin system in anesthetized male rats.

Intravenous infusion of oxytocin (OT) (10-100 nmol/kg/30 min) to 8-week-old anesthetized male rats resulted in a dose-dependent increase in urine volume, which showed a peak value 30-45 min after the start of OT-infusion. Urinary excretions of sodium, chloride and potassium were also increased by OT, showing peak values at 30-45 min, without any increase in the creatinine level. The natriuresis by OT was accompanied by increased excretion of urinary active kallikrein, which showed a peak value 15 min after the start of OT-infusion. The urinary kinin level was also increased. Intravenous infusion of a kallikrein inhibitor, aprotinin (15 mg/kg/90 min), when started 30 min before the OT-infusion, significantly inhibited the OT-induced increase in urine volume and urinary excretion of sodium, chloride and potassium. Intravenous infusion of a bradykinin B2 antagonist, Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]BK, 4.5 mg/kg/90 min), when started 30 min before the OT-infusion, significantly inhibited the OT-induced increases in urine volume and urinary excretion of sodium and chloride, but not that of potassium. These results indicate that the OT-infusion induces natriuresis in male rats, and more than half of the natriuresis is mediated by a concomitant increase in excretion of urinary active kallikrein and the kinin generated.

Anesthesia↗

PubMed1995

Increase in vascular sensitivity to angiotensin II and norepinephrine after four-day infusion of 0.3 M sodium chloride in conscious kininogen-deficient brown Norway Katholiek rats.

Kininogen-deficient Brown Norway Katholiek (deficient BN-Ka) rats excreted a small amount of kinin in their urine, compared with normal BN Kitasato (normal BN-Ki) rats from the same strain. Intraarterial (i.a.) infusion (6 ml/kg/hr) of conscious deficient BN-Ka rats with 0.15 M NaCl did not increase mean arterial blood pressure (MBP) [from 103 +/- 2 (pre) to 93 +/- 6 mmHg (day 4)] and did not cause sodium accumulation in the serum, cerebrospinal fluid or erythrocytes, but 0.3 M NaCl infusion significantly increased MBP from 104 +/- 3 (pre) to 130 +/- 5 mmHg (day 4) with increased sodium levels in the serum, cerebrospinal fluid and erythrocytes. Infusion of 0.3 M NaCl in normal BN-Ki rats neither increased MBP nor accumulated sodium. The dose-response curve of the increase in MBP for angiotensin II injection (i.a., bolus, 1-1000 pmol/kg) in 0.3 M NaCl-infused deficient BN-Ka rats shifted to the left by a factor of 10 compared with that in 0.15 M NaCl-infused deficient BN-Ka rats, and that for norepinephrine injection shifted to the left by a factor of 30. Normal BN-Ki rats did not show any enhancement in MBP elevation with 0.3 M NaCl. These results suggest that the sodium accumulation attributable to a lack of kinin generation may be related to increased vascular reactivity to angiotensin II and norepinephrine.

Angiotensin II↗