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Biomedical subjects

M Okuhira

Publications and source records attributed to M Okuhira.

At least 19 recordsLinked to original sources
PubMed1997

Pharmacologic profiles of KRH-594, a novel nonpeptide angiotensin II-receptor antagonist.

We studied pharmacologic profiles of KRH-594, dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4 -thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarb oxylate, a novel angiotensin II (AII)-receptor antagonist. KRH-594 potently displaced specific binding of [125I]-AII from AT1 receptor with a Ki of 0.39 nM in rat liver membranes, but not from AT2 receptor in bovine cerebellar membranes (Ki > 10 microM). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 microM], demonstrating its high specificity toward AT1 receptors. In isolated rabbit aorta, KRH-594 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response with a pK(B) of 10.4. We evaluated the in vivo efficacy and the duration of action in freely moving rats under nonfasting conditions. In normotensive rats, orally administered KRH-594 inhibited AII-induced pressor responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensive rats (SHRs), both KRH-594 (1 mg/kg p.o.) and losartan (10 mg/kg p.o.) exerted similar blood pressure-reducing effects, and their effects were still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT1 antagonist that may find its use in the treatment of human hypertension.

Angiotensin II↗
PubMed1997

In vitro pharmacological properties of KRH-594, a novel angiotensin II type 1 receptor antagonist.

This report describes the in vitro pharmacological properties of dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1, 3,4-thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenec arboxylate, called KRH-594, a novel angiotensin II (AII) type 1 (AT1) receptor antagonist. We exposed rabbit aortic rings to KRH-594 (0.1 nM) for increasing contact times and observed an increasing degree of insurmountable suppression of AII-induced contractions. KRH-594 (0.01, 0.1 and 1.0 nM) caused a concentration-related, insurmountable suppression of the AII concentration-response curve. Repeated washing of rabbit aortic rings preincubated with KRH-594 (0.1, 1.0 and 10 nM) slowly reversed the insurmountable suppression. The marked suppression of AII-induced contractions by KRH-594 (0.1 nM) was restored by co-incubation with losartan (100 nM). KRH-594 (10 microM) had no effect on bradykinin-, acetylcholine-, or histamine-induced contractions of guinea pig ileum, demonstrating its high specificity for AT1 receptors. These results demonstrate that KRH-594 is a potent, specific and insurmountable AT1 receptor antagonist. KRH-594 activity in rabbit aorta appears to be that of a slowly reversible (pseudo-irreversible) antagonist.

Angiotensin I↗
PubMed1995

Role of endogenous endothelin in gastric mucosal injury induced by hemorrhagic shock in rats.

We examined the role of endogenous endothelin in the pathogenesis of hemorrhagic shock-induced gastric mucosal injury in rats. Animals were bled to induce hypotension (20-30 mm Hg) for 20 min and the shed blood was retransfused. Rats were sacrificed at the end of hypotension, 20 min, and 60 min after retransfusion, respectively. Gastric erosions were induced with this experimental protocol. The total area of erosions was minimal only at the end of hypotension, and increased time-dependently after blood retransfusion. Plasma endothelin concentration significantly increased at the end of hypotension and persistently increased after retransfusion, whereas in gastric endothelin concentration a significant increase was observed at 60 min after retransfusion. The gastric mucosal hemodynamics as assessed by continuous measurement with reflectance spectrophotometry showed ischemia associated with congestion after retransfusion. Treatment with a monoclonal antibody against endothelin (0.2 mg/100 g BW/h) prevented these hemodynamic disturbances, rendering a significant decrease in the total area of erosions at 20 and 60 min after retransfusion. These results strongly suggest an important role of circulating endothelin in the pathogenesis of hemorrhagic shock-induced gastric mucosal injury through mucosal microcirculatory perturbation.

Animals↗
PubMed1993

Zollinger-Ellison syndrome and pheochromocytoma. Report of a case.

A 49-year-old woman was diagnosed in 1985 as having pheochromocytoma because of hypertension with high levels of plasma catecholamine concentration and 24-hour urine excretion of vanillyl-mandelic acid and metanephrine together with a right adrenal mass. The excised tumor cells had fine granular basophilic cytoplasm with argyrophilic granules by Grimelius' method. Four years later, she was diagnosed as having a duodenal bulb ulcer. Serum gastrin showed an abnormally high level of 1900 pg/ml. Abdominal echogram and computed tomography revealed a hypoechoic lesion in the pancreas and intrahepatic multiple tumors. A needle biopsy specimen of the liver tumor was compatible with the histology of metastatic islet cell tumor. A diagnosis of Zollinger-Ellison syndrome was made due to malignant gastrinoma with multiple liver metastases. The patient had no family history of endocrinological or neoplastic disorders. The present case indicates the possibility that pheochromocytoma and gastrinoma, that is, endocrine tumors characteristic of multiple endocrine neoplasia (MEN) I and MEN II, may be coincident even in a person without MEN. A continued awareness of previously rare or undescribed manifestations is important in patients with islet cell tumors or pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1993

Cell proliferation kinetics in acetic acid-induced gastric ulcer evaluated by immunohistochemical staining of proliferating cell nuclear antigen.

A monoclonal antibody to proliferating cell nuclear antigen (PCNA) has been previously shown to be capable of identifying proliferating cells. We investigated proliferative activity in the healing process of acetic acid-induced gastric ulcer by immunohistochemical staining of PCNA and 5-bromo-2-deoxyuridine (BrdU), and the two methods were compared. Cell proliferative activity of regenerated mucosa around ulcers showed continuous acceleration for 42 days, and PCNA-labeled cells had stained nuclei as clearly discernible as those of BrdU-labeled cells. In addition, immunohistochemical staining of PCNA provided reproducible and quantifiable results without the requirement of pretreatment. We conclude that immunohistochemical staining of PCNA may represent a useful technique for analysis of proliferative activity during healing of gastric ulcers.

Acetates↗
PubMed1993

Effects of spiraprilat, an angiotensin-converting enzyme inhibitor, on anesthetized dogs in a new model of acute left ventricular failure.

Spiraprilat, a new angiotensin-converting enzyme (ACE) inhibitor, was compared with enalaprilat for its ability to improve left ventricular (LV) function and metabolism in anesthetized open-chest dogs with a new model of acute LV failure (ALVF) induced by embolization of the left coronary artery with 50 microns plastic microspheres followed by intravenous (i.v.) infusion of methoxamine. With this procedure, LV end-diastolic pressure (LVEDP) increased from 4.2 +/- 0.7 to 12.8 +/- 1.3 mm Hg and remained at approximately 12 mm Hg throughout the experiment. Cardiac output (CO) decreased from 1.25 +/- 0.12 to 0.79 +/- 0.06 and 0.55 +/- 0.02 L/min at 30 and 90 min after methoxamine infusion, respectively. LVdP/dtmax and dP/dt/P decreased, while total peripheral resistance (TPR) increased. These hemodynamic changes indicated establishment of stable ALVF of a moderate degree. Moreover, decreases in myocardial lactate consumption and contents of creatine phosphate in the myocardium indicated the existence of moderate ischemia. The new ACE inhibitor, spiraprilat, as well as enalaprilat (30 micrograms/kg i.v.) effectively decreased mean aortic pressure (30%), LVEDP (20%), and TPR (30%) and increased stroke volume (SV) CO, and dP/dt/P. Both agents decreased myocardial oxygen consumption (20%) and caused a significant increase in myocardial creatine phosphate contents. These data indicate that the beneficial effects of both inhibitors extended not only to LV function but also to myocardial energy metabolism in ALVF.

Adenosine Triphosphate↗
PubMed1993

Role of endothelin and platelet-activating factor in indomethacin-induced gastric mucosal injury in rats.

The current study was designed to investigate the role of two potent vasoactive substances, endothelin (ET) and platelet-activating factor (PAF), in the pathogenesis of indomethacin-induced gastric lesions in rats. Treatment with anti-ET antibody before indomethacin administration resulted in a significant decline in the total length of the lesions as determined by gross evaluation. In contrast, CV-6209, a specific PAF antagonist, had no effect on the total length of the lesions. The results strongly suggest the incorporation of endogenous ET in the mechanism of gastric damage after indomethacin administration.

Animals↗
PubMed1991

Cell proliferation kinetics in the marginal mucosa of gastric ulcer evaluated by immunostaining of DNA polymerase alpha.

We studied the proliferative ability of the marginal mucosal cells surrounding the ulcer in the healing processes of gastric ulcers. We obtained a labeling index (LI) at the neck and generative zone of gastric pit using a monoclonal antibody against DNA polymerase alpha for tractable and intractable gastric ulcers located at the fundic mucosa during each endoscopic stage. The LI during the healing stage was higher than that during the active stage in both the tractable and intractable cases. However, in each stage, the LI of the tractable gastric ulcers was higher than that of their intractable counterparts. Finally, we analyzed the LI in tractable gastric ulcers after setting two groups: one treated with anti-ulcer drugs and the other untreated. There were no significant differences between these two groups. We believe that investigation of proliferative abilities in the marginal mucosa of gastric ulcers is important to understand the nature of gastric ulcers and to assess therapeutic efficacy.

Adult↗
PubMed1991

Effect of carvedilol on venous return: a mechanism of reduction in blood pressure.

We studied the effect of carvedilol, a beta-blocker with a potent alpha-blocking activity, on venous return in anesthetized dogs. Though 3 micrograms/kg of carvedilol caused a slight increase in blood pressure and total peripheral resistance, these changes disappeared by further doses of the agent. On the other hand, each dose of carvedilol (3-100 micrograms/kg) decreased venous return significantly and dose-dependently. These results indicate that the hypotensive effect of carvedilol mainly depends on the decrease in venous return rather than arterial vasodilation.

Adrenergic beta-Antagonists↗
PubMed1990

Epidermal growth factor prolongs survival time of tumor-bearing mice.

We observed that human epidermal growth factor (hEGF) alone prolonged the survival time of mice bearing various murine syngeneic tumors as well as athymic nude mice bearing human xenografts. No changes in the subcutaneous solid tumor mass volume were observed. Prolongation of survival time by hEGF was observed in mice bearing murine epidermoid carcinoma (BSC) and human gastric carcinoma (KATO III), but not in murine epidermoid carcinoma (KLN205) or human epidermoid carcinoma (A431). Human tumor cells such as A431, KATO III, and murine tumor cells, KLN205, BSC had roughly 2 X 10(6), 3 X 10(4), 1.3 X 10(3) and 1 X 10(3) EGF receptors/cell, respectively. Although KLN205 and BSC tumor cells maintained nearly the same number of EGF receptors, the effects of hEGF were very different. Although A431 tumor cells had nearly 100 times more receptors than KATO III cells, the prolongation of survival time of mice bearing A431 by hEGF was no better than that of mice bearing KATO III. Accordingly, it appears that this prolongation of survival time by hEGF is independent of the number of EGF receptors on tumor cells. In addition, hEGF was shown to inhibit experimental pulmonary metastasis of murine BSC tumor, but was ineffective with murine KLN205 tumor. These results suggest that prolongation of survival time by hEGF may result from the inhibition of tumor cell metastasis and EGF may play a role in preventing the metastasis of certain malignant neoplasms unrelated to its effects through the EGF receptor on tumor cells.

Adenocarcinoma↗
PubMed1984

Endoscopical determination of gastric mucosal blood flow by the crossed thermocouple method.

A crossed thermocouple method in combination with endoscopy was applied to determine the blood flow rate of the human gastric mucosa. Determination was carried out with 11 healthy control subjects at 8 sites of the stomach. The blood flow rates at all sites in the corpus were found to be higher than those at the antrum. In subjects less than 50 years old the blood flow rate in the corpus was higher than in older subjects. These results were in agreed well with those obtained by the hydrogen gas clearance method, which is widely adopted clinically. The crossed thermocouple method is easily applicable to all sites in the gastric mucosa and the time required for the assay is very short. This method dose not require the inhalation of hydrogen gas which is necessary for the hydrogen gas clearance method and which is possibly harmful to humans. Although the values obtained by the crossed thermocouple method are relative to the value at a certain fixed site, this method will holds great potential for the determination of gastric mucosal blood flow rate.

Adult↗