Biomedical subjects

Y Ishimura

Publications and source records attributed to Y Ishimura.

At least 73 records · Page 4Linked to original sources

PubMed1996

Effects of long term stimulation of ACTH and angiotensin II-secretions on the rat adrenal cortex.

In the rat adrenal cortex, aldosterone synthase cytochrome P450 (P450aldo), a mineralocorticoid synthesizing enzyme, localizes in the zona glomerulosa (zG), while cytochrome P45011 beta (P45011 beta), a glucocorticoid synthesizing enzyme, localizes in the zonae fasciculata-reticularis (zFR). In between zG and zF, a cell-layer which contains neither P450aldo nor P45011 beta is present, where replicating cells were abundant as judged by the incorporation of bromodeoxyuridine (BrdU) and/or by detecting PCNA in their nuclei. When plasma ACTH level of the rat was raised 3-fold for 2-3 weeks by the administration of metyrapone, a potent inhibitor of glucocorticoid formation, most of zG cells containing P450aldo disappeared, while zF cells with P45011 beta increased. Under the conditions, the cell-layer without P450aldo and P45011 beta became very thin, and replicating cells were mainly in the outermost portion of zF. When angiotensin II secretion was also stimulated for 2-3 weeks by feeding the rats on Na-deficient diet, the P450aldo-containing cells proliferated to form a thicker zG (7-8 cells-thick from 1-2), while the width of zF containing P45011 beta decreased slightly. Coincidently the cell-layer devoid of P450aldo and P45011 beta became thin, though slightly, and numbers of replicating cells significantly increased in and around the inner edge of the proliferated zG. When both ACTH and angiotensin II secretions were stimulated simultaneously, the cell-layer without P450aldo and P45011 beta almost disappeared and replicating cells were around the boundary of zG and zF. Based on these results we propose that the cell-layer between zG and zF devoid of P450aldo and P45011 beta is the stem cell layer of rat adrenal cortex.

Adrenal Cortex↗

PubMed1996

Taurocholate induces directional excretion of bilirubin into bile in perfused rat liver.

The role of taurocholate, one of the major conjugated bile acids present in portal blood, in excretion of bilirubin from liver parenchyma to biliary and vascular compartments was studied in isolated perfused rat liver. Contents of bilirubin and carbon monoxide (CO) in the bile or venous effluents were determined by enzyme-linked immunosorbent microassay with the use of antibilirubin monoclonal antibody 24G7 and myoglobin-assisted spectrophotometry, respectively. In the presence of taurocholate, bilirubin excreted into the biliary compartment constituted greater than 90% of the total bilirubin excreted from the liver (0.26 nmol.min-1.g liver-1), corresponding to 60% of the outflow of CO into the venous effluents. In its absence, however, the total amount of bilirubin excreted into extrahepatic compartments was reduced to 27% of CO flux, and more than 90% of the excreted bilirubin was in the venous effluent. Thus a choleretic bile acid such as taurocholate is necessary for directional transport of bilirubin into bile in the perfused liver preparation.

Animals↗

PubMed1996

Modulation of mitochondrion-mediated oxidative stress by nitric oxide in human placental trophoblastic cells.

Intracellular hydroperoxide generation in cultured human placental trophoblastic cells (HPTCs) was quantitatively monitored in the presence or absence of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), by digital microfluorography with use of carboxydichlorofluorescein, a hydroperoxide-sensitive fluorogenic probe. In the absence of L-NAME, HPTCs displayed a time-dependent gradual elevation of the fluorescence, suggesting the ability to produce oxidants spontaneously. In the presence of L-NAME, however, the fluorescent response in these cells increased further; the oxidative impact elicited by L-NAME treatment for 30 min was equivalent to that induced by application of 230 microM tert-butyl hydroperoxide for 5 min. This oxidative process was completely blocked by rotenone, a reagent that interferes with electron entry into complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, which blocks mitochondria at the distal site of the ubiquinone pool, potentiated the L-NAME-induced oxidative change. These findings suggest that constitutive levels of nitric oxide production contribute to regulation of mitochondrion-derived intracellular oxidant generation in HPTCs.

Cell Separation↗

PubMed1996

Evidence for 54-kD protein in chicken kidney as a cytochrome P450 with a high molecular activity of 25-hydroxyvitamin D3 1 alpha-hydroxylase.

Conversion of 25-hydroxyvitamin D3 (25(OH)D3) to the active vitamin D3, 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) is catalyzed by 25(OH)D3, 1 alpha-hydroxylase(1 alpha-hydroxylase). It has been suggested that this enzyme is cytochrome P450 (P450). We purified 1 alpha-hydroxylase 430-fold from cholate-solubilized kidney mitochondria of vitamin D-deficient chickens by utilizing hydrophobic and ion-exchange column chromatographies. Enzymatic activity was assessed by measuring on HPLC the formation of 1 alpha,25(OH)2D3 from 25(OH)D3 in the assay mixture containing NADPH, adrenodoxin reductase, adrenodoxin as a reducing system. The purified enzyme showed a CO-difference spectrum characteristic of P450. The molecular activity of this preparation was calculated to be 8.7 pmol/min/pmol P450. This value was higher by more than 87-fold than those reported so far. The present preparation was found to contain several proteins on SDS-PAGE. Among them, only the 54-kD protein became undetectable when kidney mitochondria from normal and vitamin D-replete chickens, where 1 alpha-hydroxylase activities were 15 and 0% of that found in vitamin D-deficient chicken, respectively, were used as the starting enzyme sources. Furthermore, the band intensity of the 54-kD protein accounted for the spectrophotometrically determined amount of P450 in the preparation. These results suggest that the 54-kD protein is 1 alpha-hydroxylase.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1996

TCV-116 inhibits renal interstitial and glomerular injury in glomerulosclerotic rats.

TCV-116 and enalapril were given in two stages: (early phase) for 6 to 10 weeks to 5/6 nephrectomized (NX) rats two weeks after nephrectomy, 12-week-old Wistar fatty (WF) rats and 7-week-old spontaneously hypercholesterolemic (SHC) rats; and (late phase) for 6 to 16 weeks to 5/6 NX rats 11 weeks after nephrectomy, 27-week-old WF rats and 10-week-old SHC rats. Urinary albumin, blood pressure (BP), glomerular filtration rate (GFR) and renal histology were examined. In the early phase, both agents inhibited proteinuria and tended to inhibit glomerulosclerosis. TCV-116 also inhibited interstitial inflammation. The antiproteinuric effects did not necessarily correlate with the BP-lowering effects. In the late phase, both agents showed equal antiproteinuric and antihypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubulointerstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunction, but enalapril had little effect on these parameters. In the SHC rats, TCV-116 inhibited renal tubulointerstitial inflammation and glomerulosclerosis, but enalapril inhibited only glomerulosclerosis. After drug administration, there was a positive correlation between proteinuria and BP, and a negative correlation between the severity of tissue damage and GFR, but not BP. These findings suggest that initial BP-independent tubulointerstitial inflammation may enhance glomerulosclerosis in the late phase, and TCV-116 might prevent the development of glomerulosclerosis through inhibition of angiotensin II-mediated tubulointerstitial damage in these models.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Gaseous monoxides: a new class of microvascular regulator in the liver.

Gaseous monoxides such as nitric oxide (NO) and carbon monoxide (CO) have recently attracted great interest as a regulator of cell and organ functions. When exposed to endotoxin, cytokines or ischemia-reperfusion, the liver produces larger amounts of NO than those in the control via the activity of inducible NO synthase which can alter a variety of organ functions such as sensitivity of vascular tone to catecholamine, mitochondrial membrane potential, biliary transport and tissue regeneration. On the other hand, the liver constitutively produces CO through the reaction of heme oxygenase. CO generated in the liver tissue can reach sinusoidal vessels and relax fat-storing Ito cells--the liver-specific microvascular pericytes covering the sinusoidal wall--and thereby serves as an endogenous modulator of vascular tone. Two isoforms of the CO-generating enzyme have been characterized: heme oxygenase-1 which is inducible by a variety of stressors, and heme oxygenase-2 which constitutes the major enzyme activity under physiological conditions in the liver. Although it is still unknown whether excessive CO generation by the inducible heme oxygenase activity may preserve or jeopardize the integrity of microvascular function in the liver, the potential importance of this double-edged molecule has just emerged much like nitric oxide, another gaseous molecule that was established as a neurovascular mediator inducing vascular cell relaxation. This article provides an overview of the pathophysiological roles of these gaseous monoxides in regulation of microvascular function in the liver.

Animals↗

PubMed1995

Role of Thr-252 in cytochrome P450cam: a study with unnatural amino acid mutagenesis.

Replacement of Thr-252 in the active center of cytochrome P450cam with a non-hydroxy amino acid residue such as Ala and Val by conventional site-directed mutagenesis converted this monooxygenase to an NADH oxidase (Imai, M. et al. Proc. Natl. Sci. U. S. A. 86, 7823-7827, 1989). In this study, a mutant enzyme with a methoxy group in place of the hydroxy group of Thr-252 (OMe-mutant) was synthesized by the method of unnatural amino acid mutagenesis (Noren, C. J. et al., Science 244, 182-188, 1989). Unlike other site-directed mutants without a hydroxy group at the position, the OMe-mutant retained a considerably high monooxygenase activity, yielding a stoichiometric amount of 5-exo-hydroxycamphor to that of the oxygen consumed. Thus a free hydroxy group at this position is not an indispensable requisite for the monooxygenase to cleave the O-O bond of molecular O2 as previously proposed.

Alanine↗

PubMed1995

Stimulatory effect of angiotensin II on calcium efflux from cultured bovine adrenal chromaffin cells.

The effect of angiotensin II on Ca2+ mobilization in cultured bovine adrenal chromaffin cells was examined. Angiotensin II (10(-7)M) increased the intracellular free Ca2+ level ([Ca2+]i) to a peak in the presence or absence of extracellular Ca2+, followed by decrease with time. Angiotensin II (10(-9)-10(-6)M) also stimulated 45Ca2+ efflux from cultured bovine adrenal chromaffin cells in a concentration-dependent manner. Its stimulatory effect on 45Ca2+ efflux was inhibited by the angiotensin II antagonist [Sar1, Ile8]-angiotensin II or [Sar1, Val5, Ala8]-angiotensin II. The increase in angiotensin II-stimulated 45Ca2+ efflux was dependent on the extracellular Na+ concentration. Angiotensin II also increased 22Na+ influx into the cells. These results indicate that stimulation of the angiotensin II receptor induces extracellular Na(+)-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells, probably by acceleration of Na+/Ca2+ exchange.

Adrenal Medulla↗

PubMed1995

Calcium efflux from cultured bovine adrenal chromaffin cells induced by pituitary adenylate cyclase-activating polypeptide (PACAP): possible involvement of an Na+/Ca2+ exchange mechanism.

The effect of pituitary adenylate cyclase-activating polypeptide 1-38 (PACAP1-38) on Ca2+ efflux from cultured bovine adrenal chromaffin cells was examined. PACAP1-38 stimulated the efflux of 45Ca2+ from the cells in a concentration dependent manner (10(-9)-10(-7)M). This effect was inhibited by its potent receptor antagonist PACAP6-38. PACAP1-38 increased the formation of [3H]inositol phosphates and cyclic AMP in the cells. Forskolin, an activator of adenylate cyclase, also stimulated the efflux of 45Ca2+ from the cells. 3-Isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase, enhanced PACAP1-38-induced 45Ca2+ efflux from the cells. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, had no effect on the efflux of 45Ca2+ from the cells. The increases in 45Ca2+ efflux induced by PACAP1-38 and forskolin were reduced by deprivation of extracellular Na+ and the Na+/Ca2+ exchange inhibitor amiloride. In addition, PACAP1-38 stimulated 22Na+ influx into the cells, and this action was inhibited by amiloride. These results suggest that PACAP1-38 stimulates an Na+/Ca2+ exchange mechanism through activation of adenylate cyclase in cultured bovine adrenal chromaffin cells.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Significance of steroidogenic enzymes in the pathogenesis of hyperfunctioning and non-hyperfunctioning adrenal tumor.

To elucidate the mechanisms of abnormal steroid production in hyperfunctioning and non-hyperfunctioning adrenal tumors, we examined both the activities and amounts of steroidogenic cytochromes P450 in the tumor and non-tumor portions of these adrenals at the posttranslational (protein) level. Adrenals from 5 patients with primary aldosteronism, 5 with Cushing's syndrome, 1 with deoxycorticosterone (DOC)-producing adenoma, 10 with non-hyperfunctioning adrenal adenoma, and 5 subjects with normal control adrenals (obtained from patients with renal cell carcinoma) were used in our studies. Activities of P450scc, P45011 beta and P450aldo, and P450C21 and P-45017 alpha were assayed in a reconstituted enzyme system using 20 alpha-hydroxycholesterol, DOC, and progesterone, respectively, and the substrate and the extracted products were analyzed by HPLC. Enzyme amounts were determined by immunoblot analysis with anti-bovine P450scc, P45011 beta, and P450C21 IgG, and anti-porcine P45017 alpha IgG. Human P450aldo was only detected in the tumor portion of primary aldosteronism adrenals, with both activities and amounts of other P-450s similar to those in the non-tumor portion of primary aldosteronism and normal controls. In Cushing's syndrome, both activities and amounts of P45017 alpha and P450C21 were significantly increased in the tumor compared with those in the non-tumor portion of Cushing's syndrome and normal controls. In DOC-producing adenoma, both activities and amounts of P45017 alpha and P45011 beta in the tumor portion of the adenoma decreased compared with normal control, while those of other P450s were similar to normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗

PubMed1995

Involvement of an AP-1 complex in zone-specific expression of the CYP11B1 gene in the rat adrenal cortex.

The CYP11B1 gene, which encodes steroid 11 beta-monooxygenase, which is responsible for the synthesis of cortisol and corticosterone, the major glucocorticoids in mammals, is expressed specifically in the zona fasciculata of the adrenal cortex. We have analyzed the promoter region of the rat CYP11B1 gene by using a transient-expression system with adrenocortical Y1 cells and have identified a positive regulatory region. The region contained two adjacent sites for the binding of Y1-cell nuclear proteins: the binding site for an AP-1 transcription factor composed of JunD and a Fos-related protein, and the site for Ad4-binding protein (Ad4BP). The binding of the AP-1 factor to the regulatory region had a suppressive effect on that of Ad4BP in the nuclear extracts. Mutational analyses revealed that the transcriptional activation of the CYP11B1 gene promoter in Y1 cells was attributable to the AP-1 site but not to the Ad4 site. Subsequently, nuclear extracts of the zona fasciculata cells from the rat adrenal cortex were found to contain both AP-1 factor and Ad4BP, whose binding properties to the regulatory region were almost identical to those of the two factors in the Y1-cell nuclear extracts. Moreover, immunohistochemical analyses of rat adrenal cortices showed that the AP-1 factor was present in the nuclei of CYP11B1-expressing cells in the zona fasciculata but not in the nuclei of cells in the other zones. From these results, we propose that the AP-1 transcription factor found in this study plays an important role in the zone-specific expression of the CYP11B1 gene in rat adrenal cortex.

Animals↗

PubMed1995

Recognition of consensus CHO structure in ligands for selectins by novel antibody against sialyl Lewis X.

The selectins (L, E, and P) play an important role in the earliest events of the inflammatory response, leading to the "rolling" phenomenon. All selectins react with sialyl Lewis X (SLex) in vitro, possibly suggesting that their ligands have a consensus structure. 2H5 is a monoclonal antibody against SLex that blocks L-selectin-mediated adhesion. 2H5 inhibited adhesion of HL-60 cells to P- and E-selectin-producing COS cells in vitro and immunoprecipitated a P-selectin glycoprotein ligand-1-like glycoprotein from HL-60 cell lysate, suggesting that it recognizes a functional consensus structure on the ligands for all selectins. 2H5 reacted not only with human but also with rat and mouse neutrophils. 2H5 is the first antibody against SLex that recognizes neutrophils of nonhuman mammals. The carbohydrate structure recognized by 2H5 was present not only on high endothelial venules of rat lymphoid organs but also on the endothelial cells of nonlymphoid organs. Furthermore, administration of the antibody markedly inhibited L- and P-selectin-mediated neutrophil rolling and adhesion in rat mesenteric venules in vivo. These results provide evidence for the presence of a consensus carbohydrate structure on the ligands for all selectins. The consensus structure thus has the potential to serve as a therapeutic target.

Animals↗

PubMed1995

Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats.

The present study was designed to elucidate whether molecular mechanisms for leukocyte adhesion to microvascular endothelium may differ between spontaneously hypertensive rats and Wistar Kyoto rats. Leukocyte rolling and adhesion were investigated while monitoring venular wall shear rates in the mesenteric microcirculation stimulated with histamine or tert-butyl hydroperoxide in the two strains. In Wistar Kyoto rats, 10 microM histamine as well as 500 microM tertbutyl hydroperoxide promoted a significant reduction of venular leukocyte rolling velocity and subsequent adhesion. These changes in leukocyte behavior were blocked by monoclonal antibodies against P-selectin (PB 1.3) and against sialyl Lewis X-like carbohydrates (2H5). However, spontaneously hypertensive rats exhibited a blunted response of the stimulus-elicited leukocyte rolling, which was associated with impairment of venular P-selectin expression as well as a decrease in the expression of sialyl Lewis X-like carbohydrates on circulating neutrophils. No significant differences were detected between the two strains not only in the surface CD11b/CD18 expression but also in the CD18-mediated adhesivity of neutrophils to intracellular adhesion molecule-1 transfectants in vitro. These results suggest that impairment of selectin-mediated leukocyte adhesion is an event responsible for disorders of inflammatory responses in spontaneously hypertensive rats.

Animals↗

PubMed1995

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

Heme oxygenase is a heme-oxidizing enzyme which generates biliverdin and carbon monoxide (CO). The present study was designed to elucidate whether CO endogenously produced by this enzyme serves as an active vasorelaxant in the hepatic microcirculation. Microvasculature of the isolated perfused rat liver was visualized by dual-color digital microfluorography to alternately monitor sinusoidal lining and fat-storing Ito cells. In the control liver, the CO flux in the venous effluent ranged at 0.7 nmol/min per gram of liver. Administration of a heme oxygenase inhibitor zinc protoporphyrin IX (1 microM) eliminated the baseline CO generation, and the vascular resistance exhibited a 30% elevation concurrent with discrete patterns of constriction in sinusoids and reduction of the sinusoidal perfusion velocity. The major sites of the constriction corresponded to local sinusoidal segments colocalized with Ito cell which were identified by imaging their vitamin A autofluorescence. The increase in the vascular resistance and sinusoidal constriction were attenuated significantly by adding CO (1 microM) or a cGMP analogue 8-bromo-cGMP (1 microM) in the perfusate. From these findings, we propose that CO can function as an endogenous modulator of hepatic sinusoidal perfusion through a relaxing mechanism involving Ito cells.

Animals↗

PubMed1995

Physiological significance of plasma sulfoconjugated dopamine: experimental and clinical studies.

Sulfoconjugated catecholamines have been regarded simply as metabolites of free catecholamines. However, a conjugated form of the catecholamine, dopamine has recently attracted much attention because it is present at high levels in the plasma of humans and experimental animals. We carried out experimental and clinical studies to determine the physiological significance of this large amount of dopamine conjugate in the plasma. Clinical studies showed that the plasma level of dopamine sulfate decreased significantly during the acute phase of heart failure, whereas that of free dopamine increased. Moreover, the plasma level of conjugated dopamine in patients with essential hypertension was higher than that in control subjects, and being highest in patients with renal hypertension. In experimental studies, we examined the activity for deconjugating DA sulfate in homogenates of organs from dogs. The kidney and liver exhibited the highest activities, and in the heart, the activity was higher in the atrium than the ventricle. We also examined the effect of dopamine sulfate on isolated perfused rat heart. Dopamine sulfate was found to be converted to free dopamine, which was responsible for the positive inotropic action, in atrial tissue. Moreover, deconjugation of DA sulfate to the free form was accelerated by a high work lord on the heart. From these results, we conclude that the formation of dopamine sulfate plays a role in regulating the level of plasma free dopamine and that plasma dopamine sulfate may be a storage or reserve form of dopamine. Free (or active) dopamine may be formed through a deconjugation reaction when necessary.

Adult↗

PubMed1995

Biphasic effect of staurosporine on thymocyte apoptosis.

When mouse thymocytes were incubated with staurosporine at low doses (1-100 nM), apoptosis was induced dose- and time-dependently. Staurosporine-induced apoptosis was dependent on macromolecular synthesis, and it was also dependent on protein phosphorylation sensitive to 1-(5-isoquinolinesulfonyl-2-methylpiperazine dihydrochloride (H-7). Whereas, staurosporine at high doses (above 500 nM) did not induce significant DNA fragmentation, rather it inhibited the DNA fragmentation induced by 12-O-tetradecanoyl-13-acetate, A23187, and dibutyrylcyclic AMP, as H-7 did. K252a, a derivative of staurosporine, induced apoptosis, which was inhibited by H-7, even at high doses. These results indicate that staurosporine had a biphasic effect on thymocyte apoptosis, a stimulatory effect at low concentration, and an inhibitory effect at high concentration. K252a had only the former action.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats.

TCV-116 [(+/-)-(cyclohexyloxycarbony-loxy)ethyl2-ethoxy-1-[[2' -(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate ], a nonpeptide selective angiotensin II type I receptor (AT1 receptor) antagonist, at the dose of 0.1, 1 or 10 mg kg-1 day-1, was orally given to 22-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 10 weeks (from the age of 22-32 weeks) to examine the effects on gene expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific complementary DNA probe. In the heart, left ventricular mRNA levels for fibronectin; types I, III and IV collagen; and laminin were significantly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric artery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellular matrix protein mRNAs were increased compared with Wistar-Kyoto rats. Thus, the expression of various genes was up-regulated in cardiovascular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TGF-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the medial hypertrophy of the aorta in SHRSP. These results show that angiotensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardiovascular tissues. These effects may contribute to the beneficial effects of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening.

Angiotensin II↗

PubMed1995

Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats.

OBJECTIVE AND DESIGN: To study the effects of blockade of the renin-angiotensin system on the development of hypertension and end-organ damage in hyporeninaemic deoxycorticosterone acetate (DOCA)-salt hypertensive rats, using an angiotensin II (Ang II) receptor antagonist (TCV-116) or an angiotensin converting enzyme (ACE) inhibitor (enalapril). METHODS: DOCA-salt hypertensive rats were produced by uninephrectomy, implantation with DOCA pellets and 1% NaCl loading. TCV-116 (0.1 or 1 mg/kg) or enalapril (10 mg/kg) was given orally once a day from 3 to 6 weeks after the operation. Body weight, blood pressure, plasma renin and creatinine, urinary protein and blood urea nitrogen were measured. After 3 weeks' treatment, oedema and omega 3-subtype benzodiazepine receptor binding in the brain were measured. RESULTS: Three weeks after the operation the blood pressure in the DOCA-salt hypertensive rats was approximately 200 mmHg, and the plasma renin concentration was lower than in sham-operated rats. However, after a further 3 weeks the renin concentration was slightly above the normal level, and this increase was accompanied by a decrease in body weight and increases in blood urea nitrogen, plasma creatinine, urinary protein and omega 3-subtype benzodiazepine receptor binding in the cerebral cortex, and by brain oedema. Treatment with TCV-116 or enalapril prevented renal damage and decrease in body weight with little effect on blood pressure. Enalapril prevented brain oedema and the increase in benzodiazepine binding in the brain cortex, and 1 mg/kg TCV-116 prevented them markedly. CONCLUSIONS: Although the hypertension in DOCA-salt hypertensive rats is independent of the renin-angiotensin system, the degree of cerebral and renal damage is associated with the activity of the renin-angiotensin system and has little relationship with the blood pressure level.

Administration, Oral↗