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E Kubota

Publications and source records attributed to E Kubota.

At least 19 recordsLinked to original sources
PubMed2003

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.

AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease.

In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Role of interleukin-1 in induction of matrix metalloproteinases synthesized by rat temporomandibular joint chondrocytes and disc cells.

To identify cartilage-degrading enzymes and cell types that can be specifically induced by interleukin-1 (IL-1)alpha, we studied matrix metalloproteinase (MMP) activities of cultured rat temporomandibular joint (TMJ) chondrocytes and disc cells. The cells were isolated from TMJs pre-injected with normal physiological saline (CR) or recombinant human IL-1alpha (AR). MMP activities in the conditioned media were assayed by gelatin enzymography, and they were identified by Western blot analyses. MMP mRNAs in these cells were also detected by RT-PCR. IL-1alpha significantly induced an increase of active MMP9 as well as pro- and active MMP3, but had no effect on the MMP2 activity in both types of cells. MMP3 and MMP9 mRNAs were also inducible in these cells by IL-1alpha stimulation. Furthermore, disc cells were more susceptible to IL-1alpha than chondrocytes. AR cells spontaneously produced the same MMPs in vitro as the CR cells synthesized under IL-1alpha stimulation. The results indicate that MMP9 and MMP3 were predominantly produced by disc cells, and these may be considered to play a pivotal role in ECM degradation during pathological conditions of the TMJ, such as IL-1-induced TMJ arthritis.

Analysis of Variance↗
PubMed2001

In vivo visualization of angiotensin II- and tubuloglomerular feedback-mediated renal vasoconstriction.

BACKGROUND: A noninvasive technique to monitor renal microcirculation would be a useful tool for investigation of renal disease and the effects of drugs on the renal system. We have developed a novel, less invasive technique to visualize renal microcirculation in vivo using an intravital tapered-tip (1 mm phi) lens-probe (pencil lens-probe) videomicroscopy, which only requires insertion of the probe into superficial renal cortex in situ. METHODS: To assess validity of this technique, the effects of angiotensin II (Ang II) and intrarenal sodium chloride loading (activator of tubuloglomerular mechanism) were examined. The renal microvasculature was successfully visualized and monitored. RESULTS: Administration of Ang II (1, 3, 10 and 30 ng/kg/min) produced a dose-dependent constriction of afferent and efferent arterioles in similar degrees; at 30 ng/kg/min, Ang II elicited 52 +/- 3 (N = 9) and 53 +/- 3% decreases in diameter (N = 9), respectively. The Ang II-induced arteriolar constriction was completely prevented by losartan, an Ang II type 1 (AT1) antagonist. The intrarenal hypertonic saline administration elicited transient increments (from 98 +/- 8 to 122 +/- 7 mL/min, N = 6, P < 0.05), followed by a marked reduction in renal blood flow (RBF; 78 +/- 7 mL/min, P < 0.05). This response was accompanied by prominent constriction of afferent (from 15.0 +/- 1.1 to 8.5 +/- 1.1 microm, N = 6, P < 0.05), but not efferent (from 14.3 +/- 1.2 to 13.8 +/- 1.0 microm, N = 3) arterioles. Furthermore, this response was completely inhibited by furosemide, a tubuloglomerular feedback inhibitor. CONCLUSION: : The intravital pencil lens-probe videomicroscopy can be a powerful tool for in vivo observation of renal microcirculation, with intact renal microvascular responses to two important renal homeostatic mechanisms, angiotensin II and tubuloglomerular feedback.

Adult↗
PubMed2001

In-vitro and in-vivo inhibition of rat neutral endopeptidase and angiotensin converting enzyme with the vasopeptidase inhibitor gemopatrilat.

OBJECTIVES: Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat. DESIGN AND METHODS: In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point). RESULTS: Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC50 305 +/- 5.4 nmol/I) and ACE (IC50 3.6 +/- 0.02 nmol/). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P< 0.01), and renal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P< 0.01) and inhibited plasma ACE (P< 0.05), renal NEP (P< 0.01) and renal ACE (P< 0.05) for 48 h. CONCLUSIONS: Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.

Administration, Oral↗
PubMed2001

Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo.

OBJECTIVE: To assess the in-vivo action on the renal microvasculature of the calcium antagonists nifedipine (L-type blocker), efonidipine (L/T-type blocker), and mibefradil (predominant T-type blocker). DESIGN: An intravital needle-type charge-coupled device (CCD) camera videomicroscope was introduced to visualize the renal microcirculation directly in vivo. METHODS: In anesthetized mongrel dogs, nifedipine (0.01-1 mg/kg per min), efonidipine (0.033-0.33 mg/kg per min), or mibefradil (0.01-1 mg/kg per min) was infused intravenously after the insertion of a CCD probe into the kidney. Renal microvascular responses to calcium antagonists were directly evaluated, with concomitant observation of renal clearance. RESULTS: Each calcium antagonist caused modest vasodepressor action without affecting heart rate. Nifedipine (1 mg/kg per min, n = 9) increased renal plasma flow (RPF) (14 +/- 4%, P < 0.05) and glomerular filtration rate (GFR) (19 +/- 5%, P < 0.05), and tended to increase the filtration fraction (5 +/- 2% increment, P = 0.07). Efonidipine (0.33 mg/kg per min, n = 9), however, had no effect on filtration fraction, with 14 +/- 6% increments in RPF (P < 0.05) and 14 +/- 7% increments in GFR (P = 0.08). Rather, mibefradil (1 mg/kg per min, n = 9) elicited 6 +/- 2% decreases in filtration fraction (P < 0.05), with slight increments in RPF (6 +/- 3%) and no changes in GFR. In direct in-vivo microvasculature observations, nifedipine caused predominant (22 +/- 2%) dilatation of afferent arterioles (from 15.5 +/- 0.4 to 18.9 +/- 0.4 microm, n = 5), compared with that of efferent arterioles (10 +/- 2%; from 11.0 +/- 0.4 to 12.1 +/- 0.3 microm). In contrast, efonidipine caused a similar magnitude of vasodilatation (16 +/- 4%) compared with 18 +/- 2%; n = 6), and mibefradil caused greater dilatation of efferent arterioles (20 +/- 4%, n = 7) than that of afferent arterioles (13 +/- 4%). CONCLUSIONS: There exists marked heterogeneity in action of nifedipine, efonidipine and mibefradil on the renal microvascular in canine kidneys in vivo. Furthermore, our current observations suggest an important contribution of T-type calcium channel activity to efferent arteriolar tone in vivo.

Animals↗
PubMed2001

Deformation of the ventrolateral medulla oblongata by subarachnoid hemorrhage from ruptured vertebral artery aneurysms causes neurogenic pulmonary edema.

The occurrence of neurogenic pulmonary edema (NPE) associated with subarachnoid hemorrhage (SAH) due to ruptured aneurysm was analyzed in 48 consecutive patients. Correlations of the location of the aneurysm, clinical grade, amount of subarachnoid clot, and severity of NPE were examined. NPE was observed in 29.4% of all SAH cases, but the incidence was significantly higher in cases of ruptured vertebral artery (VA) aneurysm. Clinical grade, severity of NPE, and deformation of the medulla oblongata were studied in the five cases of ruptured VA aneurysm. Deformation of the ventrolateral medulla oblongata was observed in all patients. Asymmetry index of the medulla oblongata measured on the axial computed tomography scan was correlated with the severity of NPE. Severity of NPE tended to correlate with deformation of the medulla oblongata. NPE associated with ruptured VA aneurysm is caused by deformation of the ventrolateral site of the medulla oblongata by the localized hemorrhage.

Adult↗
PubMed2001

Enhancement of matrix metalloproteinase (MMP)-2 activity in gingival tissue and cultured fibroblasts from Down's syndrome patients.

OBJECTIVES: To identify one of the possible factors responsible for periodontal disease in Down's syndrome (trisomy 21) patients, we studied the enzyme activity and the mRNA expression pattern of matrix metalloproteinases (MMPs) of cultured gingival fibroblasts (GF) and fresh gingival tissues. MATERIALS AND METHODS: Gingival tissue was used as the cell source and was biopsied at the time of dental treatment from nine patients with Down's syndrome and nine non-Down's controls. GF were cultivated in serum-free media for analyses of their MMP activities at the transcription or the protein level. The MMP activities in the supernates were measured by gelatin impregnated zymography. Relative levels of MMP mRNA from the cultured GF or freshly isolated gingival tissues were determined using the reverse transcription polymerase chain reaction (RT-PCR). RESULT AND CONCLUSIONS: The production of the active type of MMP-2 in GF from Down's syndrome patients (D-GF) was found to be significantly higher (P < 0.05) than that of the control GF (C-GF) at the protein level. The mRNA expressions of membrane-type I MMP (MT1-MMP) and MMP-2 in D-GF were constitutively augmented when compared with those of C-GF. These findings suggest that specific increase of the active form of MMP-2 in D-GF may possibly be due to the concomitant expression of MT1-MMP in the cultured cells, and this could be related to the pathogenesis of gingivitis/periodontitis associated with Down's syndrome patients.

Adolescent↗
PubMed2001

Divergent natriuretic action of calcium channel antagonists in mongrel dogs: renal haemodynamics as a determinant of natriuresis.

This study examined the effects of different types of calcium channel antagonists on renal haemodynamics and natriuresis. The intravenous infusion of nifedipine (L-type blocker), efonidipine (L/T-type blocker) or mibefradil (predominant T-type blocker) into anaesthetized dogs elicited similar, albeit modest, reductions in blood pressure. Nifedipine (1 microgram.min(-1).kg(-1)) increased renal plasma flow (RPF) (23+/-6%; P<0.05) and glomerular filtration rate (GFR) (25+/-5%; P<0.05) (all values are means+/-S.E.M., n=7). Efonidipine (0.33 microgram .min(-1).kg(-1)) also elevated RPF (18+/-6%; P<0.05), and tended to increase GFR (17+/-8%; P=0.08). These antagonists exerted contrasting actions on the filtration fraction (FF), with an increase being elicited by nifedipine, whereas efonidipine had no effect. Furthermore, mibefradil (0.01-1 microgram.min(-1).kg(-1)) slightly elevated RPF (between 5+/-3% and 8+/-3%), but failed to alter GFR, resulting in a decrease in FF. Nifedipine slightly increased urinary sodium excretion (U(Na)V) (29+/-16% increase at 1 microgram .min(-1).kg(-1)) and fractional sodium excretion (FE(Na)) (18+/-14%), whereas efonidipine (0.33 microgram .min(-1).kg(-1)) elicited marked elevations in U(Na)V (110+/-38%; P<0.05) and FE(Na) (102+/-44%; P<0.05). Mibefradil (1 microgram .min(-1).kg(-1)) exerted a moderate natriuretic action [U(Na)V, +60+/-32% (P=0.1); FE(Na), +67+/-20% (P<0.05)]. Furthermore, although a positive correlation was observed between U(Na)V and urinary nitrate/nitrite excretion, no differences were noted between the various calcium channel antagonists. Collectively, this study demonstrates that the glomerular haemodynamic and natriuretic actions of these calcium channel antagonists, which possess diverse blocking activities on L/T-type channels, vary. Based on the divergent actions on FF (i.e. increase, no change and decrease by nifedipine, efonidipine and mibefradil respectively), the natriuretic action of calcium channel antagonists is possibly attributed to the inhibition of tubular sodium reabsorption associated with increased post-glomerular blood flow, rather than increased GFR.

Animals↗
PubMed2000

Role of gut cryptopatches in early extrathymic maturation of intestinal intraepithelial T cells.

Lympho-hemopoietic progenitors residing in murine gut cryptopatches (CP) have been shown to generate intestinal intraepithelial T cells (IEL). To investigate the role of CP in progenitor maturation, we analyzed IEL in male mice with a truncated mutation of common cytokine receptor gamma-chain (CRgamma-/Y) in which CP were undetectable. IEL-expressing TCR-gammadelta (gammadelta-IEL) were absent, and a drastically reduced number of Thy-1highCD4+ and Thy-1highCD8alphabeta+ alphabeta-IEL were present in CRgamma-/Y mice, whereas these alphabeta-IEL disappeared from athymic CRgamma-/Y littermate mice. Athymic CRgamma-/Y mice possessed a small TCR- and alphaEbeta7 integrin-negative IEL population, characterized by the disappearance of the extrathymic CD8alphaalpha+ subset, that expressed pre-Talpha, RAG-2, and TCR-Cbeta but not CD3epsilon transcripts. These TCR- IEL from athymic CRgamma-/Y mice did not undergo Dbeta-Jbeta and Vdelta-Jdelta joinings, despite normal rearrangements at the TCR-beta and -delta loci in thymocytes from euthymic CRgamma-/Y mice. In contrast, athymic severe combined immunodeficient mice in which CP developed normally possessed two major TCR-alphaEbeta7+ CD8alphaalpha+ and CD8- IEL populations that expressed pre-Talpha, RAG-2, TCR-Cbeta, and CD3epsilon transcripts. These findings underscore the role of gut CP in the early extrathymic maturation of CD8alphaalpha+ IEL, including cell-surface expression of alphaEbeta7 integrin, CD3epsilon gene transcription, and TCR gene rearrangements.

Animals↗
PubMed2000

Gut cryptopatches: direct evidence of extrathymic anatomical sites for intestinal T lymphopoiesis.

Athymic cytokine receptor gamma chain mutant mice that lack the thymus, Peyer's patches, cryptopatches (CP), and intestinal T cells were reconstituted with wild-type bone marrow cells. Bone marrow-derived TCR(-) intraepithelial lymphocytes (IEL) first appeared within villous epithelia of small intestine overlying the regenerated CP, and these TCR(-) IEL subsequently emerged throughout the epithelia. Thereafter, TCR(+) IEL increased to a comparable number to that in athymic mice and consisted of TCRgammadelta and TCRalphabeta IEL. In gut-associated lymphoid tissues of wild-type mice, only CP harbored a large population of c-kit(high)IL-7R(+)CD44(+)Thy-1(+/-)CD4(+/-)CD25(low/-)alpha(E) beta(7)(-)Lin(-) (Lin, lineage markers) lymphocytes that included cells expressing germline but not rearranged TCRgamma and TCRbeta gene transcripts. These findings provide direct evidence that gut CP develop progenitor T cells for extrathymic IEL descendants.

Animals↗
PubMed2000

Erratum.

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Journal Article↗
PubMed2000

Reactive oxygen species participation in experimentally induced arthritis of the temporomandibular joint in rats.

In the temporomandibular joint (TMJ), it has been hypothesized that mechanical stresses lead to the oxidative stress of articular tissues. It has also been postulated that cells pertinent to arthritis-including endothelial cells and synovial cells-when stimulated by mechanical stresses and/or pro-inflammatory cytokines, promote oxidative damage. To determine the involvement of reactive oxygen species (ROS) in the diseased joint, we studied the generation of ROS in synovial fluid (SF) from interleukin-1alpha (IL-1alpha)-induced TMJ arthritis by electron spin resonance (ESR) spectroscopy, using the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The TMJ arthritis was experimentally induced in rats by the injection of human recombinant IL-1alpha into the TMJ; control rats were treated with normal saline solution. We found that the detected radicals in the collected SF were identified as a 1:2:2:1 quartet, characteristic of the hydroxyl radical-DMPO spin adduct. The ESR signal intensity of the hydroxyl radical-DMPO spin adduct in the SF from IL-1-treated rats was significantly higher than that from the control rats (P < 0.01). The results of ESR study also showed that hydroxyl radical (HO*) was increased in a time-dependent fashion in the presence of superoxide anion radical (O2*-) scavenger superoxide dismutase (SOD); the formation of DMPO-HO* was strongly inhibited by the iron chelater deferoxamine. We could measure higher levels of free iron (Fe2- and Fe3-) in the SF from TMJ arthritis than in that from controls (P < 0.05). Analysis of the data obtained from the present study suggests that the HO* radical detected in SF from IL-1-induced TMJ arthritis is generated via a modified Haber-Weiss reaction (biological Fenton reaction) in which O2*- can subsequently result in the production of H2O2 through dismutation reaction by SOD. Thus, HO* may be generated from the reaction of resultant H2O2 with free iron ions. The results presented here provide the first evidence of involvement of ROS in IL-1-induced TMJ arthritis.

Analysis of Variance↗
PubMed1999

Duodenal ulceration into the cystic artery with massive hemorrhage.

This is a case presentation of a unique cause of intestinal bleeding. A duodenal ulcer eroded into the superficial branch of the cystic artery, causing massive intestinal hemorrhage. The patient, a 76-year-old woman, presented with left upper abdominal and left back pain secondary to cystic lesions in the pancreas body and tail. Stress after operation and complication of leakage of pancreatic juice after distal pancreatectomy with splenectomy and diclofenac sodium administration may have caused a deep peptic ulcer to erode the cystic artery. We performed a transfixing ligation of the bleeding vessel, serosal suture of ulcer of the gallbladder, and simple closure of the duodenal ulcer with covering greater omentum. There were no serious complications after the operation, and the patient made an uneventful recovery.

Aged↗
PubMed1999

Altered pressure-natriuresis in obese Zucker rats.

It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0+/-4.0x10(-8), n=9) and blood pressure (119+/-3 mm Hg) were greater than those in lean Zucker rats (LZ; 7.0+/-1.9x10(-8) and 103+/-4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073+/-0.015 vs 0.217+/-0.047 microEq/min kidney weight/mm Hg, P<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032+/-0.331 micromol/L; medulla, 4. 329+/-0.515 micromol/L) compared with that in LZ (cortex, 7.315+/-1. 102 micromol/L; medulla: 7.698+/-0.964 micromol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639+/-0.286 micromol/L; medulla, 5.978+/-0.284 micromol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure-natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.

Animals↗
PubMed1999

Impaired nitric oxide-independent dilation of renal afferent arterioles in spontaneously hypertensive rats.

Sustained hypertension alters vasomotor regulation in various vascular beds. We studied whether nitric oxide (NO)-dependent and NO-independent vasodilator mechanisms are altered in renal microvessels in hypertension. To directly visualize the renal microcirculation, the isolated perfused hydronephrotic rat kidney model was used. After pretreatment with indomethacin (100 micromol/l), afferent arterioles were constricted by norepinephrine (NE) or by increasing renal arterial pressure (i.e., myogenic constriction; from 80 to 180 mmHg). Acetylcholine (ACH) was then added, and the renal microvascular response was assessed by computer-assisted video image analysis. A similar protocol was conducted in the presence of nitro-L-arginine methylester (L-NAME; 100 micromol/l). During NE constriction, ACH caused dose-dependent and sustained vasodilation of the afferent arteriole, similar in magnitude in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the presence of L-NAME, ACH (0.01-1 micromol/l) elicited only transient dilation, and the degree of vasodilation was very low in SHR. During myogenic constriction, afferent arterioles from WKY and SHR kidneys responded to ACH with only transient vasodilation, which was unaffected by NO inhibition; the transient vasodilative responses elicited by ACH (0.1-1 micromol/l) were smaller in SHR than in WKY. In conclusion, ACH has both sustained and transient vasodilative effects on the afferent arteriole. Sustained vasodilation is attributed to NO generation, which is similar in WKY and SHR. In contrast, transient vasodilation, mediated by NO-independent vasodilator factors, is impaired in SHR. Deranged vasodilatory mechanisms in hypertension may disturb the renal microcirculation, which may result in renal injury.

Acetylcholine↗
PubMed1999

Zonal heterogeneity in action of angiotensin-converting enzyme inhibitor on renal microcirculation: role of intrarenal bradykinin.

The present study examined the role of intrarenal bradykinin in angiotensin-converting enzyme inhibitor (ACEI)-induced dilation of renal afferent (AFF) and efferent arterioles (EFF) in vivo, and further evaluated whether ACEI-stimulated bradykinin activity differed in superficial (SP) and juxtamedullary nephrons (JM). Arterioles of canine kidneys were visualized with an intravital charge-coupled device camera microscope. E4177 (an angiotensin receptor antagonist, 30 microg/kg) dilated AFF and EFF in SP (15 +/- 3% and 19 +/- 5%) and JM (15 +/- 3% and 18 +/- 4%). Subsequently, cilazaprilat (30 microg/kg) caused further dilation of both AFF (29 +/- 4%) and EFF (36 +/- 4%) in JM, whereas in SP it dilated only EFF (29 +/-3%). Similarly, in the presence of E4177, cilazaprilat caused further increases in sodium excretion. This cilazaprilat-induced vasodilation and natriuresis was abolished by a bradykinin antagonist (N(alpha)-adamantaneacetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]b radykinin). In parallel with these results, cilazaprilat increased renal bradykinin content, more greatly in the medulla than in the cortex (5.7 +/- 0.4 versus 4.6 +/- 0.1 ng/g). Similarly, cilazaprilat elicited greater bradykinin-dependent increases of nitrite/nitrate in the medulla. In conclusion, zonal heterogeneity in renal bradykinin/nitric oxide levels and segmental differences in reactivity to bradykinin contribute to the diverse responsiveness of renal AFF and EFF to ACEI. ACEI-enhanced kinin action would participate in the amelioration of glomerular hemodynamics and renal sodium excretion by ACEI.

Angiotensin-Converting Enzyme Inhibitors↗