RESUMO
WHAT IS KNOWN AND OBJECTIVE: Renal transplant recipients receive immunosuppressive therapy to prevent acute rejection. We evaluated the immunopharmacological efficacy of vitamin K1 (VK1) and vitamin K2 (VK2) on T-cell mitogen-activated-peripheral lymphocytes of dialysis patients and healthy subjects. METHODS: The effects of VK1 and VK2 on the T-cell mitogen-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) obtained from 12 healthy subjects and 12 dialysis patients were estimated. Seven cytokines produced from the activated PBMCs were measured by a BD Cytometric Beads Array kit. Regulatory T cells (Tregs) in PBMCs were analysed as CD4 + CD25 + FoxP3 + lymphocytes by flow cytometry. RESULTS: VK2 dose-dependently suppressed the concanavalin A-stimulated proliferation of PBMCs from healthy subjects and dialysis patients, whereas VK1 had no significant effect on the PBMC proliferation. VK1 and VK2 did not influence the production of most of the Th1/Th2/Th17 cytokines from the activated PBMCs of these subjects, although VK2 increased the IL-4 production from PBMCs of healthy subjects. The Treg percentages in the PBMCs of dialysis patients were markedly decreased compared to healthy PBMCs after the treatment with relatively low concentrations of VK2. WHAT IS NEW AND CONCLUSION: The present data suggest that VK2 has immunosuppressive efficacy. VK2 may enhance the immunosuppressive efficacies of glucocorticoids while preventing osteoporosis caused by glucocorticoids.
Assuntos
Leucócitos Mononucleares/efeitos dos fármacos , Diálise Renal , Vitamina K 1/farmacologia , Vitamina K 2/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Concanavalina A/farmacologia , Citocinas/imunologia , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Transplante de Rim/métodos , Leucócitos Mononucleares/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Mitógenos/metabolismo , Linfócitos T Reguladores/imunologia , Vitamina K 1/administração & dosagem , Vitamina K 2/administração & dosagem , Adulto JovemRESUMO
Immunosuppressive therapy for prevention of acute rejection episode occasionally causes serious adverse effects, and thus it is important to develop new therapeutic approach for renal transplant recipients. This study evaluated the immunosuppressive pharmacodynamics of tetrandrine (TET) and/or methylprednisolone (MP) in haemodialysis patients in vitro by using the peripheral blood mononuclear cells (PBMCs) isolated from whole blood of haemodialysis patients. The median (range) of MP IC50 values against the proliferation of patients PBMCs was 7.04 (2.30-500.00) ng/mL. In contrast, the median (range) of MP IC50 values against the proliferation of healthy PBMCs was 4.44 (3.19-5.08) ng/mL. The median (range) of TET IC50 values against the proliferation of patients PBMCs was 1.61 (1.04-4.79) µmol/L. Lower concentrations of TET (0.3-300 nmol/L) were able to decrease the IC50 values of MP and thus potentiate the MP immunosuppressive effect on patient PBMCs. The median (range) of MP IC50 values in combination with 0.3, 3, 30, and 300 nmol/L TET were 0.92 (0.49-8.39), 2.10 (0.45-20.00), 0.35 (0.092-1.05), and 0.14 (0.05-6.78) ng/mL, respectively. TET potentiates the MP immunosuppressive pharmacodynamics and thus, it was possible to use the combination of MP and TET to attenuate MP side effects. There were significant correlations between the IC50 values of TET and stimulation indices (P=0.04, r=.58), the IC50 values of TET and the haemodialysis periods (P=0.04, r=.57), or the IC50 values of MP combined with 0.3 nmol/L TET and C-reactive protein concentrations (P=0.04, r=.64), respectively.
Assuntos
Benzilisoquinolinas/farmacologia , Imunossupressores/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Metilprednisolona/farmacologia , Mitógenos/farmacologia , Diálise Renal , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Interações Medicamentosas , Feminino , Humanos , Concentração Inibidora 50 , Interleucina-6/biossíntese , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Although anti-tumor necrosis factor-α monoclonal antibody biological preparations (BP) agents are widely used as an established treatment tool for refractory ulcerative colitis (UC), whether leukocytapheresis/granulocytapheresis (L/G-CAP) has similar beneficial impact on the disease activity remains undetermined. Furthermore, the costs defrayed for the treatment with these 2 modalities have not been compared. We retrospectively evaluated whether L/G-CAP offered sustained beneficial effects over 2-year period. The patients who had moderately to severely active UC (Rachmilewitz clinical activity index (CAI) ⧠5) and were treated with a series (10 sessions) of L/G-CAP (n = 19) or BP (n = 7) as an add-on therapy to conventional medications were followed. Furthermore, the cost-effectiveness pertaining to the treatment with L/G-CAP and BP was assessed over 12 months. At baseline, L/G-CAP and BP groups manifested similar disease activity (CAI, L/G-CAP; 7.0 [6.0-10.0], BP; 10.0 [6.0-10.0], P = .207). The L/G-CAP and BP treatment suppressed the activity, with CAI 1 or less attained on day 180. When the L/G-CAP group was dichotomized into L/G-CAP-high and L/G-CAP-low group based on CAI values (≥3 or < 3) on day 365, CAI was gradually elevated in L/G-CAP-high group but remained suppressed in L/G-CAP-low group without additional apheresis for 2 years. Anemia was corrected more rapidly and hemoglobin levels were higher in BP group. The cost of the treatment with L/G-CAP over 12 months was curtailed to 76% of that with BP (1.79 [1.73-1.92] vs 2.35 [2.29-3.19] million yen, P = .028). L/G-CAP is as effective as BP in a substantial number of patients over 2 years. The cost for the treatment of UC favors L/G-CAP although the correction of anemia may prefer BP. Thus, L/G-CAP can effectively manage the disease activity with no additional implementation for 2 years although further therapeutic modalities might be required in a certain population with high CAI observed on day 365.
Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Leucaférese , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/uso terapêutico , Resultado do Tratamento , Anticorpos Monoclonais/uso terapêuticoRESUMO
Natural compound tetrandrine was reported to inhibit the proliferation of T cells by inhibiting activation of NF-κB. Chemically, isotetrandrine differs from tetrandrine only in the stereochemistry at the chiral centers. The present study aimed to compare their anti-proliferation effects on human T cells with a focus on NF-κB. The IC50 values of tetrandrine against MOLT-4 cells, MOLT-4/DNR cells, and concanavalin A-activated peripheral blood mononuclear cells of healthy subjects and dialysis patients were 4.43 ± 0.22, 3.62 ± 0.22, 1.91 ± 0.22 and 3.03 ± 0.28 µM, respectively. Whereas, the IC50 values of isotetrandrine against the above immune cells were 2.19 ± 0.27, 2.28 ± 0.33, 1.29 ± 0.14 and 1.55 ± 0.26 µM, respectively. The inhibitory effect of isotetrandrine against the proliferation of T cells was stronger than that of tetrandrine significantly (p < 0.05). Molecular mechanism investigation showed that 10 µM of isotetrandrine largely decreased the expression of p-NF-κB and NF-κB in both MOLT-4 and MOLT-4/DNR T cells (p < 0.05), whereas 10 µM of tetrandrine slightly inhibited the phosphorylation of p-NF-κB with little influence on the expression of NF-κB. Taken together, absolute configurations of tetrandrine and isotetrandrine are suggested to influence on their anti-proliferation effects in human T cells via different regulation of NF-κB.
Assuntos
Benzilisoquinolinas/química , Proliferação de Células , Linfócitos T/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Linhagem Celular Tumoral , Humanos , NF-kappa B/metabolismo , Relação Estrutura-Atividade , Linfócitos T/metabolismo , Linfócitos T/fisiologiaRESUMO
A 73-year-old woman with chief complaint of macroscopic hematuria was diagnosed as having left renal tumor with pancreatic invasion. Nephrectomy was performed. Pathological diagnosis was clear cell carcinoma, pT3a. Three months after the operation, liver metastasis appeared and sunitinib was started. Most of the liver metastases disappeared; however, a new lesion appeared, and sunitinib was switched to axitinib, which was effective on the residual lesion, but the new lesion had poor response. Transarterial chemoembolization was performed to treat the liver metastases, and all metastatic lesions disappeared. There was no recurrence at 2 years, and axitinib was discontinued.
RESUMO
The ATP monitoring assay is a useful biomarker for risk monitoring to detect infection and rejection episodes in transplant recipients. Hemodialysis patients have a higher rate of infectious mortality. Infections in hemodialysis patients are mainly caused by venous catheters, uremia, malnutrition and inflammation. However, the risk of infection episodes has not been evaluated using a lymphocyte ATP monitoring assay in hemodialysis and chronic kidney disease (CKD) patients. We measured the ATP amounts in the peripheral CD4+ cells of CKD (N = 85) and dialysis patients (N = 17) using an "Immuknow" assay kit. These CKD patients were divided, according to kidney disease stage, into G3a, G3b, G4, and G5 groups. The ATP amounts in CD4+ cells of the dialysis patients and each of the CKD groups were compared with healthy subjects. In both the dialysis and CKD patients, the ATP amounts in CD4+ cells were lower than in healthy subjects. Furthermore, there were significant differences in the ATP amounts between healthy subjects and each of the CKD-G3a, CKD-G3b, and CKD-G4 groups (P < 0.05). Patients with CKD-G3a, CKD-G3b and CKD-G4 were evaluated as being at high risk for infection according to the lymphocyte ATP monitoring assay. However, the ATP amounts in the dialysis and CKD-G5 patients did not differ from those in healthy subjects to a statistically significant extent. These results suggest that the ATP amount in the CD4+ cells of these patients with serve renal failure are influenced by dialysis treatment, uremia and/or oxidative stress.
Assuntos
Trifosfato de Adenosina/metabolismo , Infecções/epidemiologia , Diálise Renal , Insuficiência Renal Crônica/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Infecções/etiologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Risco , Fatores de Risco , Uremia/metabolismoRESUMO
We experienced a case manifesting progressive multifocal leukoencephalopathy (PML) in a hemodialytic patient with hepatitis C virus-induced liver cirrhosis and human T-cell lymphotropic virus type-1 (HTLV-1)-associated uveitis. A 57-year-old male patient had received chronic hemodialysis therapy for 10 years, during which he received multiple blood transfusions and HTLV-1-associated uveitis developed. He complained of visual disturbance and disorientation. Brain CT scan showed diffuse and multifocal low density areas in occipital and temporal lobes, with gray matter relatively spared. MRI imaging showed high intensity lesions in the same areas. Cerebrospinal fluid culture was negative, but using nested PCR, rearranged regulatory region of JC virus DNA was detected. His consciousness level gradually deteriorated and complete paraplegia developed. Seven months after admission, he died of pneumonia. An autopsy confirmed the diagnosis of PML. Notably, mononuclear cell infiltration, gliosis and demyelinating lesions but no nuclear inclusion bodies were observed in the thoracic cord, which suggested HTLV-1-associated myelopathy. Because JC virus is activated under immunocompromised conditions, precipitating factors in this case appear multifactorial; depressed immune system induced by chronic hemodialysis as well as blood-borne hepatitis C virus/HTLV-1 infection might contribute to the activation of dormant JC virus and the development of florid clinical manifestation of PML.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Hospedeiro Imunocomprometido/fisiologia , Leucoencefalopatia Multifocal Progressiva/etiologia , Paraparesia Espástica Tropical , Diálise Renal , Imagem de Difusão por Ressonância Magnética , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Uveíte/virologiaRESUMO
We examined whether endothelial function of the renal microcirculation was impaired in a model of chronic renal failure (CRF), and further assessed the role of asymmetrical dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of acetylcholine (0.01 microg/kg/min) elicited 22+/-2% and 20+/-2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12+/-2%; efferent, 11+/-1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of homocysteine (12.2+/-0.7 vs. 6.8+/-0.4 micromol/l) and ADMA were elevated (2.60+/-0.13 vs. 1.50+/-0.08 micromol/l). The inhibition of S-adenosylmethionine-dependent protein arginine N-methyltransferase by adenosine dialdehyde decreased plasma ADMA levels, and improved the acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute methionine loading impaired the acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.
Assuntos
Amidoidrolases/metabolismo , Arginina/análogos & derivados , Arginina/sangue , Endotélio Vascular/metabolismo , Hipertensão/fisiopatologia , Falência Renal Crônica/fisiopatologia , Acetilcolina/farmacologia , Animais , Cães , Regulação para Baixo , Endotélio Vascular/efeitos dos fármacos , Hipertensão/complicações , Falência Renal Crônica/complicações , Masculino , Óxido Nítrico/metabolismo , Reação em Cadeia da PolimeraseRESUMO
Renal afferent (AFF) and efferent arteriolar (EFF) responsiveness to angiotensin II (ANG II) in superficial and juxtamedullary nephrons in vivo remains undetermined, nor has it been clarified what role intrarenal autocrines/paracrines play in modulating the renal microvascular response. The present study characterized the responsiveness to ANG II (1-30 ng/kg/min) of AFF and EFF of canine superficial and juxtamedullary nephrons under pentobarbital anesthesia, using intravital CCD-videomicroscopy that allowed direct in vivo visualization of the renal microcirculation. Furthermore, the effect of prostaglandins (PG) and nitric oxide (NO) on ANG II-induced tone was examined. In superficial nephrons, ANG II induced a similar dose-dependent constriction of both AFF (46 +/- 5% constriction) and EFF (53 +/- 3%). In juxtamedullary arterioles, ANG II induced a dose-dependent constriction of EFF, whereas AFF responses were diminished (17 +/- 4% vs. 37 +/- 4% at 10 ng/kg/min). The PG inhibition by indomethacin enhanced the ANG II-induced constriction of juxtamedullary AFF, whereas no augmentation was observed in other arterioles. In contrast, NO inhibition by nitro-L-arginine methylester (L-NAME) enhanced the ANG II-induced constriction, with greater augmentation in juxtamedullary AFF and EFF. Finally, renal interstitial PG and nitrite/nitrate contents were greater in the medulla than the superficial cortex under basal and ANG II-stimulated conditions. Taken together, the results of the intravital CCD-videomicroscopy reveal that the renal microvascular action of ANG II had both zonal (juxtamedullary vs. superficial nephrons) and segmental (AFF vs. EFF) heterogeneity under the present experimental conditions. This heterogeneity was associated with a difference in the intrarenal production of prostaglandin E2 (PGE2) and NO; PGE2 contributed to segmental and zonal differences whereas NO was responsible for the zonal heterogeneity in arteriolar responsiveness.
Assuntos
Medula Renal/irrigação sanguínea , Néfrons/irrigação sanguínea , Prostaglandinas/fisiologia , Angiotensina II/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiologia , Dinoprostona/metabolismo , Cães , Rim/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Nitratos/metabolismo , Óxido Nítrico/fisiologia , Nitritos/metabolismo , Circulação Renal/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
It has becoming clear that angiotensin receptor blockers (ARBs) show varying levels of angiotensin II type 1 (AT1) receptor blocking activity. Although the duration of activity and the efficacy on blood pressure of ARB are reported to vary, depending on the agents used, it has not been examined whether the effects on proteinuria and urinary nitrite/nitrate (NOx) excretion differ in hypertensive patients with chronic renal disease. In the present study, patients with hypertension (> 140 and/or 90 mmHg) and chronic renal disease (proteinuria > 0.5g/day; serum creatinine < 265 micromol/l or creatinine clearance > 30 ml/min/1.72 m2) were randomly assigned to perindopril- (n = 15), trandolapril- (n = 15), candesartan- (n = 17), and losartan-treated groups (n = 15), and were followed up for 96 weeks. All agents decreased blood pressure to the same level, and none of them had any effect on creatinine clearance. Candesartan, perindopril, and trandolapril reduced proteinuria markedly (from 3.0 +/- 0.6 to 1.8 +/- 0.5 g/day, 2.7 +/- 0.5 to 1.6 +/- 0.4 g/day, and 2.7 +/- 0.5 to 1.7 +/- 0.4 g/day, respectively) at 12 weeks, and the beneficial effect persisted throughout the study. The effect of losartan, however, diminished over the study period. Whereas perindopril, trandolapril, and candesartan markedly increased urinary NOx excretion (from 257 +/- 23 to 1,011 +/- 150 micromol/day, 265 +/- 70 to 986 +/- 130 micromol/day, and 260 +/- 62 to 967 +/- 67 micromol/day at 12 weeks, respectively), a relatively blunted increase was observed with losartan (from 309 +/- 42 to 596 +/- 64 micromol/day). In conclusion, renal action of ARB varies, with relatively less proteinuria-sparing, as well as NOx-enhancing, effects observed with candesartan showing the greatest reduction of proteinuria and greatest enhancement of NOx. Furthermore, renal nitric oxide may contribute to the renal protective action of these agents when administered to patients with chronic renal disease.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Benzimidazóis/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Losartan/uso terapêutico , Proteinúria/tratamento farmacológico , Tetrazóis/uso terapêutico , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/urina , Perindopril/uso terapêutico , Proteinúria/etiologiaRESUMO
Although the angiotensin-converting enzyme (ACE) inhibitor-induced bradykinin enhances nitric oxide (NO) release, bradykinin may also stimulate the production of an additional vasodilator, endothelium-derived hyperpolarizing factor (EDHF). This study examined the role of EDHF in mediating the NO-independent action of ACE inhibitors in canine renal microcirculation in vivo. We used intravital CCD camera videomicroscopy that allowed direct visualization of renal microcirculation in superficial and juxtamedullary nephrons in an in vivo, in situ, and relatively intact setting. In the presence of E4177 (an angiotensin receptor blocker), cilazaprilat (30 microg/kg) had no effect on diameter of superficial afferent arterioles (Aff), but it increased renal contents of bradykinin and nitrate plus nitrite, and it elicited dilation of juxtamedullary Aff (from 24.0+/-0.2 to 28.2+/-0.8 microm), juxtamedullary efferent arterioles (Eff) (from 24.2+/-0.2 to 28.0+/-0.8 microm), and superficial Eff (from 18.2+/-0.2 to 19.7+/-0.2 microm). These changes in diameters were prevented by N(alpha)-adamantaneacetyl-d-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]bradykinin, a bradykinin receptor antagonist. The pretreatment with nitro-l-arginine methylester (l-NAME) plus E4177 eliminated the dilator response of juxtamedullary/superficial Eff and the increase in renal nitrate plus nitrite levels induced by cilazaprilat. In contrast, in the presence of E4177+l-NAME, cilazaprilat still caused 8%+/-3% dilation of juxtamedullary Aff, which was completely eliminated by proadifen, a cytochrome-P450 and K(Ca) channel blocker. Collectively, the ACE inhibitor exerts multiple vasodilator mechanisms, including the inhibition of angiotensin II formation; blockade of angiotensin II activity appears to be a dominant mechanism in superficial Aff, whereas the bradykinin-induced NO acts on superficial Eff and juxtamedullary Aff/Eff. Furthermore, a putative EDHF is an additional mechanism for the ACE inhibitor-induced vasodilation of juxtamedullary Aff in vivo.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fatores Biológicos/fisiologia , Cilazapril/análogos & derivados , Cilazapril/farmacologia , Rim/irrigação sanguínea , Vasodilatação/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina , Animais , Bradicinina/metabolismo , Cães , Rim/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Óxido Nítrico/fisiologia , Circulação Renal/efeitos dos fármacosRESUMO
AIMS: The role of cyclooxygenase (COX)-1/2-induced prostaglandins (PG) in unilateral chronic renal ischemia of anesthetized dogs was examined. METHODS: Ischemic kidneys were established by reducing renal blood flow of left renal artery to 10% of baseline with an adjustable clip. After 4 weeks, changes in intrarenal contents of PGE2/PGI2 and angiotensin (Ang) II were evaluated with renal microdialysis and biopsy. Furthermore, the effect of a non-specific COX inhibitor (sulpyrine), a COX-2-specific inhibitor (NS398), and an Ang receptor antagonist (CS866) on renal function and renal PG contents were evaluated. RESULTS: Unilateral renal artery clipping reduced renal plasma flow (RPF) in clipped (from 59 +/- 2 to 17 +/- 1 ml/min, n = 18) and nonclipped kidneys (from 59 +/- 2 to 44 +/- 2 ml/min) and natriuresis. Intrarenal PGE2 increased only in clipped kidneys (from 114 +/- 7 to 375 +/- 25 pg/ml), whereas 6-keto-PGF1alpha increased in both kidneys. Sulpyrine reduced intrarenal PG contents, and decreased RPF, GFR, and urinary sodium excretion (UNaV), whereas NS398 reduced UNaV in clipped (from 4.0 +/- 0.9 to 1.7 +/- 0.2 microEq/min) and nonclipped kidneys (from 5.4 +/- 0.5 to 2.9 +/- 0.3 microEq/min), without affecting renal hemodynamics. Intrarenal Ang II contents increased in clipped (from 0.70 +/- 0.06 to 2.32 +/- 0.33 pg/mg, n = 18) and nonclipped kidneys (from 0.65 +/- 0.06 to 2.45 +/- 0.33 pg/mg, n = 18), and CS866 improved renal hemodynamics and natriuresis. The elevated intrarenal Ang II content was suppressed by NS398 only in clipped kidneys. CONCLUSION: Unilateral renal ischemia elevates intrarenal PGE2 contents in clipped kidneys, which serves to countervail the aggravation of renal function. Furthermore, intrarenal COX isoforms may play differential roles, with COX-1 participating in modulation of renal hemodynamics, and COX-2 contributing to sodium excretion and Ang II formation.
Assuntos
Isquemia/metabolismo , Isoenzimas/metabolismo , Falência Renal Crônica/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , 6-Cetoprostaglandina F1 alfa/metabolismo , Angiotensina II/biossíntese , Animais , Pressão Sanguínea , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Modelos Animais de Doenças , Cães , Taxa de Filtração Glomerular , Isquemia/fisiopatologia , Rim/enzimologia , Falência Renal Crônica/fisiopatologia , Masculino , Circulação Renal , Sódio/urinaRESUMO
The role of nitric oxide (NO) and prostaglandins (PG) in modifying renal hemodynamics was examined in clipped and nonclipped kidneys of unilateral renal artery stenosis. Chronic unilateral renal ischemia was established by 4-wk-clipping the left renal artery of canine kidneys, and renal interstitial nitrate+nitrite and PGE(2) contents were evaluated by the microdialysis technique. Unilateral renal artery stenosis caused 45 +/- 1 and 73 +/- 1% decrements in renal plasma flow (RPF) in moderately and severely clipped kidneys and 21 +/- 3% decrements in nonclipped kidneys with severe stenosis. Renal nitrate+nitrite decreased in moderately (-31 +/- 1%) and severely clipped kidneys (-63 +/- 4%). N(omega)-nitro-L-arginine methyl ester reduced RPF (-56 +/- 3%) and glomerular filtration rate (GFR; -54 +/- 3%) in moderately clipped kidneys, whereas this inhibitory effect was abolished in severely clipped kidneys. In contrast, renal PGE(2) contents increased modestly in moderate clipping and were markedly elevated in severely clipped kidneys (from 111 +/- 7 to 377 +/- 22 pg/ml); sulpyrine impaired renal hemodynamics only in severely clipped kidneys. In contralateral nonclipped kidneys, although renal PGE(2) was not increased, sulpyrine reduced RPF (-32 +/- 1%) and GFR (-33 +/- 3%) in severe stenosis. Collectively, NO plays a substantial role in maintaining renal hemodynamics both under basal condition and in moderate renal artery stenosis, whereas the contributory role shifts from NO to PG as renal artery stenosis progresses. Furthermore, because intrarenal angiotensin II is reported to increase in nonclipped kidneys, unilateral severe ischemia may render the nonclipped kidney susceptible to PG inhibition.
Assuntos
Isquemia/fisiopatologia , Rim/irrigação sanguínea , Óxido Nítrico/fisiologia , Prostaglandinas/fisiologia , Obstrução da Artéria Renal/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Velocidade do Fluxo Sanguíneo , Doença Crônica , Dinoprostona/análise , Dipirona/farmacologia , Cães , Inibidores Enzimáticos/farmacologia , Taxa de Filtração Glomerular , Hemodinâmica , Masculino , Microdiálise , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/análise , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/análise , Artéria Renal/cirurgiaRESUMO
Although acute renal ischaemia alters the production of various paracrines, there has been little investigation examining the role of intrarenal vasoactive substances. In the present study, we investigated the role of intrarenal nitric oxide and prostaglandins in modulating the acute renal hypoperfusion-induced alterations in renal function. After a 90% clipping of the left renal artery for 60 min, the clip was released, and the renal haemodynamics and sodium excretion were evaluated in both clipped and non-clipped kidneys of anaesthetized dogs. Furthermore, the changes in renal contents of nitrate/nitrite (NOx) and prostaglandin E2 (PGE2) were assessed by using the renal microdialysis technique. The release of the clipping elicited a gradual recovery of renal plasma flow and glomerular filtration rate, and a sustained increase in fractional sodium excretion (FENa) in the clipped kidney. Renal interstitial NOx was reduced in both the cortex (from 8.2 +/- 1.1 to 2.5 +/- 0.3 micromol/L, P < 0.01) and medulla (from 10.1 +/- 0.9 to 3.1 +/- 0.2 micromol/L, P < 0.01), but the levels gradually elevated after declamping. The treatment with nitro-l-arginine methylester only modestly impaired the recovery of renal plasma flow (RPF; at hour 4) and glomerular filtration rate (GFR; at hours 3 and 4 after declamping), without affecting FENa. Conversely, the renal PGE2 levels increased prominently upon the onset of ischaemia (medulla, from 149 +/- 19 to 378 +/- 39 pg/mL, P < 0.01; cortex, from 107 +/- 13 to 302 +/- 34 pg/mL, P < 0.01). Furthermore, the pretreatment with a non-specific cyclo-oxygenase (COX) inhibitor, sulpyrine, and a COX-2-specific inhibitor, NS398, prominently inhibited the increases in FENa induced by the acute renal arterial clipping in a similar manner. In conclusion, in acute renal hypoperfusion, nitric oxide (NO) plays a permissive role in the recovery of the renal haemodynamics. In contrast, sustained increases in renal PGE2 in both clipped and non-clipped kidneys indicate that the COX-2-mediated PGE2 contributes importantly to the failure of the sodium reabsorption in response to acute renal hypoperfusion.
Assuntos
Dinoprostona/fisiologia , Isquemia/etiologia , Rim/irrigação sanguínea , Óxido Nítrico/fisiologia , Animais , Cães , Hemodinâmica , Isquemia/metabolismo , Isquemia/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Sódio/metabolismoRESUMO
The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.
Assuntos
Angiotensina II/metabolismo , Cilazapril/análogos & derivados , Isquemia/metabolismo , Rim/metabolismo , Angiotensina I/metabolismo , Animais , Doença Crônica , Quimases , Cilazapril/farmacologia , Cães , Hemodinâmica/efeitos dos fármacos , Hipertensão Renal/metabolismo , Hipertensão Renal/fisiopatologia , Imidazóis/farmacologia , Isquemia/fisiopatologia , Rim/irrigação sanguínea , Masculino , Oligopeptídeos/farmacologia , Olmesartana Medoxomila , Peptidil Dipeptidase A/metabolismo , Circulação Renal/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Serina Endopeptidases/metabolismo , Tetrazóis/farmacologiaRESUMO
Time-sequential responses to endothelium-dependent and -independent vasodilators and angiotensin-converting enzyme (ACE) inhibitors were studied in the subendocardial arterioles (Endo) of canine renovascular hypertension (HT) compared with subepicardial arterioles (Epi; both <120 microm) by charge-coupled device intravital microscope. Vascular responses to acetylcholine, papaverine, and cilazaprilat were compared between normotensive (NT) and HT dogs [4 wk and 12 wk of HT (4wHT and 12wHT)]. The acetylcholine-induced vasodilation of Endo in both 4wHT and 12wHT was smaller than that of NT (both P < 0.01 vs. 4wHT and 12wHT), and that of Epi was smaller than that of NT only in 12wHT (P < 0.05). The papaverine-induced vasodilation of Endo, but not Epi, was impaired only in 12wHT (both P < 0.01 vs. NT and 4wHT). Vasodilation by cilazaprilat remained unchanged at 4wHT and 12wHT in both Epi and Endo. In conclusion, at the early stage, the endothelium-dependent response of Endo was impaired, whereas at the later stage, the endothelium-dependent and -independent responses of Endo and the endothelium-dependent response of Epi were impaired. However, the vasodilatory responses to the ACE inhibitor were maintained in both Endo and Epi of HT.