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1.
Diabetes Obes Metab ; 13(3): 243-50, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21205116

RESUMEN

AIM: D-chiro-inositol (DCI) has been shown to prevent and reverse endothelial dysfunction in diabetic rats and rabbits. The present study evaluates the preventive effect of DCI on experimental diabetic neuropathy (DN). METHODS: Streptozotocin-induced (STZ) diabetic mice were treated by oral gavage for 60 days with DCI (20 mg/kg/12 h) or saline (NaCl 0.9%; 0.1 ml/10 g/12 h; Diab) and compared with euglycaemic groups treated with saline (0.1 ml/10 g/12 h; Eugly). We compared the response of the isolated sciatic nerve, corpora cavernosa or vas deferens to electrical stimulation. RESULTS: The electrically evoked compound action potential of the sciatic nerve was greatly blunted by diabetes. The peak-to-peak amplitude (PPA) was decreased from 3.24 ± 0.7 to 0.9 ± 0.2 mV (p < 0.05), the conduction velocity (CV) of the first component was reduced from 46.78 ± 4.5 to 26.69 ± 3.8 ms (p < 0.05) and chronaxy was increased from 60.43 ± 1.9 to 69.67 ± 1.4 ms (p < 0.05). These parameters were improved in nerves from DCI-treated mice (p < 0.05). PPA in the DCI group was 5.79 ± 0.8 mV (vs. 0.9 ± 0.2 mV-Diab; p < 0.05) and CV was 45.91 ± 3.6 ms (vs. 26.69 ± 3.8 ms-Diab; p < 0.05). Maximal relaxation of the corpus cavernosum evoked by electrical stimulation (2-64 Hz) in the Diab group was 36.4 ± 3.8% compared to 65.4 ± 2.8% in Eugly and 59.3 ± 5.5% in the DCI group (p < 0.05). Maximal contraction obtained in the vas deferens was 38.0 ± 9.2% in Eugly and 11.5 ± 2.6% in Diab (decrease of 69.7%; p < 0.05), compared to 25.2 ± 2.3% in the DCI group (p < 0.05 vs. diabetic). Electron microscopy of the sciatic nerves showed prevention of neuronal damage. CONCLUSIONS: DCI has a neuroprotective action in both autonomic and somatic nerves in STZ-induced DN.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/inducido químicamente , Inositol/administración & dosificación , Nervio Ciático/efectos de los fármacos , Estreptozocina/administración & dosificación , Animales , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/prevención & control , Estimulación Eléctrica , Inositol/farmacología , Masculino , Ratones , Nervio Ciático/fisiopatología , Estreptozocina/farmacología
2.
Braz J Med Biol Res ; 52(6): e8589, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31166385

RESUMEN

The transport of myo-inositol is the main mechanism for the maintenance of its high intracellular levels. We aimed to measure the mRNA and protein levels of myo-inositol cotransporters in the sciatic nerve (SN) and dorsal root ganglia (DRG) during experimental diabetes. Streptozotocin-induced (STZ; 4, 8, and 12 weeks; 65 mg/kg; ip) diabetic rats (DB) and age-matched euglycemic (E) rats were used for the analysis of mRNA and protein levels of sodium myo-inositol cotransporters 1, 2 (SMIT1, SMIT2) or H+/myo-inositol cotransporter (HMIT). There was a significant reduction in the mRNA levels for SMIT1 in the SN and DRG (by 36.9 and 31.0%) in the 4-week DB (DB4) group compared to the E group. SMIT2 was not expressed in SN. The mRNA level for SMIT2 was up-regulated only in the DRG in the DB4 group. On the other hand, the protein level of SMIT1 decreased by 42.5, 41.3, and 44.8% in the SN after 4, 8, and 12 weeks of diabetes, respectively. In addition, there was a decrease of 64.3 and 58.0% of HMIT in membrane and cytosolic fractions, respectively, in the SN of the DB4 group. In the DRG, there was an increase of 230 and 86.3% for SMIT1 and HMIT, respectively, in the DB12 group. The levels of the main inositol transporters, SMIT1 and HMIT, were greatly reduced in the SN but not in the DRG. SMIT-1 was selectively reduced in the sciatic nerve during experimental STZ-induced diabetes.


Asunto(s)
Transporte Biológico Activo/fisiología , Diabetes Mellitus Experimental/metabolismo , Ganglios Espinales/metabolismo , Inositol/metabolismo , ARN Mensajero/metabolismo , Nervio Ciático/metabolismo , Animales , Western Blotting , Masculino , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estreptozocina , Regulación hacia Arriba
3.
Oral Microbiol Immunol ; 23(6): 486-91, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18954355

RESUMEN

OBJECTIVE: We aimed to compare the effect of sodium fluoride and chlorhexidine on salivary levels of mutans streptococci (MS), in a double-blind, randomized clinical trial. METHODS: Thirty-five healthy volunteers, aged 4-8 years, with at least one active carious lesion and no previous history of allergies were selected to participate in the study. A gel formulation containing either 1.23% sodium fluoride or 1% chlorhexidine was topically administered to the dentition every 24 h for 6 consecutive days. Salivary MS levels were measured at baseline (D1) and on the 6th (D6), 15th (D15), and 30th (D30) days. For microbiological analysis, Mitis Salivarius-Bacitracin agar medium was used. RESULTS: Difference between treatments was only verified on D6. On the last day of treatment 1% chlorhexidine gel was significantly more effective than fluoride (P = 0.0000). The use of sodium fluoride did not cause a statistically significant variation in salivary MS levels throughout the duration of the study. Following treatment, a subsequent increase in MS counts between D6 and D15 (P = 0.0001) was observed with chlorhexidine. CONCLUSION: A 6-day treatment with a 1% chlorhexidine gel was effective in reducing salivary MS; there was a significant MS increase once treatment was suspended. The use of 1.23% sodium fluoride under the same regimen was not able to reduce salivary MS levels. Our results suggest repeated treatment with 1% chlorhexidine as a means for maintaining low salivary MS levels in children with dental caries.


Asunto(s)
Cariostáticos/uso terapéutico , Clorhexidina/uso terapéutico , Caries Dental/tratamiento farmacológico , Fluoruro de Sodio/uso terapéutico , Streptococcus mutans/efectos de los fármacos , Administración Tópica , Antiinfecciosos Locales/uso terapéutico , Niño , Preescolar , Caries Dental/microbiología , Método Doble Ciego , Femenino , Fluoruros Tópicos/uso terapéutico , Humanos , Masculino , Saliva/microbiología
4.
Braz J Biol ; 68(1): 149-54, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18470390

RESUMEN

Guanylin and uroguanylin are small cysteine-rich peptides involved in the regulation of fluid and electrolyte homeostasis through binding and activation of guanylyl cyclases signaling molecules expressed in intestine and kidney. Guanylin is less potent than uroguanylin as a natriuretic agent and is degraded in vitro by chymotrypsin due to unique structural features in the bioactive moiety of the peptide. Thus, the aim of this study was to verify whether or not guanylin is degraded by chymotrypsin-like proteases present in the kidney brush-border membranes. The isolated perfused rat kidney assay was used in this regard. Guanylin (0.2 microM) induced no changes in kidney function. However, when pretreated by the black-eyed pea trypsin and chymotrypsin inhibitor (BTCI - 1.0 microM; guanylin - 0.2 microM) it promoted increases in urine flow (DeltaUF of 0.25 +/- 0.09 mL.g(-1)/min, P < 0.05) and Na+ excretion (% Delta ENa+ of 18.20 +/- 2.17, P < 0.05). BTCI (1.0 microM) also increased %ENa+ (from 22.8 +/- 1.30 to 34.4 +/- 3.48, P < 0.05, 90 minutes). Furthermore, BTCI (3.0 microM) induced increases in glomerular filtration rate (GFR; from 0.96 +/- 0.02 to 1.28 0.02 mL.g(-1)/min, P < 0.05, 60 minutes). The present paper strongly suggests that chymotrypsin-like proteases play a role in renal metabolism of guanylin and describes for the first time renal effects induced by a member of the Bowman-Birk family of protease inhibitors.


Asunto(s)
Hormonas Gastrointestinales/farmacología , Glomérulos Renales/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Natriuresis/efectos de los fármacos , Péptidos Natriuréticos/farmacología , Inhibidores de Proteasas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Glomérulos Renales/fisiología , Túbulos Renales/fisiología , Masculino , Natriuresis/fisiología , Proteínas de Plantas/farmacología , Ratas , Ratas Endogámicas WKY
5.
Toxicon ; 47(8): 831-7, 2006 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-16730045

RESUMEN

Renal changes determined by Lys49 myotoxin I (BmTx I), isolated from Bothrops moojeni are well known. The scope of the present study was to investigate the possible mechanisms involved in the production of these effects by using indomethacin (10 microg/mL), a non-selective inhibitor of cyclooxygenase, and tezosentan (10 microg/mL), an endothelin antagonist. By means of the method of mesenteric vascular bed, it has been observed that B. moojeni myotoxin (5 microg/mL) affects neither basal perfusion pressure nor phenylephrine-preconstricted vessels. This fact suggests that the increase in renal perfusion pressure and in renal vascular resistance did not occur by a direct effect on renal vasculature. Isolated kidneys from Wistar rats, weighing 240-280 g, were perfused with Krebs-Henseleit solution. The infusion of BmTx-I increased perfusion pressure, renal vascular resistance, urinary flow and glomerular filtration rate. Sodium, potassium and chloride tubular transport was reduced after addition of BmTx-I. Indomethacin blocked the effects induced by BmTx-I on perfusion pressure and renal vascular resistance, however, it did not revert the effect on urinary flow and sodium, potassium and chloride tubular transport. The alterations of glomerular filtration rate were inhibited only at 90 min of perfusion. The partial blockade exerted by indomethacin treatment showed that prostaglandins could have been important mediators of BmTx-I renal effects, but the participation of other substances cannot be excluded. The blockage of all renal alterations observed after tezosentan treatment support the hypothesis that endothelin is the major substance involved in the renal pathophysiologic alterations promoted by the Lys49 PLA(2) myotoxin I, isolated from B. moojeni. In conclusion, the rather intense renal effects promoted by B. moojeni myotoxin-I were probably caused by the release of renal endothelin, interfering with the renal parameters studied.


Asunto(s)
Bothrops , Indometacina/farmacología , Riñón/efectos de los fármacos , Fosfolipasas A/toxicidad , Piridinas/farmacología , Tetrazoles/farmacología , Animales , Venenos de Crotálidos , Endotelinas/metabolismo , Fosfolipasas A2 Grupo II , Riñón/irrigación sanguínea , Riñón/metabolismo , Masculino , Ratas , Ratas Wistar , Proteínas de Reptiles , Circulación Esplácnica/efectos de los fármacos , Vasodilatadores/farmacología
6.
Int J Impot Res ; 28(1): 20-4, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26510967

RESUMEN

We studied the mechanisms involved in the human corpora cavernosa (HCC) relaxation induced by a new metal-based nitric oxide (NO) donor, the ruthenium complex cis-[Ru(bpy)2Imn(NO)](+3) (FOR0811). FOR0811 produced relaxation in phenylephrine (PE)-precontracted HCC with a maximal response that achieved 112.9 ± 10.6%. There was no difference between the maximal relaxation induced by FOR0811 when compared with sodium nitroprusside (SNP) (106.8 ± 7.3%), BAY41-2272 (107.6 ± 4.1%) or vardenafil (103.4 ± 3.8%), however, FOR0811 was less potent than SNP and vardenafil. L-N(G)-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, had no effect in the concentration-response curve elicited by FOR0811. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-site inhibitor of soluble guanylyl cyclase (sGC) was able to either block or reverse the relaxation induced by FOR0811. On the other hand, the relaxation induced by FOR0811 was not affected by glibenclamide, a blocker of ATP-sensitive potassium channels. FOR0811 (10 µM) was able to increase cyclic guanosine monophosphate (cGMP) levels in corpora cavernosa strips. FOR0811 completely relaxes HCC by a sGC-cGMP-dependent mechanism and can be a lead compound in the development of new stable NO donors.


Asunto(s)
Guanilato Ciclasa/fisiología , Relajación Muscular , Donantes de Óxido Nítrico/farmacología , Erección Peniana , Pene , Receptores Citoplasmáticos y Nucleares/fisiología , Compuestos de Rutenio/farmacología , GMP Cíclico/fisiología , Humanos , Masculino , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Óxido Nítrico/metabolismo , Nitroprusiato/farmacología , Erección Peniana/efectos de los fármacos , Erección Peniana/fisiología , Pene/patología , Pene/fisiología , Pene/fisiopatología , Proyectos de Investigación , Guanilil Ciclasa Soluble
7.
Int J Impot Res ; 17(1): 27-32, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15510188

RESUMEN

To investigate the pharmacodynamics of phentolamine in human corpus cavernosum (HCC) with special attention to the role of the K+ channels. Strips of HCC precontracted with nonadrenergic stimuli and kept in isometric organ bath immersed in a modified Krebs-Henseleit solution enriched with guanethidine and indomethacine were used in order to study the mechanism of the phentolamine-induced relaxation. Phentolamine caused relaxation (approximately 50%) in HCC strips precontracted with K+ 40 mM. This effect was not blocked by tetrodotoxin (1 microM) (54.6+/-4.6 vs 48.9+/-6.4%) or (atropine (10 microM) (52.7+/-6.5 vs 58.6+/-5.6%). However, this relaxation was significantly attenuated by L-NAME (100 microM) (59.7+/-5.8 vs 27.8+/-7.1%; P<0.05; n = 8) and ODQ (100 microM) (62.7+/-5.1 vs 26.8+/-3.9%; P<0.05; n = 8). Charybdotoxin and apamin (K(Ca)-channel blockers) did not affect the phentolamine relaxations (54.6+/-4.6 vs 59.3+/-5.2%). Glibenclamide (100 microM), an inhibitor of K(ATP)-channel, caused a significant inhibition (56.7+/-6.3 vs 11.3+/-2.3%; P<0.05; n = 8) of the phentolamine-induced relaxation. In addition, the association of glibenclamide and L-NAME almost abolished the phentolamine-mediated relaxation (54.6+/-5.6 vs 5.7+/-1.4%; P<0.05; n = 8). The results suggest that phentolamine relaxes HCC by a nonadrenergic-noncholinergic mechanism dependent on nitric oxide synthase activity and activation of K(ATP)-channel.


Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Sistema Nervioso Autónomo/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Pene/efectos de los fármacos , Fentolamina/farmacología , Adulto , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Fentolamina/antagonistas & inhibidores , Canales de Potasio , Cloruro de Potasio/farmacología
8.
Toxicon ; 46(4): 376-86, 2005 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16115661

RESUMEN

Bothrops jararacussu myotoxin I (BthTx-I; Lys 49) and II (BthTX-II; Asp 49) were purified by ion-exchange chromatography and reverse phase HPLC. In this work we used the isolated perfused rat kidney method to evaluate the renal effects of B. jararacussu myotoxins I (Lys49 PLA2) and II (Asp49 PLA2) and their possible blockage by indomethacin. BthTX-I (5 microg/ml) and BthTX-II (5 microg/ml) increased perfusion pressure (PP; ct120=110.28+/-3.70 mmHg; BthTX I=171.28+/-6.30*mmHg; BthTX II=175.50+/-7.20*mmHg), renal vascular resistance (RVR; ct120=5.49+/-0.54 mmHg/ml.g(-1)min(-1); BthTX I=8.62+/-0.37*mmHg/ml g(-1)min(-1); BthTX II=8.9+/-0.36*mmHg/ml g(-1)min(-1)), urinary flow (UF; ct(120)=0.14+/-0.01ml g(-1)min(-1); BthTX I=0.32+/-0.05*ml g(-1)min(-1); BthTX II=0.37+/-0.01*ml g(-1)min(-1)) and glomerular filtration rate (GFR; ct120=0.72+/-0.10 ml g(-1)min(-1); BthTX I=0.85+/-0.13*ml g(-1)min(-1); BthTX II=1.22+/-0.28*ml g(-1)min(-1)). In contrast decreased the percent of sodium tubular transport (%TNa(+); ct(120)=79,76+/-0.56; BthTX I=62.23+/-4.12*; BthTX II=70.96+/-2.93*) and percent of potassium tubular transport (%TK(+);ct120=66.80+/-3.69; BthTX I=55.76+/-5.57*; BthTX II=50.86+/-6.16*). Indomethacin antagonized the vascular, glomerular and tubular effects promoted by BthTX I and it's partially blocked the effects of BthTX II. In this work also evaluated the antibacterial effects of BthTx-I and BthTx-II against Xanthomonas axonopodis. pv. passiflorae (Gram-negative bacteria) and we observed that both PLA2 showed antibacterial activity. Also we observed that proteins Also we observed that proteins chemically modified with 4-bromophenacyl bromide (rho-BPB) decrease significantly the antibacterial effect of both PLA2. In conclusion, BthTx I and BthTX II caused renal alteration and presented activity antimicrobial. The indomethacin was able to antagonize totally the renal effects induced by BthTx I and partially the effects promoted by BthTx II, suggesting involvement of inflammatory mediators in the renal effects caused by myotoxins. In the other hand, other effects could be independently of the enzymatic activity of the BthTX II and the C-terminal domain could be involved in both effects promoted for PLA2.


Asunto(s)
Bothrops , Venenos de Crotálidos/química , Fosfolipasas A/aislamiento & purificación , Fosfolipasas A/toxicidad , Fenómenos Fisiológicos del Sistema Urinario/efectos de los fármacos , Acetofenonas/farmacología , Secuencia de Aminoácidos , Animales , Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Fosfolipasas A2 Grupo II , Indometacina/farmacología , Pruebas de Función Renal , Espectrometría de Masas , Microscopía Electrónica de Transmisión , Datos de Secuencia Molecular , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A/genética , Fosfolipasas A2 , Ratas , Proteínas de Reptiles , Xanthomonas/efectos de los fármacos , Xanthomonas/ultraestructura
9.
Endocrinology ; 132(2): 652-7, 1993 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8425485

RESUMEN

Two insulin mediators, inositol phosphoglycans, were isolated from bovine liver by methods previously developed for rat liver, i.e. chromatography on an AG 1 x 8 ion exchange column and selective elution with HCl at pH 2.0 and 1.3. The pH 2.0 mediator containing D-chiroinositol stimulated pyruvate dehydrogenase phosphatase, whereas the pH 1.3 mediator containing myo-inositol inhibited cAMP-dependent protein kinase. Each mediator was further purified by thin layer and Bio-Gel P4 column chromatography and injected ip into normal fed rats together with [U-14C]glucose. After 2.5 h, diaphragms were removed, and glycogen isolated. Insulin mediators, like insulin, stimulated [U-14C]glucose incorporation into glycogen by 150-160% in a dose-dependent manner in the nanomolar range. Mediators injected iv in the nanomolar range into low dose streptozotocin-diabetic rats decreased plasma glucose 30-45% in 30-60 min, with a return to basal concentrations after 150-180 min. These in vivo insulin-like effects of mediator were observed without changes in serum insulin concentrations. The pH 2.0 mediator was 50-100 times more active (per nmol organic phosphate) than the pH 1.3 mediator in the ip diaphragm glycogenesis assay. Mediator effects on diaphragm were completely blocked by preincubation with an immunopurified inositol phosphoglycan antibody. Both mediators were equally active iv in lowering plasma glucose (per nmol inositol) at concentrations comparable to those of insulin.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Glucógeno/biosíntesis , Inositol/análogos & derivados , Inositol/deficiencia , Resistencia a la Insulina/fisiología , Insulina/farmacología , Músculos/metabolismo , Fosfatos de Azúcar/farmacología , Animales , Bovinos , Diabetes Mellitus Experimental/sangre , Concentración de Iones de Hidrógeno , Isomerismo , Hígado/fisiología , Masculino , Músculos/efectos de los fármacos , Proteínas Quinasas/aislamiento & purificación , Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Fosfatos de Azúcar/aislamiento & purificación
10.
Toxicon ; 39(12): 1841-6, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11600146

RESUMEN

The most common complication in the lethal cases of ophidian bites in Brazil is acute renal failure, but its pathogenesis is obscure. The effects of Bothrops jararacussu venom (3, 10 and 30 microg/ml) were examined using the isolated perfused kidney from Wistar rats. Dexamethasone, and WEB 2086, a triazolobenzodiazepine substance, which is a platelet activating factor receptor antagonist, were tested for a possible blockade of the renal effects in the presence of 10 microg/ml of venom. The most intense effects of the venom were noticed at 120 min after using 30 microg/ml. We observed a decrease in the perfusion pressure and in the renal vascular resistance. However, the glomerular filtration rate (GFR) and the urinary flow (UF) increased significantly. The percent of sodium (%Na(tot)(+)) and potassium (%K(tot)(+)) tubular transport were also decreased. Dexamethasone was unable to block the effects of B. jararacussu in the kidney, while WEB 2086 blocked its effect in glomerular filtration rate, urinary flow and in the percentage of total tubular potassium reabsorption. We suggest that this venom promotes diuresis independently of perfusion pressure drop. The alterations in GFR, UF and %K(tot)(+) are probably mediated by platelet activating factor. Dexamethasone did not block the renal effects maybe because of the concentration used in this work or maybe the renal effects are promoted by the myotoxin, which does not have PLA(2) activity.


Asunto(s)
Antígenos de Plaqueta Humana/fisiología , Bothrops/fisiología , Venenos de Crotálidos/toxicidad , Riñón/efectos de los fármacos , Factor de Activación Plaquetaria/fisiología , Animales , Azepinas/farmacología , Transporte Biológico/efectos de los fármacos , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Técnicas In Vitro , Riñón/irrigación sanguínea , Riñón/fisiopatología , Masculino , Perfusión , Factor de Activación Plaquetaria/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/farmacología , Potasio/metabolismo , Presión , Ratas , Ratas Wistar , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Sodio/metabolismo , Triazoles/farmacología , Micción/efectos de los fármacos , Micción/fisiología , Urodinámica
11.
Toxicon ; 36(10): 1441-50, 1998 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9723842

RESUMEN

Crotalus durissus cascavella (C.d.c) is a snake usually found in scrubland of Brazilian Northeast and its bite constitutes an important public health problem. Isolated kidneys from wistar rats, weighing 240 to 280 g, were perfused with Krebs Henseleit solution containing 6 g% of previously dialysed bovine serum albumin. The effects of C.d.c venom were studied on the perfusion pressure (PP), urinary flow (UF), glomerular filtration rate (GFR), percent of sodium tubular transport (%TNa+) and percent of proximal tubule sodium transport (%pTNa+). All experiments were preceded by a 30 min internal control period and an external control group. The infusion of C.d.c (10 microg ml(-1)) increased the PP, UF at 60 and 90min of perfusion, and decreased the GFR, %TNa+ and %pTNa+ at 120 min of perfusion. The proximal renal tubule was the major site for this toxic effect. In the group treated with the venom we found hyalin cylinders inside all tubules and proteinaceous material, alternating from moderate to intense presence in urinary space. Dexamethasone (Dexa 20 microg ml(-1)) protected against the increase in PP, UF, and against the decrease in GFR, it produced the reversion of the effect also in %TNa+ and %pTNa+. Indomethacin (Indo 10 microg ml(-1)) antagonized the effect observed in PP and UF, but was not able to reverse the changes in GFR, %TNa+ and %pTNa+. Nifedipine (Nif 10 microg ml(-1)) promoted a reversion of almost all functional changes, except the %pTNa+ was not reversed. We conclude that these alterations may be caused by a direct action of the venom on the kidneys and indirectly by the release of mediators from endothelial cells. Dexa protected against renal lesions caused by the venom, perhaps by inhibiting phospholipase A2 a toxic component of the venom. The reversion partially induced by indo may be due to cyclooxygenase inhibition that will inhibit the formation of prostaglandins. Nif blocked the renal alterations that may involve cell calcium influx that resulted from the venom aggression.


Asunto(s)
Venenos de Crotálidos/toxicidad , Crotalus , Riñón/efectos de los fármacos , Animales , Bovinos , Dexametasona/farmacología , Diuresis/efectos de los fármacos , Diuresis/fisiología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Técnicas In Vitro , Indometacina/farmacología , Riñón/patología , Riñón/fisiología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/fisiología , Masculino , Nifedipino/farmacología , Perfusión , Ratas , Ratas Wistar , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Sodio/metabolismo
12.
Toxicon ; 39(5): 721-4, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11072052

RESUMEN

We have shown previously that exposure to microcystin-LR (MCLR) causes renal toxic effects in isolated perfused rat kidney. That study was extended further to approach the perspective of pharmacological blockade of renal toxic effects by MCLR through the use of experimental therapeutic agents. An isolated kidney perfusion system was utilized and samples of urine and perfusate were collected at 10min intervals to determine the levels of inulin, sodium, potassium and osmolality. Dexamethasone (20microg ml(-1)) and indomethacin (10microg ml(-1)) were administered in the beginning of the perfusion and MCLR was employed in a dose of 1microg ml(-1) after an internal control of 30min to evaluate the perfusion pressure (PP), renal vascular resistance (RVR), glomerular filtration rate (GFR) and urinary flow (UF). Dexamethasone and indomethacin antagonized the toxic effects of MCLR on PP, RVR, GFR and UF. Histologic analysis of dexamethasone and indomethacin treated groups did not show any vascular or interstitial alterations. MCLR potentially impairs the renal function, probably causing vascular and glomerular lesions and, promoting renal alterations through direct or indirect actions. These data seem to indicate that the renal alterations promoted by MCLR involves also phospholipase A(2) and arachidonic acid-derived mediators.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéutico , Indometacina/uso terapéutico , Riñón/efectos de los fármacos , Péptidos Cíclicos/antagonistas & inhibidores , Fosfolipasas A/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Análisis de Varianza , Animales , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Inulina/metabolismo , Riñón/enzimología , Riñón/metabolismo , Masculino , Toxinas Marinas , Microcistinas , Péptidos Cíclicos/toxicidad , Potasio/metabolismo , Ratas , Ratas Wistar , Sodio/metabolismo
13.
Toxicon ; 41(3): 377-81, 2003 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-12565761

RESUMEN

We have demonstrated previously that microcystin-LR promoted some renal alterations using the isolated perfused rat kidney preparation. However, these effects were not proved to be direct or indirect. The aim of the current work is to examine the renal effects promoted by supernatants from rat macrophages stimulated with microcystin-LR and the role of inflammatory mediators. Peritoneal macrophages were collected previously and were incubated for 1h in fresh medium (control) and in medium containing microcystin-LR. Dexamethasone, quinacrine, thalidomide and cycloheximide were administered 30 min before microcystin-LR. Supernatants of macrophages stimulated with or without pharmacological inhibitors were added on the perfused rat kidney model. The infusion of macrophages supernatants stimulated by microcystin-LR caused significant increases in renal vascular resistance (C: 4.93+/-0.33 vs T: 5.15+/-0.21), glomerular filtration rate (C: 0.559+/-0.008 vs T: 0.978+/-0.15) and urinary flow (C: 0.16+/-0.01 vs T: 0.23+/-0.03). Cycloheximide, quinacrine and dexamethasone blocked these effects and thalidomide blocked renal vascular resistance. Macrophages stimulated by microcystin-LR release mediators capable of promoting nephotoxicity in isolated perfused rat kidney. Phospholipase A(2), TNF-alpha and other protein mediators appear to be involved on its renal toxic mechanism.


Asunto(s)
Medios de Cultivo Condicionados/farmacología , Riñón/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Péptidos Cíclicos/farmacología , Animales , Medios de Cultivo Condicionados/química , Cicloheximida/farmacología , Dexametasona/farmacología , Combinación de Medicamentos , Femenino , Riñón/irrigación sanguínea , Riñón/fisiopatología , Macrófagos Peritoneales/metabolismo , Masculino , Toxinas Marinas , Microcistinas , Perfusión , Quinacrina/farmacología , Ratas , Ratas Wistar , Talidomida/farmacología , Resistencia Vascular/efectos de los fármacos
14.
Toxicon ; 42(5): 509-14, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14529732

RESUMEN

Thalassophryne nattereri, popularly known as Niquim, is a venomous fish responsible for many accidents in fishermen in the Northeast of Brazil. The effects of T. nattereri venom on renal physiology has not been tested. Isolated kidneys from Wistar rats of 240-280 g weight were perfused with Krebs-Henseleit solution containing 6g% of previously dialyzed bovine serum albumin. The effects of Niquim venom were studied on the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), percent of sodium tubular transport (%TNa(+)), percent of potassium tubular transport (%TK(+)) and percent of chloride tubular transport (%TCl(-)). The venom of T. nattereri (0.3, 1.0, and 3.0 microg/ml) was always added to the system 30 minutes after the beginning of each experiment (n=6). All experiments were preceded by 30 minutes internal control period and an external control group, where kidneys were perfused with only Krebs-Henseleit solution. All three doses tested promoted increases in PP and RVR. The first two doses also increased GFR and UF. The higher dose promoted decreases in GFR, UF, %TNa(+), %TK(+), %TCl(-). In the treated groups we observed hyalin casts inside all tubules and proteinaceous material in the urinary space. We conclude that the effects resulted from niquim venom agents that promoted a direct effect in kidney cells causing the release of vasoactive factors.


Asunto(s)
Batrachoidiformes , Venenos de los Peces/farmacología , Riñón/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Hialina/efectos de los fármacos , Riñón/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Masculino , Perfusión , Ratas , Ratas Wistar , Urodinámica/efectos de los fármacos , Urodinámica/fisiología , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología
15.
Toxicon ; 40(10): 1427-35, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12368112

RESUMEN

Acute renal failure is one the most common systemic complications after snakebite, however, its pathogenesis remains obscure. In this study we evaluated the renal effects of Bothrops moojeni venom and its myotoxins (Bmtx-I and BmtxII) in rat isolated perfused kidneys. The myotoxins were purified by ion-exchange chromatography and reverse phase HPLC. The whole venom (10 microg/ml) and myotoxins (5 microg/ml) were added to the perfusion system 30 min after the beginning of each perfusion. The renal effects were compared to a control group perfused with modified Krebs-Henseleit solution alone. B. moojeni venom decreased the perfusion pressure (PP), renal vascular resistance (RVR), and the percent sodium, potassium and chloride tubular transport (%TNa(+), %TK(+), %TCl(-)). In contrast, the venom increased the urinary flow (UF), glomerular filtration rate (GFR), and the sodium, potassium and chloride excretion (ENa(+), EK(+), ECl(-)). The renal effects of myotoxin I was very similar to those of the whole venom, but there was an increase rather than a decrease in the PP and RVR. Myotoxin II had no effect on renal physiology, except for a transient decrease in %TK(+). In conclusion, B. moojeni venom caused intense alterations in renal physiology, including a drop in vascular resistance associated with diuresis, natriuresis and kaliuresis. Bmtx-I had an opposite effect when compared to whole venom, showed in the parameters of PP and RVR. Bmtx-II had a mild effect in %TK(+). The apparent inability of Bmtx-II to induce the renal effect similarly to Bmtx-I should be explained by the absence in the Bmtx-II of the C-terminal lysine rich region.


Asunto(s)
Bothrops/fisiología , Venenos de Crotálidos/toxicidad , Enfermedades Renales/inducido químicamente , Fosfolipasas A/toxicidad , Secuencia de Aminoácidos , Animales , Venenos de Crotálidos/análisis , Fosfolipasas A2 Grupo II , Técnicas In Vitro , Enfermedades Renales/fisiopatología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/fisiopatología , Masculino , Datos de Secuencia Molecular , Perfusión , Fosfolipasas A/análisis , Presión , Ratas , Ratas Wistar , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Proteínas de Reptiles , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Micción/efectos de los fármacos , Urodinámica , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología
16.
Life Sci ; 33(5): 431-6, 1983 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-6877029

RESUMEN

Renal handling of glycyl-proline was studied in the isolated perfused rat kidney. Glycyl-proline disappeared from the perfusate as a function of time. The dipeptide was freely filtered at the glomerulus but only 6% of the filtered load was excreted in the urine as the intact peptide. More than 90% of the filtered dipeptide was reabsorbed as the intact peptide and/or its hydrolytic products. Non-filtration mechanisms were also involved to a significant extent in the clearance of the peptide. Hydrolysis at intratubular, intracellular and peritubular sites all contribute to the disappearance of the dipeptide from the perfusate, though the relative contributions of each mechanism are not known. Significant metabolic conversions, especially the conversion of glycine to serine, were also observed during perfusion.


Asunto(s)
Dipéptidos/metabolismo , Riñón/metabolismo , Animales , Transporte Biológico , Biotransformación , Tasa de Filtración Glomerular , Cinética , Masculino , Perfusión , Ratas
17.
Lipids ; 26(12): 1329-32, 1991 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-1819726

RESUMEN

Renal vascular escape is a physiological phenomenon of adaptation that occurs in vascular smooth muscle. It has been described in many preparations subjected to electrical stimulation or treated with vasoactive agents, such as noreprinephrine, angiotensin and vasopressin. We have recently demonstrated that a naturally occurring ginkgolide (BN 52021), which is a PAF antagonist, was able to block norepinephrine-induced escape in perfused rabbit kidney. In the present work other PAF antagonists, such as the ginkgolides BN 52022 and BN 52024, and the synthetic compounds 48740 RP and WEB 2086, were tested. Their effects on renal vascular escape, perfusion pressure and tachyphylaxis were evaluated. They all were shown to block the escape. Among the ginkgolides, BN 52024 is generally recognized as one of the weaker PAF antagonists. However, in spite of this, BN 52024 was able to significantly and simultaneously block renal vascular escape and tachyphylaxis in perfused rabbit kidney infused with norepinephrine.


Asunto(s)
Azepinas/farmacología , Diterpenos , Riñón/fisiología , Lactonas/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Piridinas/farmacología , Circulación Renal/efectos de los fármacos , Taquifilaxis , Tiazoles/farmacología , Triazoles/farmacología , Animales , Femenino , Gangliósidos/farmacología , Ginkgólidos , Técnicas In Vitro , Riñón/efectos de los fármacos , Cinética , Masculino , Perfusión , Conejos , Factores de Tiempo
18.
J Pharm Pharmacol ; 43(10): 741-3, 1991 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1682456

RESUMEN

The influence of the dihydropyridine calcium antagonist nifedipine has been studied on the diuretic response to frusemide, acetazolamide and hydrochlorothiazide in water-loaded (25 mL kg-1) conscious rats. Oral administration of nifedipine (10 mg kg-1) markedly inhibited frusemide- and hydrochlorothiazide-induced diuresis as evidenced by a reduction in 5 h urine volume and urinary sodium and potassium elimination. However, it neither significantly enhanced nor limited urine and electrolyte excretion promoted by acetazolamide. Nifedipine, 5 and 10 mg kg-1 but not 1 mg kg-1, significantly (P less than 0.05) inhibited the diuretic response of hydrochlorothiazide. At doses which affect hydrochlorothiazide diuresis (5 and 10 mg kg-1), nifedipine was found to depress the mean arterial pressure by 32% in normotensive rats. These results are of interest in view of the often reported clinical side effect of nifedipine in promoting peripheral oedema in hypertensive patients and its use in combination with a thiazide or loop diuretic.


Asunto(s)
Diuréticos/farmacología , Riñón/efectos de los fármacos , Nifedipino/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Electrólitos/orina , Femenino , Ratas , Ratas Endogámicas
19.
J Pharm Pharmacol ; 40(5): 362-4, 1988 May.
Artículo en Inglés | MEDLINE | ID: mdl-2899634

RESUMEN

Adrenergic presynaptic functions were evaluated in the cat isolated perfused heart preparation. The sympathetic nerve endings were labelled with [3H]noradrenaline ([3H]NA) and the effect of electric neural stimulation was determined in the presence of drugs which inhibit neuronal or extraneuronal uptake, or which antagonize alpha-adrenoceptors. [3H]NA overflow was measured in control and diabetic cats and was significantly increased by electric neural stimulation on both conditions. Perfusion with 0.1 microM phentolamine increased transmitter overflow in control hearts but failed to do so on organs obtained from alloxan-treated cats. The data provide evidence that in alloxan diabetic cats there is an abnormality of the adrenergic synapse.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Corazón/inervación , Receptores Adrenérgicos alfa/fisiología , Animales , Gatos , Técnicas In Vitro , Perfusión
20.
Braz J Med Biol Res ; 24(3): 319-21, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1823245

RESUMEN

The participation of platelet-activating factor (PAF, PAF-acether) in a mouse model of pulmonary edema was studied using specific antagonists. Mice were treated before induction of edema with the PAF antagonists BN52021 (10 mg/kg, ip), PCA4248 (10 mg/kg, po) or WEB2170 (10 mg/kg, ip), the lipoxygenase inhibitor EP10161 (10 mg/kg, ip), the cyclo-oxygenase inhibitor aspirin (250 mg/kg, po), or with the mixed cyclo-lipoxygenase inhibitor BW755C (50 mg/kg, ip). The test drugs were administered to animals either 30 min (when the ip route was used) or 60 min (when given po) prior to the induction of pulmonary edema. Pulmonary edema was induced by intravenous administration of adrenaline (2 mg/kg). When the lung-body index was used as the criterion for comparison between groups, BN52021, PCA4248 and WEB2170 were found to have no significant effect on pulmonary edema. In contrast, EP10161, aspirin and BW755C significantly inhibited pulmonary edema by 49%, 30% and 27%, respectively. The results suggest that arachidonate metabolites are likely to play a major role in adrenaline-induced pulmonary edema in mice, whereas PAF-acether does not seem to play an important role in this model.


Asunto(s)
Eicosanoides/antagonistas & inhibidores , Factor de Activación Plaquetaria/antagonistas & inhibidores , Edema Pulmonar/inducido químicamente , Animales , Permeabilidad Capilar , Eicosanoides/fisiología , Epinefrina , Infusiones Intravenosas , Ratones , Tamaño de los Órganos , Factor de Activación Plaquetaria/fisiología , Edema Pulmonar/patología , Edema Pulmonar/fisiopatología
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