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1.
Can J Physiol Pharmacol ; 91(10): 830-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24144054

RESUMO

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.


Assuntos
Amidas/farmacologia , Vasos Coronários/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Endotelina-1/metabolismo , Fumaratos/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Peptídeos/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina B/efeitos dos fármacos , Peçonhas/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Vasos Coronários/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Exenatida , Masculino , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Estreptozocina , Fatores de Tempo
2.
Biochem Genet ; 50(11-12): 922-35, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22983684

RESUMO

Selenium and exendin-4 exert antidiabetic effects by unknown mechanisms. Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. Diabetic rats were injected intraperitoneally with exendin-4 (0.03 µg/kg body weight) twice daily or treated with 5 ppm selenium as sodium selenite in drinking water for 4 weeks. Both selenium and exendin-4 reduced the hyperglycemia in diabetic rats. Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver.


Assuntos
Proteínas Substratos do Receptor de Insulina/metabolismo , Fígado/efeitos dos fármacos , MAP Quinase Quinase Quinases/metabolismo , Peptídeos/farmacologia , Receptores de Glucagon/metabolismo , Selenito de Sódio/farmacologia , Peçonhas/farmacologia , Animais , Glicemia , Western Blotting , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Insulina/farmacologia , Proteínas Substratos do Receptor de Insulina/genética , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase Quinases/genética , Masculino , Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas c-raf , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glucagon/genética , Selênio/metabolismo , Selênio/farmacologia , Selenito de Sódio/administração & dosagem , Estreptozocina/administração & dosagem , Estreptozocina/efeitos adversos , Fatores de Tempo , Peçonhas/administração & dosagem
3.
Exp Diabetes Res ; 2011: 489708, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21747829

RESUMO

This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with (125)I-GLP-1 was performed to estimate GLP-1 binding affinity (τ = 1/k-n) to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the τ value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.


Assuntos
Amidas/farmacologia , Diabetes Mellitus Tipo 1/patologia , Fumaratos/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Coração/efeitos dos fármacos , Peptídeos/farmacologia , Receptores de Glucagon/metabolismo , Renina/antagonistas & inibidores , Peçonhas/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Avaliação Pré-Clínica de Medicamentos , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Coração/fisiologia , Hipoglicemiantes/farmacologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Glucagon/agonistas , Estreptozocina
4.
Gen Physiol Biophys ; 30(1): 34-44, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21460410

RESUMO

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L cells upon nutrients ingestion, and is currently used for treating diabetes mellitus. It plays an important role in receptor modulation and cross talk with insulin at the coronary endothelium (CE) and cardiomyocytes (CM) in diabetic type 1 rat heart model. We studied the effects of insulin, GLP-1 analogues (exendin-4), and dipeptidyl peptidase-IV (DPP-IV) inhibitor on GLP-1 cardiac receptor modulation. The binding affinity of GLP-1 to its receptor on CE and CM was calculated using a rat heart perfusion model with [(125)I]-GLP-1(7-36). Tissue samples from the heart were used for immunostaining and Western blot analyses. GLP-1 systemic blood levels were measured using ELISA. GLP-1 binding affinity (τ) increased on the CE (0.33 ± 0.01 vs. 0.25 ± 0.01 min; p < 0.001) and decreased on the CM (0.29 ± 0.02 vs. 0.43 ± 0.02 min; p < 0.001) in the diabetic non-treated rats when compared to normal. There was normalization of τ back to baseline on the CE and CM levels with insulin and DPP-IV inhibitor treatment, respectively. Histological sections and immunofluorescence showed receptor up-regulation in diabetic rats with significant decrease and even normalization with the different treatment strategies. Systemic GLP-1 levels increased after 14 days of diabetes induction (10 ± 3.7 vs. 103 ± 58 pM; p = 0.0005). In conclusion, there is a significant GLP-1 receptor affinity modulation on the CE and CM levels in rats with diabetes type 1, and a cross talk with GLP-1 analogues in early prevention of cardiac remodeling.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptores de Glucagon/metabolismo , Remodelação Ventricular , Animais , Glicemia/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Exenatida , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1 , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Insulina/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk , Receptores de Glucagon/efeitos dos fármacos , Peçonhas/farmacologia
5.
Can J Physiol Pharmacol ; 88(7): 753-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20651823

RESUMO

The aim of this study was to determine whether the jejunal oligopeptide transporter PepT1 is regulated by insulin and whether this regulation is sex-dependent in type 1 diabetic rats. PepT1 expression, real-time polymerase chain reaction, and Western blots were performed using jejunal segments from 4 groups of male and female rats: normal (nondiabetic), insulin-treated nondiabetic, streptozotocin (STZ)-induced diabetic (type 1 diabetes), and insulin-treated diabetic models. Furthermore, the same segments from all groups underwent perfusion to assess uptake of the dipeptide glycylsarcosine through PepT1. Our results showed that insulin treatment of nondiabetic female rats decreased blood glucose level but did not affect nondiabetic male rats. In both male and female diabetic rats, insulin did not completely decrease blood glucose level. Insulin treatment decreased PepT1 mRNA level in nondiabetic male rats and increased mRNA level in nondiabetic female rats without affecting the PepT1 protein level in either sex. Inducing diabetes with STZ increased PepT1 mRNA and protein levels in female rats; however, in diabetic male rats, the increase in mRNA level was accompanied by a decrease in PepT1 protein level. Treatment of diabetic male rats with insulin partially reversed the effect of diabetes on PepT1 mRNA and protein levels, whereas the same treatment completely restored both PepT1 mRNA and protein to control levels in insulin-treated diabetic female rats. In both nondiabetic male and female rats, insulin treatment had no effect on PepT1 influx rate, and STZ treatment decreased the transporter influx rate. Treatment of diabetic male and female rats with insulin significantly increased PepT1 influx rate; however, complete recovery was found only in diabetic female rats. These results clearly show that insulin and diabetes affected blood glucose level as well as PepT1 activity, expression, and protein levels in a sex-dependent manner. These results suggest that a factor, probably estrogen, could be responsible for the sex-dependent effects of diabetes and insulin in PepT1 level and activity.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Insulina/farmacologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Simportadores/genética , Simportadores/metabolismo , Animais , Sequência de Bases , Glicemia/metabolismo , Primers do DNA/genética , Diabetes Mellitus Experimental/genética , Dipeptídeos/metabolismo , Estrogênios/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Transportador 1 de Peptídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
6.
Can J Physiol Pharmacol ; 88(1): 54-63, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20130739

RESUMO

This study focused on the regulation and affinity modulation of the insulin receptor of coronary endothelium and cardiomyocytes in nondiabetic and STZ-induced type 1 diabetic rats. Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. The results showed that diabetes (D) decreased the tau value on the coronary endothelium and increased it on cardiomyocytes compared with the nondiabetic group (N). Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. On the coronary endothelium, tau values of DI and DIDp were normalized. Western blots of the insulin receptor showed upregulation in D, downregulation in DI, and normalization in DE and DDp. Immunohistochemistry and RT-PCR findings indicated atrial natriuretic factor (ANF) in all diabetic ventricles, thus ascertaining hypertrophy. Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Receptor de Insulina/metabolismo , Animais , Glicemia/metabolismo , Bovinos , Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Masculino , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Peçonhas/administração & dosagem , Peçonhas/uso terapêutico
7.
Artigo em Inglês | MEDLINE | ID: mdl-17703431

RESUMO

This study focused on the regulation and affinity modulation of angiotensin II (Ang II) binding to its receptor subtypes (AT(1)- and AT(2)-receptor) in the coronary endothelium (CE) and cardiomyocytes (CM) of Sprague-Dawley male rats in normal (N), normal treated with losartan (NL), streptozotocin-induced diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and diabetic co-treated with insulin and losartan (DIL). Heart perfusion was used to estimate Ang II binding affinity (tau=1/k-(n)) to its receptor subtypes on CE and CM. Diabetes decreased tau value on CE and increased it on CM as compared to normal. In DL group, the tau value decreased on CE but was normalised on CM. Insulin treatment alone (DI) or with losartan (DIL) restored t to normal on both CE and CM. Western blot results for AT(1)-receptor density showed an increase in diabetics compared to normal with no normalising effect with insulin treatment. The AT(1)-receptor density was normalised in the diabetic groups treated with losartan +/- insulin. Results for AT(2)-receptor regulation revealed a significant difference between untreated (D) and losartan-treated (DL, DIL) diabetic groups. All of these data show the interrelated pathway and cross-talk between insulin and Ang II system indicating potentially negative effects on the diabetic heart.


Assuntos
Angiotensina II/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Coração/fisiopatologia , Insulina/metabolismo , Losartan/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Receptor Cross-Talk/fisiologia , Animais , Antiarrítmicos/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Coração/anatomia & histologia , Insulina/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Ratos , Receptor de Insulina/fisiologia , Receptores de Angiotensina/fisiologia , Valores de Referência
8.
Can J Physiol Pharmacol ; 85(2): 215-24, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17487263

RESUMO

This project assesses the treatment role with insulin and (or) angiotensin II receptor subtype-1 (AT1-R) blocker (ARB) on insulin receptor and endothelin-1 receptor subtype (ETA-R and ETB-R) regulation in rat hearts suffering from insulin-dependent diabetes mellitus (IDDM). Animals were divided into 6 groups: groups 1, 3, and 5 were controls consisting of normal, diabetic (streptozotocin-treated, once at 0 time), and diabetic supplemented daily with insulin, respectively, whereas groups 2, 4, and 6 were the controls treated daily with losartan. One month after enrollment, rats were sacrificed and samples of cardiac tissue were snapped frozen for immunostaining and Western blotting. Insulin receptor density was observed to be upregulated in the cardiomyocytes of diabetic animals, but downregulated with insulin supplementation alone. Cotreatment with insulin and an ARB resulted in drastic increase in insulin-receptor density in the diabetic rats. In addition, expression of ETA-R in cardiomyocytes was upregulated and was consistently maintained within the various treatment modalities. However, ETB-R expression was significantly reduced in the diabetic group treated with both insulin and an ARB. The changes in the expression of the insulin, the ETA-Rs, and the ETB-Rs at the various sites of the myocardium and the effect of both insulin treatment and blockade of the AT1-R explain the new benefits related to the halting of myocardial remodeling in IDDM rats.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Miocárdio/química , Receptor de Endotelina A/análise , Receptor de Endotelina B/análise , Receptor de Insulina/análise , Animais , Western Blotting , Endotelina-1/metabolismo , Imunofluorescência , Losartan/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
9.
Clin Pharmacokinet ; 44(9): 957-67, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16122282

RESUMO

BACKGROUND: To study the pharmacokinetics and clinical outcome of gemcitabine (2'-2'-difluoro-deoxcytidine [dFdC]) during intra-arterial versus intravenous delivery in locally advanced and regionally metastatic pancreatic cancer. PATIENTS AND METHODS: Seven patients with unresectable pancreatic cancer received escalating intra-arterial doses of gemcitabine ranging from 800 to 1400 mg/m2, after selective embolisation of all pancreatic blood supply, except for the tumour-feeding arteries. Four patients received intravenous gemcitabine (control). Venous blood samples at different time intervals were taken throughout 270 minutes for pharmacokinetic analyses of gemcitabine and its inactive metabolite 2'-2'-difluorodeoxyuridine (dFdU). RESULTS: Pharmacokinetic data revealed differences in plasma concentrations between intra-arterial and intravenous delivery routes. The plasma concentration-time curve of gemcitabine during and after cessation of intra-arterial pancreatic target administration through the proximal splenic artery showed a profile with an area under the plasma concentration-time curve from 0 to 270 minutes (intra-arterial 29.0 +/- 0.4 vs intravenous 331.0 +/- 2.7 ng.min/mL; p < 0.0001) and peak plasma concentration (intra-arterial 1.1 +/- 0.2 vs intravenous 7.6 +/- 2.0 ng/mL; p < 0.0001) significantly lower than that for the corresponding systemic intravenous route. A plot of ln (% of dose) versus time showed a bi-compartmentalised metabolic model for intravenous administration of gemcitabine, one indicating rapid conversion of gemcitabine to dFdU, and another at a significantly lower affinity resulting in no conversion. Hence, this could be the main reason why dFdU was not detected in the systemic circulation during pancreatic intra-arterial target delivery. Furthermore, during intravenous administration a pseudo first-order rate constant ( approximately 0.20 min(-)(1)) for in vivo conversion of gemcitabine to dFdU was estimated, indicating a rapid cellular deamination which was not shown in the intra-arterial route. Clinically, one patient had a partial response and six patients had a stable disease after intra-arterial administration of gemcitabine. The median time to disease progression was 4 months and the median overall survival was 5 months. One patient survived for 26 months. No grade III or IV toxicity was documented. CONCLUSION: Intra-arterial administration of gemcitabine has a major advantage related to reduced toxicity as increasing the dose through this administration route will eventually result in pancreatic cellular drug target delivery prior to systemic availability. Despite the low number of patients recruited, the clinical results are encouraging and this approach should be tested in a randomised study.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Metástase Neoplásica , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Análise de Sobrevida , Resultado do Tratamento , Gencitabina
10.
J Hypertens ; 23(2): 381-92, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15662227

RESUMO

OBJECTIVES: To assess the role of insulin or an angiotensin II receptor antagonist (losartan), or both, in preventing cardiomyocyte damage in rats suffering from insulin-dependent diabetes mellitus (IDDM), and to correlate it with insulin receptor modulation at the cardiomyocyte, coronary endothelium and skeletal muscle cell level. DESIGN: Animals were divided into groups of normal rats, diabetic rats, and diabetic rats given insulin, each subdivided into a control group and an experimental group treated with losartan. METHODS: The animals were killed 1 month after enrollment to the study. Perfusion of the heart with iodine-125-labelled insulin was carried out for all the groups and the binding kinetics of insulin to its receptors on the coronary endothelial cells and the cardiomyocytes were determined using a physical/mathematical model. In addition, tissue samples from the heart and intercostal skeletal muscle were snap frozen and used for histological, indirect immunofluorescence and western blot analysis. RESULTS: Cardiac muscle from diabetic animals exhibited diffuse cardiomyopathic changes consisting of widespread vacuolation, loss of striation and cellular hypertrophy, which were reduced and even prevented by treatment with insulin and losartan. In addition, losartan seemed to mediate the upregulation of insulin receptor density on cardiomyocytes and skeletal muscle, and increase insulin receptor affinity at the coronary endothelial site. Finally, treatment with losartan induced a significant decrease in glucose concentrations in the diabetic group compared with the appropriate controls. CONCLUSIONS: Addition of losartan to the standard insulin treatment in non-hypertensive animals with IDDM offers new benefits concerning cardiac protection and prevention of damage. This may be attributed, in part, to insulin receptor density and sensitization.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Endotélio Vascular/efeitos dos fármacos , Masculino , Músculo Esquelético/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
11.
Endothelium ; 12(5-6): 225-31, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16410221

RESUMO

This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Diabetes Mellitus Experimental/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Miocárdio/metabolismo , Receptor de Endotelina A/biossíntese , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Técnicas In Vitro , Masculino , Modelos Biológicos , Miocárdio/patologia , Perfusão , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética
12.
Mol Pharm ; 1(4): 300-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15981589

RESUMO

This investigation focused on studying the effects of insulin-dependent diabetes mellitus and insulin treatment on absorption of glycylsarcosine (Gly-Sar) across the Sprague-Dawley rat jejunum, using in situ perfusion in a physiologic acidic microenvironment at pH 6.0. Rats were divided into five groups: normal controls in group I, normal colchicine-treated rats in group II, normal cytochalasin-treated rats in group III, streptozotocin-induced diabetic rats in group IV, and insulin-treated diabetic rats in group V. Histologic studies of the five different groups showed morphologic changes upon induction of diabetes and treatments with colchicine and cytochalasin and several variations in post-1 month diabetic rats treated with insulin. The rate of uptake of Gly-Sar was significantly reduced in the diabetic state. The comparison of colchicine-treated and cytochalasin-treated rats to the diabetic group suggests that an intact cytoskeleton and tight junctions may play a role in jejunal dipeptide absorption. In the diabetic and insulin-treated group, the dipeptide influx rate was significantly increased compared to that of the nontreated controls. The regulation of the PepT 1 symporter was further assessed by immunostaining and Western blot analyses in the normal, diabetic, and diabetic and insulin-treated groups. Our results showed that a downregulation of PepT 1 in the diabetics seemed to be due in part to the low systemic insulin levels, and not necessarily to hyperglycemia. In addition, the results suggest a probable role of systemic insulin binding at the vascular site of the jejunal epithelium, and the role that this hormone may be playing in the regulation and probably cellular trafficking of PepT1.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Dipeptídeos/metabolismo , Insulina/farmacologia , Jejuno/metabolismo , Simportadores/metabolismo , Animais , Western Blotting , Feminino , Imuno-Histoquímica , Jejuno/efeitos dos fármacos , Transportador 1 de Peptídeos , Ratos , Ratos Sprague-Dawley
13.
Can J Physiol Pharmacol ; 81(3): 267-73, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12733825

RESUMO

Ischemic heart disease is considered to be one of the leading causes of death in adults. While extensive research on mechanisms contributing to the pathogenesis of myocardial infarction (MI) has been underway, it is not known whether insulin receptor characteristics and postreceptor signaling have been fully addressed as yet. Present work attempts to investigate whether the remodeling process effectively induces alteration(s) in insulin-binding characteristics at the coronary endothelium and cardiomyocytes using a rat heart model of MI. MI was induced by ligation of the left anterior descending coronary artery of adult male Sprague-Dawley rats. Two animal groups were used in the study: (i) sham-operated CHAPS-untreated and CHAPS-treated, and (ii) MI CHAPS-untreated and MI CHAPS-treated. A physical model describing 1:1 stoichiometry of reversible insulin binding to its receptors present on the endothelium and at cardiomyocytes after CHAPS treatment was considered for data analysis. Quantitation of the collected effluents after heart perfusion, the inlet at the aortic and outlet at the coronary sinus sites, were curve fitted using a first-order Bessel function, which determines the binding constants (k(n)), the reversible constant (k(-n)), the dissociation constant (k(d) = k(-n)/k(n)), and the residency time constant (tau = 1/k(-n)). In addition, hearts were excised, separated into right and left ventricles, and individually weighed, and areas of infarcted regions were measured. Results of the MI group showed significant increases in relative heart mass, left ventricle mass, and right ventricle mass normalized to total body mass. MI induced severe ischemia and irreversible myocardial injury as assessed by planimetry and histologic studies. The data showed differences in insulin receptor affinities at the endothelial and cardiac myocytes in the sham and in the MI-operated rats. The observed reduction in the binding affinity of insulin at the myocyte postinfarction may explain the pathogenic role of insulin in ischemic heart disease and, hence, resistance. Therefore, insulin administration during and post MI might be cardioprotective.


Assuntos
Endotélio Vascular/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptor de Insulina/metabolismo , Animais , Cardiomegalia/etiologia , Cardiomegalia/patologia , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Insulina/metabolismo , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miocárdio/patologia , Perfusão , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
14.
Artigo em Inglês | MEDLINE | ID: mdl-12524016

RESUMO

Endothelin-1 (ET-1) pathophysiologic actions are mediated via binding with two receptor subtypes, ET(A) and ET(B). Release of ET-1 from endocardial endothelial cells and cardiac myocytes can modulate heart tissue necrosis and alterations. This study investigates the remodeling processes in Sprague-Dawley rats of myocardial infarction (MI) induced by ligating the left anterior descending coronary artery. Histological studies were done on cell type distribution using cell specific markers and Western blot analysis to localize ET-1 receptor subtypes and assess their expression post-MI. In addition, the binding kinetics of ET-1 with its receptors in heart perfusion, inlet via the aortic lumen and effluent outlet via the right atrium, between two animal model-subgroups were done: (1) sham-operated, and sham-operated-CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate)-treated; and (2) MI-operated, and MI-operated-CHAPS-treated. Effluent ET-1 concentration was plotted vs. time using a physical model for 1:1 ligand-receptor binding at coronary endothelium and myocytes. First order impulse function was used to calculate the affinity constants. In MI hearts, fluorescence activity increased for ET(A) vs. ET(B) across areas of the muscle compared to normal hearts. Western blotting showed upregulation of ET(A) and ET(B) receptors in MI compared with normal hearts. Results of ET-1 binding affinity post-MI indicated drastic reduction in spite the upregulation of ET(B) on coronary endothelium. Furthermore, substantial affinity increase was observed between ET-1 binding with ET(A) at the myocyte site. These findings stipulate that during 1 month post-MI some biochemical and hormonal effects could alter ET-1 receptor subtype(s) regulation and pharmacodynamics thus predisposing to cardiac hypertrophy and mitogenesis.


Assuntos
Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptores de Endotelina/metabolismo , Remodelação Ventricular/fisiologia , Animais , Western Blotting , Ácidos Cólicos/farmacologia , Detergentes/farmacologia , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Coração/efeitos dos fármacos , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Perfusão , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A , Receptores de Endotelina/classificação
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