RESUMO
In experimental diabetes, diastolic dysfunction of the left ventricle has been associated with collagen-linked glycation. To determine whether less severe hyperglycemia may have similar effects, we gave alloxan to mongrel dogs (group 2) to induce impaired glucose tolerance (IGT) for comparison with normal subjects (group 1). After 6 months, hemodynamic studies were performed in the anesthetized animals. Basal heart rate, aortic pressure, and ejection fraction were comparable in the two groups, but calculated chamber stiffness was increased in group 2, associated with a reduced end diastolic volume and increased pressure. During infusion of dextran, the volume and pressure responses were similarly abnormal in group 2. In the myocardium, the collagen concentration rose with an increased interstitial distribution histologically. To assess glycation, collagen was extracted, digested with collagenase, and measured for fluorescence. Advanced glycation end products were increased in group 2 to 10.6 +/- 1.6 vs. 6.9 +/- 0.7 fluorescent units (FU)/mg collagen in group 1 (P < 0.01). To assess whether this could be pharmacologically prevented, we administered enalapril to inhibit ACE during the 6 months of glucose intolerance to group 3. This resulted in normal glycation and significant reduction in chamber stiffness increment. We gave group 4 animals aminoguanidine daily for 6 months, which prevented abnormal collagen glycation and chamber stiffness. Thus, in animals with IGT, collagen-linked glycosylation appeared to be a major factor affecting diastolic function and was shown to be amenable to pharmacological intervention.
Assuntos
Colágeno/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Intolerância à Glucose , Contração Miocárdica/fisiologia , Animais , Configuração de Carboidratos , Diabetes Mellitus Experimental/metabolismo , Cães , Glicosilação , Hemodinâmica/fisiologia , Técnicas In Vitro , Masculino , Músculos Papilares/fisiopatologiaRESUMO
Calcium entry blockers, particularly diltiazem, have been shown to lower not only systemic blood pressure but also improve proteinuria in non-insulin-dependent diabetic patients. The presence of proteinuria is attributed to the loss of glomerular heparan sulfate, which confers a negative charge on the basement membrane. In the present study, we evaluated the efficacy of diltiazem in lowering blood pressure and proteinuria in diabetic rats and also examined the possibility that diltiazem prevents proteinuria through glomerular preservation of heparan sulfate. Diabetes was induced in male Wistar rats by streptozotocin (60 mg/kg). One group of diabetic rats was treated with diltiazem (25 mg/L) in drinking water for 20 weeks. Another group of diabetic rats and a group of nondiabetic rats were given tap water only. Systolic blood pressure was measured at 4, 8, 12, and 20 weeks. Urinary excretion of albumin was done at 4, 8, 12, 16, and 20 weeks. At the end of 20 weeks, all rats were killed, kidneys were removed, and glomeruli were isolated. Total glycosaminoglycan and heparan sulfate synthesis were determined by incubating glomeruli in the presence of [35S]sulfate. Diltiazem lowered blood pressure significantly in diabetic rats at 8, 12, and 20 weeks. Diabetic glomeruli synthesized less total glycosaminoglycan and heparan sulfate than glomeruli from normal rats. Characterization of heparan sulfate by ion-exchange chromatography showed that the fraction eluted with 1 M NaCl was significantly lower and the fraction eluted with 1.25 M NaCl significantly higher in diabetic than in normal rats. Diltiazem therapy returned not only glomerular synthesis but also various fractions of heparan sulfate to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Albuminúria/urina , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/urina , Diltiazem/farmacologia , Heparitina Sulfato/biossíntese , Glomérulos Renais/metabolismo , Albuminúria/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
We examined whether blood pressure reduction or good glycemic control equally lower albuminuria by preventing glomerular loss of heparan sulfate and progression of glomerulosclerosis in streptozotocin-induced diabetic rats. We used doxazosin, and alpha 1-adrenergic blocker, to lower systemic blood pressure, and good glycemic control was achieved by insulin treatment. Rats were killed after 20 weeks of treatment. Doxazosin significantly lowered systolic pressure in diabetic rats; however, it had no effect in normal rats. Good glycemic control also lowered systolic pressure. In diabetic rats with good glycemic control, doxazosin had an additive effect on blood pressure. Glomerular heparan sulfate synthesis was significantly lower and urinary albumin excretion higher in diabetic than in normal rats. Both doxazosin treatment and good glycemic control normalized these abnormalities in diabetic rats. Insulin normalized plasma glucose and glycosylated HbA1 concentrations in diabetic rats, as did doxazosin. Significant increases in mesangial area and glomeruloscelerosis were observed in diabetic rats. Only good glycemic control normalized these pathological changes in all diabetic rats. Two-way factorial ANOVA showed an interaction between the effects of doxazosin and insulin on systolic pressure and plasma glucose. The data show that after 20 weeks of doxazosin treatment, albuminuria was reduced by 80%; however, this treatment had no significant effect on mesangial expansion or progression to glomerulosclerosis. Conversely, good glycemic control prevented all three of the preceding sequelae.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Diabetes Mellitus Experimental/metabolismo , Doxazossina/farmacologia , Heparitina Sulfato/metabolismo , Glomérulos Renais/metabolismo , Proteinúria/prevenção & controle , Albuminúria , Animais , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/patologia , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/patologia , Incidência , Insulina/farmacologia , Glomérulos Renais/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , SístoleRESUMO
Male Wistar rats with streptozotocin induced diabetes were treated every third day with 10 mg/kg (13 rats) of cyclosporine A (CyA) for 20 weeks. At sacrifice, 7 of 13 rats (53.8%) demonstrated renal tumors. By contrast, only 2 of 16 streptozotocin diabetic rats (12.5%) without CyA demonstrated renal tumors. No tumors were noted in 10 non-diabetic control rats. These studies suggest that CyA potentiates renal tumorigenicity in streptozotocin diabetic rats.
Assuntos
Ciclosporinas/toxicidade , Diabetes Mellitus Experimental/patologia , Neoplasias Renais/induzido quimicamente , Estreptozocina/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Sinergismo Farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Rim/ultraestrutura , Neoplasias Renais/patologia , Masculino , Microscopia Eletrônica , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Valores de ReferênciaRESUMO
This study evaluated the effect of chronic hyperglycemia on erythrocyte membrane Ca and Na/K-ATPase activities in streptozotocin-induced diabetic rats. The activity of Ca-ATPase was significantly lower in diabetic than in normal rats. Good glycemic control by insulin restored the Ca-ATPase activity to normal. By contrast, diltiazem, a calcium entry blocker, had no effect on the enzyme activity. Calmodulin stimulated Ca-ATPase activity in all groups of rats. Na/K-ATPase activity was not altered in diabetic rats, and no effects of either insulin or diltiazem treatments were observed. The results suggest that erythrocyte Ca-ATPase activity is decreased in diabetic rats and is normalized by good glycemic control.
Assuntos
Glicemia/análise , ATPases Transportadoras de Cálcio/sangue , Cálcio/antagonistas & inibidores , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diltiazem/uso terapêutico , Eritrócitos/enzimologia , ATPase Trocadora de Sódio-Potássio/sangue , Animais , Glicemia/efeitos dos fármacos , Glicemia/fisiologia , Calmodulina/farmacologia , Diabetes Mellitus Experimental/enzimologia , Diltiazem/farmacologia , Hemoglobinas Glicadas/análise , Masculino , Ratos , Ratos Wistar , Estreptozocina , Fatores de TempoRESUMO
Concentrations of vitamins, biopterin, free inositol and acid-soluble carnitine were determined in cyclosporine A induced renal adenocarcinoma and uninvaded renal tissue from streptozotocin diabetic rats. Vitamin B6, thiamin, riboflavin, nicotinate, free inositol and acid-soluble carnitine were significantly decreased in tumor than nontumor tissue. Concentrations of folic acid, B12, biotin, pantothenate and biopterin were similar in both tissues. These studies suggest that renal adenocarcinoma affects concentrations of only certain vitamins and micronutrients.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Renais/metabolismo , Rim/química , Vitaminas/análise , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/patologia , Animais , Biopterinas/análise , Glicemia/análise , Carnitina/análise , Ciclosporina/toxicidade , Diabetes Mellitus Experimental/metabolismo , Inositol/análise , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/patologia , Masculino , Ratos , Ratos EndogâmicosRESUMO
The aldose reductase pathway has been implicated in the development of chronic complications of diabetes. In this study, we investigated the effect of an aldose reductase inhibitor, statil, on glomerular synthesis of heparan sulfate and albuminuria in male Wistar rats made diabetic with streptozotocin. Heparan sulfate is the predominant glycosaminoglycan (GAG) proteoglycan in the glomerular basement membrane (GBM). It confers a negative charge on the GBM, and its loss has been related to the presence of albumin in the urine. Diabetic rats synthesized less glomerular heparan sulfate and excreted more albumin than normal rats. Glomerular sorbitol concentration was significantly higher in diabetic than in normal rats. Chronic treatment of diabetic rats with statil did not improve either heparan sulfate synthesis or albuminuria despite normalization of glomerular sorbitol content. The present study does not support the role of excess sorbitol in the development of glomerular abnormalities in this rat model of streptozotocin diabetes.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Diabetes Mellitus Experimental/fisiopatologia , Glomérulos Renais/metabolismo , Ftalazinas/farmacologia , Proteinúria , Animais , Membrana Basal/efeitos dos fármacos , Membrana Basal/metabolismo , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Sulfatos de Condroitina/biossíntese , Creatinina/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/urina , Proteínas Alimentares , Eletroforese em Gel de Poliacrilamida , Heparitina Sulfato/biossíntese , Rim/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Potássio/sangue , Proteinúria/prevenção & controle , Ratos , Ratos Wistar , Sorbitol/metabolismo , Fatores de TempoRESUMO
The long-term effects of angiotensin-converting enzyme inhibitors (captopril and enalapril), calcium-entry blockers (diltiazem and nicardipine), and good glycemic control on plasma lipids and lipoproteins were studied in streptozotocin diabetic rats. Diabetic rats had increased plasma cholesterol, tryiglycerides, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol than in normal rats. Compared to other antihypertensives, nicardipine seems to have a less beneficial effect on lipids and lipoproteins. However, it is only the good glycemic control that normalized these plasma lipids and lipoproteins in diabetic rats. This suggests that good glycemic control prevents dyslipidemia in diabetic rats. The observed beneficial effects of antihypertensives were unrelated to either food or water intake.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Lipídeos/sangue , Animais , Glicemia/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Captopril/farmacologia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diltiazem/farmacologia , Comportamento de Ingestão de Líquido , Enalapril/farmacologia , Ingestão de Energia , Hemoglobinas Glicadas/metabolismo , Masculino , Nicardipino/farmacologia , Ratos , Ratos Wistar , Valores de Referência , Triglicerídeos/sangueRESUMO
Changes in circulating and tissue concentrations of several vitamins have been reported in diabetic animals and human subjects. In this study, the effect of short-term (2 weeks) streptozotocin diabetes on folate, B6, B12, thiamin, nicotinate, pantothenate, riboflavin and biotin in liver, kidney, pancreas, heart, brain and skeletal muscle of rats was investigated. The tissue distribution of vitamins varied widely in normal rats. Diabetes significantly lowered folate in kidney, heart, brain, and muscle; B6 in brain; B12 in heart; thiamin in liver and heart; nicotinate in liver, kidney, heart and brain; pantothenate in all tissues; riboflavin in liver, kidney, heart, and muscle. These results indicate that experimental diabetes causes a depression of several water-soluble vitamins in various tissues of rats.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Vitaminas/farmacocinética , Água/química , Animais , Masculino , Ratos , Ratos Wistar , Valores de Referência , Solubilidade , Distribuição Tecidual/fisiologia , Vitaminas/metabolismoRESUMO
Noninsulin-dependent diabetic KK mice, aged 90-100 days, with hyperinsulinemia and insulin resistance were treated with either metformin (N = 13) or water (control, N = 10) orally at a concentration of 50 mg/kg twice daily for 28 weeks. Age-matched nondiabetic Swiss Webster (SW) mice were also similarly treated. Liver and skeletal muscle glycogen synthase and phosphorylase enzymes were determined in all groups of mice. Both enzymes were significantly lower in control KK than in control SW mice. Metformin did not influence either of these enzymes in nondiabetic SW mice. However, it significantly increased the active form of glycogen synthase (a form) in both the liver and muscle of KK mice. Metformin also increased the active form of phosphorylase (a form) in the liver but not in the muscle of these mice. Hepatic glycogen content was similar in both control and metformin-treated KK mice. However, the muscle glycogen content was significantly higher in metformin-treated than in control KK mice. These data suggest that metformin preferentially stimulates glycogen synthesis in skeletal muscle, and this seems to be responsible for the observed improvement in fasting glucose and glucose response to an oral glucose load in KK mice.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glicogênio/metabolismo , Glicogênio Hepático/metabolismo , Fígado/metabolismo , Metformina/farmacologia , Músculos/metabolismo , Análise de Variância , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/genética , Glicogênio Sintase/metabolismo , Cinética , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Mutantes , Músculos/efeitos dos fármacos , Fosforilase a/metabolismo , Fosforilase b/metabolismo , Valores de ReferênciaRESUMO
Non-obese KK mice, aged 90-100 days, demonstrating an abnormal tolerance to glucose, hyperinsulinaemia with insulin resistance and glomerulosclerosis were treated with either water (control N = 10) or metformin (N = 15), a biguanide, orally at a concentration of 50 mg/kg twice daily for 16 weeks. Oral glucose tolerance was performed at 7 weeks. Only 10 of 15 metformin-treated mice (responders) improved their oral glucose tolerance. The remaining 5 mice (non-responders) did not improve their tolerance to the oral glucose load. A repeated oral glucose tolerance test at 16 weeks showed similar results. Blood lactate and insulin levels were similar in all 3 groups of mice. At sacrifice, responders had significantly less glomerulosclerosis compared to control mice. No difference in the incidence of glomerulosclerosis was found between control mice and non-responders. The data suggest that chronic metformin treatment improves glucose tolerance in 70% of KK mice without increasing blood lactate or insulin levels. This improvement in glycaemic control is associated with a lesser incidence of glomerulosclerosis in KK mice.
Assuntos
Glicemia/metabolismo , Glomérulos Renais/patologia , Metformina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Teste de Tolerância a Glucose , Insulina/sangue , Glomérulos Renais/efeitos dos fármacos , Lactatos/sangue , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
The incorporation of [14C] U-glucose into glycogen by liver, kidney and skeletal muscle and that into total lipid by adipose tissue was studied in noninsulin-dependent genetically diabetic KK mice treated either with metformin (50 mg/kg) or water for 10 weeks. Results show that glycogen synthesis was increased in the skeletal muscle from metformin-treated mice. Liver and kidney glycogen synthesis was not affected by metformin. Glucose incorporation was significantly increased into lipid in metformin-treated mice. Insulin administration stimulated lipid synthesis in adipose tissue, but had no effect on muscle glycogen synthesis in metformin-treated mice. These data suggest that chronic metformin treatment potentiates the endogenous insulin action on glucose in skeletal muscle and adipose tissue, and thus confirm our previous results of increased glycogen synthesis by skeletal muscle in metformin-treated KK mice.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glicogênio/biossíntese , Lipídeos/biossíntese , Metformina/farmacologia , Animais , Glicemia , Glucose/metabolismo , Insulina/sangue , Insulina/farmacologia , Masculino , Camundongos , Camundongos MutantesRESUMO
In this study, we examined the hypothesis whether exogenous administration of L-lysine in drinking water would reduce nonenzymatic glycation of glomerular basement membrane (GBM) collagen and thus albuminuria in streptozotocin-diabetic rats. The rationale is that the administered lysine would combine with the circulating glucose and make it unavailable to react with epsilon-amino groups of lysine of various proteins in these diabetic rats. Lysine (0.1%) was given to diabetic rats 7 days (early treatment) or 90 days (late treatment) after induction of hyperglycemia. The treatment was continued for 60 days. Diabetic rats had significantly higher glucose, glycosylated HbA(1), kidney weight, nonenzymatic glycation of GBM collagen, albuminuria, and systolic blood pressure than normal rats. Early treatment with lysine prevented the rise in glycosylated HbA(1) (normal 6.98 +/- 0.71% vs. diabetic - early treatment - 7.78 +/- 1.50%; p = NS), reduced glycosylation of GBM collagen by 86%, and significantly improved albuminuria. There was no significant effect on plasma glucose and systolic blood pressure. However, late treatment reduced the glycosylation of GBM collagen by 46% with a significant improvement in albuminuria. Plasma creatinine levels were not different between normal and untreated diabetic or lysine-treated diabetic rats; however, the creatinine clearance was significantly higher in all groups of diabetic rats (normal 0.45 +/- 0.09 vs. diabetic 2.02 +/- 0.39 ml/min; p < 0.001). The data suggest that early rather than late treatment is more beneficial in reducing nonenzymatic glycation of collagen, although both treatments significantly reduced albuminuria. There was no nephrotoxicity as assessed by plasma creatinine levels or creatinine clearances. These beneficial effects occurred independent of changes either in blood pressure or plasma insulin concentration.
Assuntos
Albuminúria/tratamento farmacológico , Colágeno/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Lisina/farmacologia , Albuminúria/etiologia , Albuminúria/metabolismo , Animais , Membrana Basal/efeitos dos fármacos , Membrana Basal/metabolismo , Glicemia/metabolismo , Colágeno/química , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Hemoglobinas Glicadas/metabolismo , Glicosilação , Masculino , Ratos , Ratos WistarRESUMO
1. The effect of short- (2 wk) and long-term (20 wk) streptozotocin diabetes was studied on urine, blood, liver, heart, brain, skeletal muscle, pancreas and kidney concentrations of acid-soluble carnitine and free myo-inositol. 2. Short-term diabetic rats excreted significantly higher concentrations of carnitine as well as myoinositol than normal rats. Blood carnitine and myo-inositol were not different between normal and diabetic rats. Diabetes caused a decrease in liver, brain and pancreatic carnitine, but not in heart, skeletal muscle and kidney. Myo-inositol concentration was decreased in liver, heart and kidney but not in brain, pancreas and skeletal muscle. 3. Long-term diabetic rats had higher urinary excretions of both carnitine and myo-inositol. Blood carnitine did not change; however, myo-inositol was higher in diabetic than in normal rats. Diabetes caused a significant increase in liver and a decrease in heart, brain, skeletal muscle and pancreatic content of carnitine; no difference in kidney carnitine was noted. Myo-inositol content was elevated only in liver of diabetic rats. 4. We suggest that carnitine and myo-inositol concentrations are influenced both by short- and long-term diabetes through changes in tissue metabolism.
Assuntos
Carnitina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Inositol/metabolismo , Doença Aguda , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Doença Crônica , Diurese/fisiologia , Ingestão de Alimentos/fisiologia , Masculino , Ratos , Ratos EndogâmicosRESUMO
The effect of short term (8 weeks) sodium (Na+) depletion and its repletion on glomerular synthesis of heparan sulfate and urinary excretions of albumin, total protein, heparan sulfate, Na+ and potassium (K+) was studied in spontaneous hypertensive rats (SHR) and their control normotensive Wistar-Kyoto rats (WKY). Na+ depletion in SHRs significantly increased the synthesis of glomerular heparan sulfate and decreased urinary excretions of albumin, Na+ and heparan sulfate when compared with the Na+ repleted group. In WKY rats, Na+ depletion did not cause any of the above changes. These data suggest that Na+ depletion prevents the urinary loss of protein through preservation of glomerular heparan sulfate only in SHRs.
Assuntos
Albuminúria/prevenção & controle , Hipertensão/complicações , Sódio/fisiologia , Albuminúria/etiologia , Albuminúria/metabolismo , Animais , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Ingestão de Líquidos , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/metabolismo , Heparitina Sulfato/urina , Hipertensão/metabolismo , Glomérulos Renais/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sódio/urinaRESUMO
Concentrations of acid-soluble L-carnitine and inositol were determined in heart, kidney, muscle, pancreas, liver, brain and blood of genetically diabetic obese db/db and their nondiabetic control C57BL/6J (CBL) mice. Results were compared to a group of diabetic and CBL mice fed ethanol (ETOH) 4 g/kg daily for 58-64 days. In CBL and db/db mice, heart muscle was found to have the greatest and brain the least content of carnitine. Diabetes caused a significant decrease in hepatic concentration of carnitine but did not affect carnitine concentration of heart, kidney, skeletal muscle, brain and pancreas. ETOH intake had no effect on carnitine content of any of the tissues studied. Free inositol content was highest in brain and lowest in skeletal muscle of CBL and db/db mice; diabetes or ETOH intake did not affect tissue inositol content. Except for liver, neither diabetes nor ETOH intake affects tissue carnitine or inositol concentration.
Assuntos
Consumo de Bebidas Alcoólicas/fisiologia , Carnitina/sangue , Diabetes Mellitus Experimental/genética , Inositol/sangue , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Obesos , Distribuição Tecidual/fisiologiaRESUMO
1. The effect of long-term (20 wk) treatment of cyclosporine A (CyA) was studied in urine, blood, liver, kidney and pancreatic concentrations of acid-soluble carnitine and free myo-inositol in streptozotocin diabetic rats. 2. Diabetic rats excreted significantly higher concentrations of carnitine and myo-inositol; CyA prevented the urinary loss of carnitine but not myo-inositol. 3. Blood carnitine levels were not different between normal and diabetic rats, however, CyA significantly decreased these levels. Conversely, blood myo-inositol concentrations were higher in diabetic than in normal rats; CyA prevented this increase. 4. Hepatic concentrations of both carnitine and myo-inositol were increased in diabetic rats; CyA treatment caused even further increase. 5. Pancreas from diabetic rats contained less carnitine and myo-inositol compared to normal pancreas. CyA treatment did not affect pancreatic carnitine, but it normalized myo-inositol in diabetic rats. 6. The kidney carnitine or myo-inositol levels were not influenced either by diabetes or by CyA treatment. 7. These results suggest that CyA treatment causes changes in carnitine and myo-inositol concentrations in biologic fluids and certain tissues.
Assuntos
Carnitina/metabolismo , Ciclosporina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Inositol/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Ratos , Ratos EndogâmicosRESUMO
Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction ( approximately 40%) in age-related left ventricular stiffness was observed [(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.