RESUMO
We demonstrated that aldose reductase inhibition corrects the impaired microvascular responses to inflammatory mediators in diabetic rats. To study the mechanism involved in the restoring effect of aldose reductase inhibition, we examined the effects of minalrestat, another aldose reductase inhibitor, on the responses of mesenteric microvessels studied in vivo to permeability-increasing agents in diabetic and galactosemic rats. The diabetic group was treated from 3 days after the alloxan injection with minalrestat (10 mg/kg/day) for 30 days and the minalrestat treatment (10 mg/kg/day/7 days) of galactosemic rats started concomitantly with the induction of galactosemia. The mesenteric microvessel reactivity was studied using intravital microscopy and changes in vessel diameters were estimated after the topical application of vasoactive agents. The impaired responses to bradykinin, histamine, and platelet-activating factor of arterioles and venules observed in diabetic and galactosemic rats were completely prevented by minalrestat. Neither diabetes nor galactosemia affected responses to acetylcholine and sodium nitroprusside. Responses to these agents were not modified by aldose reductase inhibition. The restoring effect of minalrestat was reversed by inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester, by blocking K(+) channel with tetraethylammonium but not by cyclooxygenase inhibition with diclofenac. Therefore, we concluded that NO, membrane hyperpolarization, but not cyclooxygenase products are involved in the beneficial effect of minalrestat on the microvascular reactivity in diabetes. Together, these findings led us to suggest that aldose reductase inhibition might ameliorate diabetic complications through the correction of the altered microvascular reactivity by a mechanism that involves NO and membrane hyperpolarization.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Diabetes Mellitus Experimental/fisiopatologia , Imidas/farmacologia , Quinolonas/farmacologia , Circulação Esplâncnica/efeitos dos fármacos , Vasoconstritores/farmacologia , Aldeído Redutase/metabolismo , Animais , Modelos Animais de Doenças , Interações Medicamentosas , Galactosemias/induzido quimicamente , Galactosemias/fisiopatologia , Masculino , Ratos , Ratos WistarRESUMO
Se presentan cuatro casos de galactosemia clásica cuya manifestación clínica inicial fue colestasis neonatal prolongada, atendidos en el Servicio de Gastroenterología del Instituto Nacional de Pediatría de la Ciudad de México, durante el período comprendido de 1987 a 1990. El diagnóstico definitivo se hizo mediante la medición de la actividad de la enzima galactosa 1-fosfato uridil transferasa en eritrocitos (prueba de Beutler). El manejo de los pacientes consistió básicamente en la restricción de galactosa en la dieta. Dos de los pacientes tuvieron una evolución clínica desfavorable, presentamos uno de ellos secuelas neurológicas importantes y el otro paciente falleció (septicemia)
Assuntos
Recém-Nascido , Lactente , Humanos , Masculino , Feminino , Colestase/enzimologia , Colestase/fisiopatologia , Galactosemias/diagnóstico , Galactosemias/fisiopatologia , Galactose , Galactose/deficiênciaRESUMO
Forty children and adults with classic galactosemia had vertebral bone density determined by standard quantitative computed tomography at 3.4 to 44.2 years of age. Compared with age- and sex-matched control subjects, patients with galactosemia had diminished bone density (p = < 0.001). Prepubertal patients of both sexes had bone density determinations below those of the control group (p = 0.008); similar findings were seen in postpubertal patients as well (women, p = 0.001; men, p = 0.008). Women receiving replacement estrogen-progestin therapy for premature ovarian failure had abnormal bone density (136.3 +/- 17.3 mg/cm3 vs 166.0 +/- 17.5 mg/cm3 for control subjects; p = 0.002); patients with evidence of ovarian insufficiency not receiving replacement sex steroids had even lower bone density (92.4 +/- 14.3 mg/cm3 vs 160.2 +/- 20.2 mg/cm3 for control subjects; p < 0.001). Calcium intake for the entire galactosemia group was 540 +/- 344 mg/day. Calcium intake correlated positively with bone density in women given exogenous estrogen (r = 0.87; p = 0.002) and in men (r = 0.74; p = 0.009). Thus the diminished mineralization of bones appears to be another abnormality associated with galactosemia. The results of our study suggest that this is likely secondary to abnormal levels of sex steroids in female patients, low calcium intake, and perhaps an intrinsic defect in the normal galactosylation of the collagen matrix of bone caused by the enzyme defect. Strategies to improve bone formation should be considered to diminish morbidity in patients with this inborn error of metabolism.