Enalapril treatment corrects the reduced response to bradykinin in diabetes increasing the B2 protein expression

Considering the growing importance of the interaction between components of kallikreinkinin and renin-angiotensin systems in physiological and pathological processes, particularly in diabetes mellitus, the aim of the present study was to investigate the effect of enalapril on the reduced response of bradykinin and on the interaction between angiotensin-(1-7) (Ang-(1-7)) and bradykinin (BK), important components of these systems, in an insulin-resistance model of diabetes. For the above purpose, the response of mesenteric arterioles of anesthetized neonatal streptozotocin-induced (n-STZ) diabetic and control rats was evaluated using intravital microscopy. In n-STZ diabetic rats, enalapril treatment restored the reduced response to BK but not the potentiation of BK by Ang-(1-7) present in non-diabetic rats. The restorative effect of enalapril was observed at a dose that did not correct the altered parameters induced by diabetes such as hyperglycernia, glicosuria, insulin resistance but did reduce the high blood pressure levels of n-SZT diabetic rats. There was no difference in mRNA and protein expressions of B1 and B2 kinin receptor subtypes between n-STZ diabetic and control rats. Enalapril treatment increased the B2 kinin receptor expression. From our data, we conclude that in diabetes enalapril corrects the impaired BK response probably by increasing the expression of B2 receptors. The lack of potentiation of BK by Ang-(1-7) is not corrected by this agent. (c) 2008 Elsevier Inc. All rights reserved.

Estudo morfofisiológico de órgãos isolados de ratos diabéticos submetidos a exercício físico e a aminoguanidina

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação dos efeitos fisiológicos e bioquímicos do tratamento com curcumina incorporada ao iogurte no diabetes experimental

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Valutazione del rapporto urinario proteine totali/creatinina e albumina/creatinina in cani affetti da iperadrenocorticismo e da diabete mellito

INTRODUCTION – In human medicine, diabetes mellitus (DM), hypertension, proteinuria and nephropathy are often associated although it is still not clear whether hypertension is the consequence or the cause of nephropathy and albuminuria. Microalbuminuria, in humans, is an early and sensitive marker which permits timely and effective therapy in the early phase of renal damage. Conversely, in dogs, these relationships were not fully investigated, even though hypertension has been associated with many diseases (Bodey and Michell, 1996). In a previous study, 20% of diabetic dogs were found proteinuric based on a U:P/C > 1 and 46% were hypertensive; this latter finding is similar to the prevalence of hypertension in diabetic people (40-80%) (Struble et al., 1998). In the same canine study, hypertension was also positively correlated with the duration of the disease, as is the case in human beings. Hypertension was also found to be a common complication of hypercortisolism (HC) in dogs, with a prevalence which varies from 50 (Goy-Thollot et al., 2002) to 80% (Danese and Aron, 1994).The aim of our study was to evaluate the urinary albumin to creatinine ratio (U:A/C) in dogs affected by Diabetes Mellitus and HC in order to ascertain if, as in human beings, it could represent an early and more sensitive marker of renal damage than U:P/C. Furthermore, the relationship between proteinuria and hypertension in DM and HC was also investigated. MATERIALS AND METHODS – Twenty dogs with DM, 14 with HC and 21 healthy dogs (control group) were included in the prospective case-control study. Inclusion criteria were hyperglycaemia, glicosuria and serum fructosamine above the reference range for DM dogs and a positive ACTH stimulation test and/or low-dose dexamethasone test and consistent findings of HC on abdominal ultrasonography in HC dogs. Dogs were excluded if affected by urinary tract infections and if the serum creatinine or urea values were above the reference range. At the moment of inclusion, an appropriate therapy had already been instituted less than 1 month earlier in 12 diabetic dogs. The control dogs were considered healthy based on clinical exam and clinicopathological findings. All dogs underwent urine sample collection by cystocentesis and systemic blood pressure measurement by means of either an oscillometric device (BP-88 Next, Colin Corporation, Japan) or by Doppler ultrasonic traducer (Minidop ES-100VX, Hadeco, Japan). The choice of method depended on the dog’s body weight: Doppler ultrasonography was employed in dogs < 20 kg of body weight and the oscillometric method in the other subjects. Dogs were considered hypertensive whenever systemic blood pressure was found ≥ 160 mmHg. The urine was assayed for U:P/C and U:A/C (Gentilini et al., 2005). The data between groups were compared using the Mann-Whitney U test. The reference ranges for U:P/C and U:A/C had already been established by our laboratory as 0.6 and 0.05, respectively. U:P/C and U:A/C findings were correlated to systemic blood pressure and Spearman R correlation coefficients were calculated. In all cases, p < 0.05 was considered statistically significant. RESULTS – The mean ± sd urinary albumin concentration in the three groups was 1.79 mg/dl ± 2.18; 20.02 mg/dl ± 43.25; 52.02 mg/dl ± 98.27, in healthy, diabetic and hypercortisolemic dogs, respectively. The urine albumin concentration differed significantly between healthy and diabetic dogs (p = 0.008) and between healthy and HC dogs (p = 0.011). U:A/C values ranged from 0.00 to 0.34 (mean ± sd 0.02 ± 0.07), 0.00 to 6.72 (mean ± sd 0.62 ± 1.52) and 0.00 to 5.52 (mean ± sd 1.27 ± 1.70) in the control, DM and HC groups, respectively; U:P/C values ranged from 0.1 to 0.6 (mean ± sd 0.17 ± 0.15) 0.1 to 6.6 (mean ± sd 0.93 ± 1.15) and 0.2 to 7.1 (mean ± sd 1.90 ± 2.11) in the control, DM and HC groups, respectively. In diabetic dogs, U:A/C was above the reference range in 11 out of 20 dogs (55%). Among these, 5/20 (25%) showed an increase only in the U:A/C ratio while, in 6/20 (30%), both the U:P/C and the U:A/C were abnormal. Among the latter, 4 dogs had already undergone therapy. In subjects affected with HC, U:P/C and U:A/C were both increased in 10/14 (71%) while in 2/14 (14%) only U:A/C was above the reference range. Overall, by comparing U:P/C and U:A/C in the various groups, a significant increase in protein excretion in disease-affected animals compared to healthy dogs was found. Blood pressure (BP) in diabetic subjects ranged from 88 to 203 mmHg (mean ± sd 143 ± 33 mmHg) and 7/20 (35%) dogs were found to be hypertensive. In HC dogs, BP ranged from 116 to 200 mmHg (mean ± sd 167 ± 26 mmHg) and 9/14 (64%) dogs were hypertensive. Blood pressure and proteinuria were not significantly correlated. Furthermore, in the DM group, U:P/C and U:A/C were both increased in 3 hypertensive dogs and 2 normotensive dogs while the only increase of U:A/C was observed in 2 hypertensive and 3 normotensive dogs. In the HC group, the U:P/C and the U:A/C were both increased in 6 hypertensive and 2 normotensive dogs; the U:A/C was the sole increased parameter in 1 hypertensive dog and in 1 dog with normal pressure. DISCUSSION AND CONCLUSION- The findings of this study suggest that, in dogs affected by DM and HC, an increase in U:P/C, U:A/C and systemic hypertension is frequently present. Remarkably, some dogs affected by both DM and HC showed an U:A/C but not U:P/C above the reference range. In diabetic dogs, albuminuria was observed in 25% of the subjects, suggesting the possibility that this parameter could be employed for detecting renal damage at an early phase when common semiquantiative tests and even U:P/C fall inside the reference range. In HC dogs, a higher number of subjects with overt proteinuria was found while only 14% presented an increase only in the U:A/C. This fact, associated with a greater number of hypertensive dogs having HC rather than DM, could suggest a greater influence on renal function by the mechanisms involved in hypertension secondary to hypercortisolemia. Furthermore, it is possible that, in HC dogs, the diagnosis was more delayed than in DM dogs. However, the lack of a statistically significant correlation between hypertension and increased protein excretion as well as the apparently random distribution of proteinuric subjects in normotensive and hypertensive cases, imply that other factors besides hypertension are involved in causing proteinuria. Longitudinal studies are needed to further investigate the relationship between hypertension and proteinuria.