The protective effect of losartan in the nephropathy of the diabetic rat includes the control of monoamine oxidase type A activity.

Monoamine oxidase activity (MAO-A and B) levels, as intracellular source of reactive oxygen species, might increase in diabetic nephropathy (DN) contributing to reduce dopamine levels and to unbalance kidney redox state. We explored the hypothesis that beneficial effects of losartan, an angiotensin-II type 1 receptor (AT1) blocker, in DN included the control of MAO activity levels. In kidneys of normoglycemic and diabetic, streptozotocin-injected (55 mg/kg) rats, treated or untreated with losartan, an AT1 antagonist (20mg/kg/day in the drinking water), we investigated MAO activity radiochemically and antioxidant enzymes including catalase, aldehyde dehydrogenase and superoxide dysmuthase spectrophotometrically. In addition, we also evaluated malondialdehyde and carbonylated protein levels spectrophotometrically as indexes of oxidative attack to lipids and proteins. Diabetic rats showed signs of nephropathy, including renal hypertrophy, proteinuria, high acethylglucosaminidase and γ-glutamyltranspeptidase urinary levels. In diabetic kidneys, MAO-A and catalase activities as well as malondialdehyde levels, were found significantly higher than in normoglycemic ones. Interestingly, in diabetic kidneys, MAO-A activity correlated not only with catalase but also with γ-glutamyltranspeptidase urinary levels. Our results indicate that the control of MAO-A activity is to be included amongst the mechanisms of protection afforded by losartan in DN. In fact, the prevention of MAO-A raise might increase dopamine availability and, as suggested by the correlation with γ-GGT, reduce oxidative attack to tubular cells.

Exposure of cardiomyocytes to angiotensin II induces over-activation of monoamine oxidase type A: implications in heart failure.

Several evidences indicate that increased cardiac mitochondrial monoamine oxidase type A (MAO-A) activity associates with a failing phenotype. Till now, the mechanism underlying such relation is largely unknown. We explored the hypothesis that exposure of cardiomyocytes to AT-II caused activation of MAO-A and also of catalase and aldehyde dehydrogenase activities, enzymes involved in degrading MAO's end products. Left ventricular cardiomyocytes were isolated from normoglycemic (N) and streptozotocin-injected (50 mg/kg) rats (D) treated or not treated with losartan (20 mg/kg/day in drinking water; DLos and NLos, respectively), a type 1 receptor (AT1) antagonist, for 3 weeks. In each group of cells, MAO, catalase and aldehyde dehydrogenase activities were measured radiochemically and spectrophotometrically. The same enzymes were also measured in HL-1 immortalized cardiomyocytes not exposed and exposed to AT-II (100 nM for 18 h) in the absence and in the presence of irbesartan (1 µM), an AT1 antagonist. MAO-A catalase and aldehyde dehydrogenase activities were found significantly higher in D, than in N cells. MAO-A positively correlated with catalase activity in D cells. MAO-A and aldehyde dehydrogenase but not catalase over-activation, were prevented in DLos cells. Similarly, MAO-A activity, but not catalase and aldehyde dehydrogenase increased significantly in HL-1 cells acutely exposed to AT-II and this increase was prevented when irbesartan, an AT1 antagonist was present. Over-activation of cardiomyocyte MAO-A activity is among acute (18 h) and short-term (2-weeks of diabetes) cardiac effects of AT-II and a novel target of AT1 antagonists, first line treatments of diabetic cardiomyopathy.

Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold.

BACKGROUND AND PURPOSE: 3-Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg(-1) , i.p.), an inhibitor of amine oxidative metabolism. EXPERIMENTAL APPROACH: T1AM (0.13, 0.4, 1.32 and 4 µg·kg(-1) ) or vehicle was injected i.c.v. into male mice, and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot plate and movements on the hole-board platform. Plasma glycaemia was measured using a glucorefractometer. Brain levels of triiodothyroxine (T3), thyroxine (T4) and T1AM were measured by HPLC coupled to tandem MS. ERK1/2 activation and c-fos expression in different brain regions were evaluated by Western blot analysis. RESULTS: T1AM improved learning capacity, decreased pain threshold to hot stimuli, enhanced curiosity and raised plasma glycaemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. T1AM effects on learning and pain were abolished or significantly affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at the rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behaviour. CONCLUSIONS AND IMPLICATIONS: T1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders.