THE EFFECTS OF LONG-TERM METFORMIN TREATMENT ON THE ACTIVITY OF ADENYLYL CYCLASE SYSTEM AND NO-SYNTHASES IN THE BRAIN
AND THE MYOCARDIUM OF RATS WITH OBESITY
K.V. Derkach, L.A. Kuznetsova, T.S. Sharova, P.A. Ignatieva, V.M. Bondareva, A.O. Shpakov 1
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg;
1 e-mail:alex_shpakov@list.ru
Biguanide metformin, which is widely used for the treatment of type 2 diabetes mellitus, improves carbohydrate
and lipid metabolism and shows a pronounced cardio- and neuroprotective effects. It is assumed that an
important role in these effects of metformin plays its ability to positively influence the activity of NO-synthase
catalyzing the synthesis of NO, the most important vasodilator, and the activity of hormone-sensitive adenylyl
cyclase signaling system (ACSS. To prove this, we have carried out a study whose purpose was to study the effect
of long-term metformin treatment on the metabolic rates in obese rats, as well as on the activity of ACSS
and NO-synthase in the myocardium and the brain of these animals. The metformin treatment of Wistar rats
with obesity induced by high-fat diet was carried out for 2 months (daily dose of 200 mg/kg). The treatment
with metformin led to a decrease in body weight and body fat, reduced glucose and insulin levels as well as reduced
insulin resistance index HOMA-IR, improved glucose tolerance, and decreased the level of atherogenic
forms of cholesterol. In the myocardium of obese rats, the attenuation of ACSS stimulation induced by the agonists
of β1/β2-adrenergic receptors (AR) and the strengthening of
β3-AR signaling has been found. At the same
time, in the myocardium of animals treated with metformin, the regulation of ACSS by adrenergic agonists was
restored, and the ratio of β-AR-signaling pathways returned to normal. In the brain of rats treated with metformin,
adenylyl cyclase stimulating effects of serotonin and agonists of type 4 melanocortin receptors, which had
been weakenend for obesity, were restored. Metformin treatment completely restored activity of total and endothelial
NO-synthase in the myocardium decreased in obesity. It as also shown that metformin treatment induced
hyperactivation of NO-synthase in the myocardium and brain of healthy animals. Thus, we conclude that
the effects of metformin identified by us in rats with long-term treatment of obesity may explain cardio- and neuroprotective
influence of this drug.
Key words:
metformin, adenylyl cyclase, NO-synthase, obesity, adgenergic receptor, serotonin, brain, myocardium, vasodilatation
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