[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].
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.
K V
KV
Derkach
L A
LA
Kuznetsova
T S
TS
Sharova
P A
PA
Ignatieva
V M
VM
Bondareva
A O
AO
Shpakov
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects; D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction
D000322:Adrenergic Agonists; D002316:Cardiotonic Agents; D004041:Dietary Fats; D007328:Insulin; D018696:Neuroprotective Agents; D011943:Receptors, Adrenergic, beta; D044101:Receptors, Melanocortin; D012701:Serotonin; D008687:Metformin; D002784:Cholesterol; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000262:Adenylyl Cyclases; D005947:Glucose