The Cardioprotective Role of Carvedilol, A Non-Selective -Adrenoceptor Blocker, in Albino Rats with Type 2 Diabetes Mellitus

The present work aimed to study the effects of carvedilol, a third generation -blocker
with antioxidant and -blocking activities, on glycemic control and cardioprotection
in type 2 diabetes mellitus (DM) induced in rats by high fat diet (HFD). Seventy-two
male albino rats (5 weeks of age) weighing 80-90g were exposed to dark/light cycle of
12/12 hours and randomly divided into six groups, each of 12 rats. Rats of Control
Groupwere fed standard rat chow. Rats of HFD Groupwere fed HFD for induction
of type 2 DM. Rats of the last 4 groups were the Carvedilol-S Group, the Carvedilol-L Group, the Propranolol Groupand the Aminoguanidine Group.They were fed
HFD and treated with carvedilol (2mg/kg/day), carvedilol (20 mg/kg/day),
propranolol (30 mg/kg/day) and aminguanidine (20 mg/kg/day) respectively All drugs
were given orally by gavage in the morning. The animals were under feeding and
subsequent treatments daily for 12 weeks. At the end of the experiment, rats were
sacrificed, blood samples collected, centrifuged and sera were separated and stored
at -80°C till the time of analysis. The epididymal fat pads and one of the
gastrocnemius muscles were excised, blotted dry and weighed and the weight ratio
was recorded as the body composition index (BCI). Hearts were rapidly exposed and
excised, washed in cold phosphate buffered saline (PBS), pH 7.4, blotted dry and
weighed. The ratio between heart weight and body weight was calculated as heart
weight index (HWI). Immediately, the hearts were flash-frozen in liquid nitrogen and
kept frozen at -80°C until the time of analysis. The parameters assayed were: serum
lipid profile, lipid peroxides, insulin, glucose, myocardial lipid peroxides, superoxide
dismutase (SOD) and catalase (CAT) enzymes, nitric oxide (NO)and oral glucose
tolerence test (OGTT) where rats were fasted for 15 hours and glucose was given by
gavage at a dose of 2 g/kg then 6 blood samples were taken from retroorbital vien at
half hour intervals. Results:HFD in male albino rats for 12 weeks induced type 2
DM. Dyslipidemic changes in these animals were observed as increased serum levels
of total cholesterol (TC), low density lipoporotein-cholesterol (LDL-C), triglycerides
(TGs) and decreased levels of high density lipoporotein-cholesterol (HDL-C). In
addition, HFD induced oxidative and nitrative stress as evidenced by the increase in
serum and myocardial levels of lipid peroxides and concomitant decrease in
myocardial SOD and CAT and increased NO metabolites. HFD also induced
cardiovascular complications as indicated by increased HWI in the HFD group.
Administration of carvedilol in both dose levels had positive impact on glucose 
homeostasis and lipid profile in HFD-fed animals. Propranolol, on the other hand,
had an ameliorative effect on glucose metabolism but did not improve dyslipidemic
changes induced by HFD and diabetes. In addition, administration of
aminoguanidine had slight effect on glucose tolerance and lipid profile. No
appreciable differences were observed among the four treated groups with regard to
glucose homeostasis. The best effects of the drugs under investigation regarding
prevention of dyslipidemia were attributed to large dose carvedilol followed by small
dose and aminoguanidine while propranolol did not prevent development of
dyslipidemia. Oxidative stress was antagonized to variable extents in the four drug
treatment regimens. The best results were attributed to carvedilol in both dose levels.
However, both propranolol and aminoguanidine showed antioxidant activities. All the
three groups on -blocker regimen displayed normalization of myocardial NO level.
Conversely, aminoguanidine decreased this level dramatically.Conclusion:
carvedilol showed dose-dependent improvements on glucose and lipid homeostasis,
oxidative and nitrative stress. However, better effects were observed with the small
dose on myocardial antioxidant activity. These effects might contribute but do not
fully explain the dose-independent cardioprotection observed in the present study.