Anti-metabolic syndrome activity of adenosine in stroke-prone spontaneously hypertensive rats

Ardiansyah*, Hitoshi Shirakawa, Takuya

1, Koseki

Michio Komai

Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai-Japan; 1 Faculty of Agriculture, Yamagata University, Tsuruoka-Japan * Email: ardy@biochem.tohoku.ac.jp
Abstract
Despite the well-documented that adenosine has health-related physiological activities in animal and human studies, but the detail mechanisms remain unknown. Thus, the purpose of the present study was to identify whether oral administration of adenosine affects on metabolic syndrome-related parameters in stroke-prone spontaneously hypertensive rats (SHRSP) after high fat diet intake. The rats aged 6-weeks-old were divided into control and adenosine groups, were administered water or water with adenosine, respectively, for 8 week. The rats had free access to high fat diet. The present results showed that oral administration of adenosine has blood pressure lowering effect compared with control group. Oral administration of adenosine also showed increased plasma nitric oxide level; this result corresponded well with its blood pressure lowering effect. We found out that adenosine is effective to improve plasma lipid, glucose, and kidney functions parameters. Adenosine also increases plasma adiponectin level and accompanied by the alleviation of hyperinsulinemia in SHRSP. In conclusion, oral administration of adenosine is effective to improve metabolic syndrome-related parameters in SHRSP and could prevent the progression of metabolic syndrome.

Introduction
Adenosine has physiological functions; 1. Therapy of neonatal refractory pulmonary hypertension 2. Attenuates proliferation in both human and rat glomerular mesangial cell 3. Decrease in blood glucose and insulin level after oral administration

Adenosine, an identified active component from the Driselase-treated fraction of rice bran, has novel functions in blood pressure lowering effect and improving plasma lipid level in stroke-prone spontaneously hypertensive rats (SHRSP) (Ardiansyah et al., 2009 J. Agric Food Chem 57, 2558-2564)

Objectives
Adenosine

The purposes of these studies are to identify whether oral administration of adenosine affects on metabolic syndrome-related parameters in SHRSP after high fat diet intake.

Experimental methods
6 weeks-old male SHRSP/Izumo. The rats had free access to fresh diet (AIN-93M-based experimental diet; Table 1) and drinking water. The control and adenosine groups (n=6) were administered distilled water (control) and distilled water containing adenosine 10 mg/L (A10) and 100 mg/L (A100) for 8 weeks. Blood pressure was measured using tail cuff method without warming once a week (MK-2000, Muromachi Kikai Co., Ltd., Tokyo, Japan). On the 11th week-old of SHRSP, all groups were used for an oral glucose tolerance test (OGTT). Blood plasma was taken from abdominal aorta for biochemical analyses. The rats were housed individually in stainless steel cages under a controlled atmosphere (temperature, 23 + 2 oC; humidity 50 + 10 %; 12 h light-dark cycle, 08:00 am-08:00 pm)

Table 1. Composition of control diet (g/kg)

TBHQ1 L-cystine Choline bitartrate Vitamin Lard Cellulose Sucrose Casein Cornstarch
1tert-butylhydroquinone; 2Oriental

Growth parameters
1.8 2.5 10 35 200 Relative organs weight (%) 50 100 140 460.69
3 300 250 200 150 Control A10 A100

Water intake (mL/day)

0.008

Final body weight (gram)

350

30 20 10 0 Control A10 A100

mixture2

Mineral mixture2

Similar body weight gain and food intake were observed for three groups during experimental period.
*

mixture

1 Mean + SEM; n= 6 Liver Epididymal fat Abdominal fat

* (P<0.069) vs Control

Hypotensive effect of adenosine administration

Systolic blood pressure (mmHg)
240

Plasma kidney function parameters and lipid levels

Blood urea nitrogen (mg/dL) Creatinine (mg/dL)
16
# #

Adenosine improves plasma adiponectin and hepatic mRNA AdipoR2 levels

Adiponectin (g/mL)
10 8 6 4 2 0 4 3 2 1 0 Control Ad 10 Ad 100 Control Ad 10 Ad 100

200 160 120 80 6 7 8 9 10 11 age (week) 12 13 14

Control A10 A100

12 8 4 0 Control 100 A10 A100

0.8 0.6 0.4 0.2 0.0 Control A10 A100

#

*
Adipose tissue

Plasma adiponectin level

Hepatic mRNA AdipoR2 level Insulin resistance

Nitric oxide (mol/L)

8 6 4 2 0 Control A10 A100

Plasma lipid levels (mg/dL)

80 60 40 20 0 TG
#

* * * * *
TC

* (P<0.05) vs Control
#

(P<0.01) vs Control Control Ad10 Ad100

HDL-cholesterol LDL-cholesterol

Adenosine improves plasma glucose and insulin levels

Insulin (ng/mL)
180

Oral glucose tolerance test parameters

250

AdipoR2 relative mRNA level

The systolic BP of both adenosine groups showed a significant reduction compared control group beginning at 7th weeks of age until the end of the experimental period

Conclusion
Adenosine

Glucose (mg/dL)

Glucose (mg/dL)

200 150 100 50 0

Insulin (ng/mL)

4 3 2 1 0
# #

160 140 120 100 Control 20

2 1 0

* *
#

Insulin sensitivity Plasma adiponectin and hepatic mRNA AdipoR2 level

120

A10

A100

Control

A10

A100

30

60

120

30

60

time after administration (h)

10000

time after administration (min)

Blood pressure
# #

iAUC glucose

HOMA-R

15 10 5 0 Control

250

Improvement glucose metabolism

Improvement lipid metabolism

6000 4000 2000 0

iAUC insulin

8000

200 150 100 50 0 Control A10 A100

# #

Beneficial to improve the metabolic syndrome-related diseases parameters

A10

A100

Control

A10

A100