Antihyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats.
OBJECTIVE
In the present study, we use valsartan, a highly selective antagonist for angiotensin(1) (AT(1)) receptor subtype, to investigate the effect of AT(1) receptor on the plasma glucose metabolism in streptozotocin-induced diabetic rats (STZ-diabetic rats).


METHODS
The plasma glucose concentration was assessed by glucose oxidase method and plasma insulin was measured using enzyme-linked immunosorbent assay. Systolic blood pressure (SBP) was determined by the tail-cuff method. The intravenous glucose challenge test (IVGCT) was carried out to evaluate the effect of valsartan on the glucose utilization in vivo. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis. Moreover, the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis.


RESULTS
A single intravenous injection of valsartan decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Plasma glucose-lowering action of valsartan also observed in normal rats although in a way not so effective as that in STZ-diabetic rats. Valsartan at the dose of 0.2 mg/kg that produced the maximal plasma glucose-lowering activity in STZ-diabetic rats is also effective to lower the SBP. However, oral treatment with nifedipine or nicorandil in STZ-diabetic rats at the dose sufficient to decrease SBP showed no change of plasma glucose. Otherwise, infusion of saralasin (10 microg/kg per min) into STZ-diabetic rats produced a plasma glucose-lowering activity similar to that by valsartan at 0.2 mg/kg. Moreover, valsartan (0.2 mg/kg) significantly attenuated the raise of plasma glucose induced by IVGCT in normal rats. Repeated intravenous administration of valsartan (0.2 mg/kg) in STZ-diabetic rats resulted in the lowering of plasma glucose after 3 days. The mRNA and protein levels of GLUT4 in the soleus muscle were increased after repeated intravenous administration of valsartan in STZ-diabetic rats for 3 days. Moreover, similar repeated treatment with valsartan reversed the elevated mRNA and protein levels of PEPCK in the liver of STZ-diabetic rats.


CONCLUSIONS
These results suggest that the plasma glucose-lowering activity of AT(1) receptor antagonism was associated with an increase in the glucose utilization in peripheral tissue and/or a reduction in hepatic gluconeogenesis in the absence of insulin.
Chan
Paul
P
Divison of Cardiovascular Medicine, Graduate Institute of Medical Science, Taipei Medical University, Taipei City, Taiwan, ROC.
Wong
Kar-Lok
KL
Liu
I-Min
IM
Tzeng
Thing-Fong
TF
Yang
Tzu-Lin
TL
Cheng
Juei-Tang
JT
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006943:Hyperglycemia / Q000188:drug therapy*; D008099:Liver / Q000201:enzymology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012504:Saralasin / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495694:Slc2a4 protein, rat; D013777:Tetrazoles; D020108:Nicorandil; D000068756:Valsartan; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D012504:Saralasin; D014633:Valine; D009543:Nifedipine