A comparison of the hypotensive and hypoglycaemic actions of an angiotensin converting enzyme inhibitor, an AT1a antagonist and troglitazone.
OBJECTIVE
To define the relationship between changes in insulin sensitivity and attenuation of hypertension.


METHODS
We investigated whether troglitazone (CS-045, an insulin sensitizer) has an antihypertensive effect in fructose (FRU)-fed Wistar rats with insulin resistance and simultaneously compared its hypotensive efficacy with those of alacepril (ALA, an angiotensin converting enzyme inhibitor) and TCV-116 (an AT1a receptor antagonist). Male rats aged 8 weeks were divided into five groups: controls fed normal chow, a FRU group fed FRU-rich (55%) chow, a FRU plus ALA group fed 30 mg/kg ALA per day, a FRU plus TCV-116 group fed 1 mg/kg TCV-116 per day and a FRU plus CS-045 group fed 70 mg/kg CS-045 per day). After 8 weeks, the body weight and systolic blood pressure were recorded and glucose tolerance was determined by glucose loading (2 g/kg, intraperitoneally) and a steady-state plasma glucose (SSPG) method. The plasma membrane glucose transporter 4 content in gastrocneumius muscle was determined by Western blot analysis.


RESULTS
FRU increased blood pressure from 125 mmHg in controls to 141 mmHg (P < 0.01). ALA and TCV-116 administration decreased blood pressure to 111 and 107 mmHg, respectively (P < 0.01). CS-045 administration lowered blood pressure significantly to 121 mmHg. Area under the curve levels for plasma insulin during glucose loading increased from 1.7 in controls to 3.6 ng/ml x h in FRU-fed rats, but were lowered by the three drugs. SSPG levels increased from 12.5 in controls to 18.3 mmol/l in FRU-fed rats (P < 0.01), but were decreased by ALA and TCV-116 administration (P < 0.01). CS-045 administration also lowered SSPG levels to 15.3 mmol/l (P < 0.05). FRU-feeding induced a 1.24-fold increase in plasma membrane glucose transporter 4, which was not affected by ALA and TCV-116 administration, but was augmented 1.82-fold by CS-045 administration. Furthermore, the increased triglyceride level after FRU was diminished both by ALA and by CS-045 administration.


CONCLUSIONS
These results suggest that, in the insulin-resistant state, troglitazone, an angiotensin converting enzyme inhibitor and an AT1a receptor antagonist show comparable hypotensive and hypoglycaemic effects.
Chen
S
S
Fourth Department of Medicine, Saitama Medical School, Japan.
Noguchi
Y
Y
Izumida
T
T
Tatebe
J
J
Katayama
S
S
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D004032:Diet; D005632:Fructose / Q000008:administration & dosage; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D002839:Chromans; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D013777:Tetrazoles; D013844:Thiazoles; D045162:Thiazolidinediones; D005632:Fructose; D002216:Captopril; D000077288:Troglitazone; C077793:candesartan cilexetil; C046835:alacepril