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.

Conclusion: 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.