Effects of angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist on the insulin resistance and pressor mechanism of insulin in essential hypertension

To investigate the mechanism in which angiotensin converting enzyme (ACE) inhibition increases insulin dependent glucose disposal (insulin sensitivity) in essential hypertension, we examined the effect of ACE inhibitor (delapril) and angiotensin II receptor antagonist (TCV-116) on insulin sensitivity in essential hypertensives (EHT). Effects of these drugs on the sodium retaining action and activation of pressor system by hyperinsulinemia, which might relate to pressor mechanisms in EHT, were also investigated in this study. Fifteen EHT and 18 age- and body mass index- matched normotensive controls (NT) were all hospitalized and 2-hour euglycemic hyperinsulinemic glucose clamp (GC) was performed in a fasting condition. After 2 weeks' control period, 7 EHT were treated with delapril (120 mg/day) and 8 EHT, with TCV-116 (8 mg/day) for 2 weeks. At the end of the treatment period, GC was repeated in these two groups. Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose during hyperinsulinemia by GC. Blood and urine samples were collected before and during the hyperinsulinemia. In the control period, M value was lower in EHT than in NT. Hyperinsulinemia by GC decreased urinary sodium excretion (UNaV) and fractional excretion of sodium (FENa), and increased plasma norepinephrine (PNE) and plasma renin activity (PRA) in EHT. Plasma aldosterone concentration (PAC) tended to increase during hyperinsulinemia. After delapril or TCV-116 treatment in EHT, mean blood pressure (MBP) significantly decreased and M-value significantly increased to the ranges of those parameters in NT. No significant difference was observed in MBP and M value between the delapril treated group and the TCV-116 treated group either before or after the treatments. In addition, under both treatments, the decreases in UNaV and FENa during the hyperinsulinemia were significantly suppressed. The increases in PNE and PRA during the hyperinsulinemia were observed even under these treatments; the rises of PRA tended to increase, but the rises of PAC tended to decrease comparing to those before the treatments. There was no significant difference in UNaV, FENa, PNE, PRA or PAC between the delapril treated group and the TCV-116 treated group either before or after the treatments. Furthermore, these changes during hyperinsulinemia were not significantly different between the two groups. In summary, (1) both delapril and TCV-116 improve insulin sensitivity in EHT to the level of that in NT, (2) both the treatments attenuate the sodium retaining action of hyperinsulinemia and (3) there were no statistically significant differences in these effects between delapril treatment and TCV-116 treatment. These findings suggest that inhibition of angiotensin II production by ACE inhibitor can play a major role in improvement of insulin sensitivity and inhibit sodium retaining action by hyperinsulinemia in EHT