EFFECTS OF CHRONIC ANGIOTENSIN CONVERTING ENZYME-INHIBITION ON GLUCOSE-TOLERANCE AND INSULIN SENSITIVITY IN ESSENTIAL-HYPERTENSION

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49+/-1 years; body mass index (BMI), 26.1+/-0.4 kg/m2) with essential hypertension (blood pressure, 155+/-3/105+/-1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril, 5 mg/day). Furthermore, a two-step euglycemic insulin clamp was performed after placebo and again at the end of treatment. Blood pressure fell by 7+/-4/10+/-3 mm Hg (p<0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470 pM) whole body glucose use averaged 42.5+/-1.6-mu-mol . min-1 . kg-1 before and 43.6+/-1.9 after ACE inhibition (p=NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p<0.05) improved after treatment (area under OGTT curve (AUC), 240+/-24 versus 282+/-23 mmol 2 hr . l-1). The latter change was associated with enhanced (+16%, p<0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75+/-0.05 and 0.92+/-0.05 mmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p<0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/l, p<0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (-22%, p<0.01) and ACE inhibition (-21%, p<0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r=0.60, p<0.005). In conclusion, in essential hypertension 1) chronic ACE inhibition does not interfere with insulin's effect on glucose uptake, substrate oxidation, or thermogenesis, but causes resistance to the potassium-lowering action of insulin; 2) this electrolyte change is associated with heightened insulin secretory response to glucose stimulation and improved oral glucose tolerance; and 3) higher plasma potassium levels predict a better blood pressure response to ACE inhibition.