Ramipril in angina pectoris: short-term effects on glucose, insulin, C-peptide, adrenocorticotropic hormone, and cortisol levels

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We studied the effects of the angiotensin-converting enzyme inhibitor ramipril on plasma levels of adrenocorticotropic hormone (ACTH), cortisol, glucose, insulin, and C-peptide in patients with coronary artery disease. Patients were randomly assigned to treatment with ramipril 5 mg once daily, ramipril 5 mg once daily in combination with 20 mg of the oral nitrate isosorbide dinitrate (ISDN), ISDN alone 20 mg twice daily, or placebo. After a 72-hour washout period from their previous vasoactive medication, 32 patients (1 woman, 31 men) aged 42 to 72 years (mean age, 63.3 years) received a single dose of the study medication. Plasma levels of ACTH, cortisol, glucose, insulin, and C-peptide were measured before drug administration and 1, 2, 3, 4, 5, 6, 8, and 24 hours after drug administration. After the initial 24-hour treatment period, a randomized, double-masked, placebo-controlled, four-way, crossover phase started in which each patient was treated with each study medication for 1 week. Individual treatment phases were separated by weekly washout periods, and plasma levels of insulin, C-peptide, and glucose were assessed in the morning at trough and 3 hours after intake of the study medication. The typical circadian variation was observed for cortisol, without any difference between the four treatment groups. On average, ACTH levels were significantly higher in the patients treated with ISDN alone. No significant effect on glucose, insulin, or C-peptide levels was observed among patients receiving the first dose of ramipril, ISDN, ramipril + ISDN, or placebo, nor between the crossover phases during continued treatment. We conclude that in patients with angina pectoris, a single dose of ramipril has no acute effects on insulin secretion and glucose utilization, nor does multiple dosing of ramipril affect glucose hemeostasis. Ramipril also did not affect circadian cortisol secretion. These findings also pertain to the combination of ramipril and ISDN. In contrast, after administration of a single dose of ISDN alone, a statistically significant increase in ACTH levels was observed. The increase in ACTH levels could be a marker for sympathetic nervous system activation resulting from counterregulation.