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Comparison of the Oral Angiotensin II Receptor Antagonist UP 269–6 or Enalapril 20 mg on Blood Pressure and Neurohormonal Effects in Salt-Deplete Man

1995; Lippincott Williams & Wilkins; Volume: 25; Issue: 6 Linguagem: Inglês

10.1097/00005344-199506000-00020

1533-4023

Martin McIntyre, Robert J. MacFadyen, Peter Meredith, Joël Ménard, Hans R. Brunner, Jesús Insuasty, John L. Reid,

Electrolyte and hormonal disorders

We compared the response of the oral angiotensin II (Ang II) receptor antagonist (ARA) UP 269–6 with an angiotensin converting enzyme inhibitor (ACEI) enalapril 20 mg or placebo, during salt depletion in normal men. We also evaluated safety and tolerability. Sixteen healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Seven different doses of UP 269–6 (5, 10, 20, 40, 80, 120 and 180 mg) were administered double blind in a four-panel dose escalation, with enalapril and placebo randomised within each panel. Supine and erect blood pressure (BP) and heart rate (HR); serum and urinary electrolytes; plasma active renin (PAR), aldosterone, and Ang II were measured at intervals. Urinary electrolytes and aldosterone were measured for the 24 h before dosing and for 24 h after dosing. Dizziness and light-headedness on standing were reported after UP 269–6 at higher doses. Enalapril caused one episode of symptomatic postural hypotension. No other drug-related adverse events (AE) were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with UP 269–6 at ±40 mg, with no change in HR. Based on the maximal decrease in mean arterial pressure (MAP), UP 269–6 at 180 mg had an effect largely comparable to that of enalapril 20 mg. There was a dose-related increase in PAR with UP 269–6. Although this was greater with UP 269–6 180 mg than with enalapril, serum and 24-h urinary aldosterone suppression was greater with enalapril than with any dose of UP 269–6. There was a dose-related increase in Ang II, with the expected decrease after enalapril. Our results indicate a clear BP and hormonal dose-response relation for UP 269–6. The BP-lowering effect is observed starting with the 40-mg dose. Based on the maximal decrease in MAP, UP 269–6 180 mg is largely comparable to enalapril 20 mg.