Changes critical to persistent lowering of arterial pressure in spontaneously hypertensive rat occur early in antihypertensive treatment

Abstract

Angiotensin-converting enzyme inhibition (ACEI) in adult spontaneously hypertensive rats (SHRs) produces reductions in mean arterial pressure (MAP) and vascular structure that persist after treatment cessation. This study used an intermittent treatment strategy to determine the time course of changes in MAP, vascular resistance properties, and the tissue levels of endothelin. Adult SHRs were treated with enalapril and low sodium diet for three 2-week treatment cycles, each separated by 2-week washout periods. MAP was measured via radiotelemetry. Hindlimb structurally based vascular resistance properties were assessed after two treatment cycles. Endothelin was measured in mesenteric vessels, renal cortex and medulla in untreated SHR (Con), and at day 10 of the first and third treatment cycles. Treatment produced a persistent reduction in MAP; however, the magnitude of change in the 'off-treatment' level decreased following successive treatments (cycle 1: -15 ± 1.7%, cycle 2: -8 ± 1.9%, and cycle 3: -1 ± 1.7%). Reduction in hindlimb vascular structure after two cycles of treatment was not different from that previously observed after one cycle. Endothelin levels were significantly elevated during the third cycle in renal medulla (Con: 797 ± 102 pg/g tissue, cycle 1: 767 ± 81 pg/g tissue, cycle 3: 1097 ± 205 pg/g tissue) and mesenteric vessels (Con: 711 ± 226 pg/g tissue, cycle 1: 696 ± 231 pg/g tissue, cycle 3: 1063 ± 741 pg/g tissue). Concomitant treatment with an endothelin antagonist did not impact arterial pressure. These findings demonstrate that during ACEI treatment, most of the changes that confer persistent changes in MAP and vascular structure occur within the first 2 weeks. Elevation in endothelin levels is likely unrelated to arterial pressure.