INHIBITION OF TISSUE ANGIOTENSIN-CONVERTING ENZYME-ACTIVITY PREVENTS MALIGNANT HYPERTENSION IN TGR(MREN2)27

Background Activation of the renin-angiotensin system has been implica ted strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a dire ct effect on the vascular wall by initiating fibrinoid necrosis and my ointimal proliferation, Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heteroz ygotes (HanRen2/Edin--) have previously been shown to develop malignan t hypertension spontaneously and exhibit the characteristic features o f human malignant hypertension, Objective Tissue renin-angtiotensin sy stems have been implicated in the pathogenesis of malignant hypertensi on, We set out to determine whether inhibition of this system might pr otect against development of the disease in a rat model,Method Male TG R(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 mu g/kg per d ay) from 28 to 120 days of age, untreated rats acting as controls (n = 40), The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treat ment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. Results Sixty-three pe r cent of control rats and 4% of angiotensin converting enzyme inhibit or-treated rats had developed malignant hypertension by 120 days despi te there having been no significant difference in systolic blood press ure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats, The degree of m edial wall thickening did not differ between the two groups whereas ev idence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angio tensin converting enzyme inhibitor-treated group, Conclusions Tissue a ngiotensin converting enzyme inhibition at a non-hypotensive dose almo st completely prevented mortality from malignant hypertension and sign ificantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' ag ent in malignant hypertension, (C) 1998 Lippincott-Raven Publishers.