Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27

BACKGROUND: Activation of the renin-angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin- -) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. OBJECTIVE: Tissue renin-angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. METHOD: Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 microg/kg per day) 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 treatment; 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 per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure 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 medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. CONCLUSIONS: Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' agent in malignant hypertension.