Abstract-There is uncertainty about the contribution of angiotensin-converting enzyme (ACE) to angiotensin II formation, with recent studies suggesting that non-ACE enzymes may be the predominant pathway of angiotensin II formation in kidney, heart, and lung. To investigate the role of ACE in angiotensin II formation, we measured angiotensin I and II levels in blood, kidney, and heart of 2 mouse genetic models (ACE.1 and ACE.4) of reduced somatic ACE gene expression and in blood, kidney, heart, lung, adrenal, and brain of mice administered the ACE inhibitor lisinopril. We also measured the levels of bradykinin (1-9) and its ACE metabolite bradykinin (1-7). Reduced ACE gene expression and ACE inhibition had similar effects on angiotensin and bradykinin peptide levels. Angiotensin II levels were reduced by 70% to 97% in blood, 92% to 99% in kidney, 93% to 99% in heart, 97% in lung, and 85% in adrenal and brain. The marked reductions in angiotensin II/angiotensin I ratio indicated that ACE was responsible for at least 90% of angiotensin I conversion to angiotensin II in blood, kidney, heart, lung, and brain, and at least 77% in adrenal.Blood bradykinin (1-9) levels were increased 6.4-fold to 8.4-fold. Heart bradykinin (1-9) levels were increased in ACE.4 mice and the bradykinin (1-7)/bradykinin (1-9) ratio was reduced in kidney and heart of ACE.4 mice and heart of lisinopril-treated mice. These studies demonstrate that ACE is the predominant pathway of angiotensin II formation in blood and tissues of mice and plays a major role in bradykinin (1-9) metabolism in blood and, to a lesser extent, in kidney and heart. Key Words: mice Ⅲ angiotensin-converting enzyme Ⅲ angiotensin I Ⅲ angiotensin II Ⅲ bradykinin A ngiotensin-converting enzyme (ACE) inhibitors are of established benefit for the treatment of cardiovascular and renal disease. However, there is continuing uncertainty about the mechanism of their therapeutic benefit and the effect of ACE inhibition on angiotensin II levels. Many patients receiving ACE inhibitor therapy fail to show reduction in angiotensin II levels, leading to the proposal that alternate enzymes such as chymase may convert angiotensin I to angiotensin II. 1 In support of this proposal, Wei et al 2 reported that although plasma angiotensin II levels of ACE gene knockout (KO) mice were reduced to below the limit of detection, angiotensin II levels in kidney, heart, and lung of ACE KO mice were no different from the levels in wild-type (WT) mice. These authors also reported that chymase levels were increased 14-fold in kidney and 1.5-fold in heart of ACE KO mice, in comparison with WT mice, and they suggested that prolonged suppression of ACE activity may lead to the induction of alternate enzymatic pathways of angiotensin II formation in tissue. 2 We and others have shown that ACE inhibition produces marked reduction in angiotensin II levels in blood and tissues of rats and humans. [3][4][5][6] However, ACE inhibition is reported to have variable effects on angiotensin II levels in mice. 7 To fu...

The impact of endotoxemia on cerebral endothelium and cerebral blood flow (CBF) regulation was studied in conscious newborn lambs. Bacterial endotoxin [LPS, 2 microg/kg iv] was infused on 3 consecutive days. Cerebrovascular function was assessed by monitoring CBF and cerebral vascular resistance (CVR) over 12 h each day and by the endothelium-dependent vasodilator bradykinin (BK) (n = 10). Inflammatory responses were assessed by plasma tumor necrosis factor-alpha (TNF-alpha, n = 5). Acutely, LPS disrupted the cerebral circulation within 1 h, with peak cerebral vasoconstriction at 3 h (CBF -28 and CVR +118%, P < 0.05) followed by recovery to baseline by 12 h. TNF-alpha and body temperature peaked approximately 1 h post-LPS. BK-induced vasodilatation (CVR -20%, P < 0.05) declined with each LPS infusion, was abolished after 3 days, and remained absent for at least the subsequent 5 days. Histological evidence of brain injury was found in four of five LPS-treated newborns. We conclude that endotoxin impairs cerebral perfusion in newborn lambs via two mechanisms: 1) acute vasoconstriction (over several hours); and 2) persistent endothelial dysfunction (over several days). Endotoxin-induced circulatory impairments may place the newborn brain at prolonged risk of CBF dysregulation and injury as a legacy of endotoxin exposure.