Effects of angiotensin and angiotensin-converting enzyme inhibition on hepatic, and renal perfusion, organ function, and on the hepatic arterial buffer response in septic and healthy animals

Abstract

Mortality in sepsis remains unacceptably high and its incidence still tends to progressively increase. The renin-angiotensin system (RAS) plays a major role in cardiovascular homeostasis, and, currently, several actions, beyond the blood pressure control are known. Proinflammatory effects, procoagulant activity, and potential induced endothelial dysfunction and organ failure were already attributed to this substance. In addition, other possible deleterious effects over liver flow, renal and cardiac functions, reduced the initial interested over its possible use as a vasopressor agent in sepsis. Mitochondrial dysfunction has been considered one of the possible causes of sepsis progression, in spite of adequate treatment. Last years, a crescent number of publications have reported possible interactions between angiotensin and mitochondrial function, including the existence of a local and independent RAS. Classical data about negative effects of noradrenalin in sepsis; present subanalysis of large clinical trials suggesting negative impacts in mortality after higher doses; by the other hand, recent experimental evidence of beneficial effect of angiotensin in renal function (in spite of reduced local flow), and the University of Bern group experience on positive effects of angiotensin II over the mitochondrial function in sepsis, justify a new research to definitely clarify the existence or not of beneficial effects of this substance as a vasopressor agent in sepsis. SPECIFIC AIMS: a) Phase 1: to study the impact of progressive higher doses of angiotensin II and Enalapril in: regional flows, regional metabolism, and mitochondrial function, in healthy pigs. b) Phase 2: in septic animal, treated following the SSC international guidelines compare the effects of noradrenalin versus angiotensin versus noradrenalin + enalapril in: regional flows, regional metabolism, mitochondrial function, and mortality. METHODS: a) * Phase 1: 14 healthy pigs, 35 - kg, randomized to progressively higher doses of enalapril or angiotensin II; * phase 2: 24 pigs after abdominal sepsis (peritonitis), 35 - 40 kg, randomized to 3 different treatment groups: noradrenalin, angiotensin II or noradrenalin + enalapril, by 48h. b) Approval obtained by the cantonal Ethics Committee, and all experiments to be realized in the Experimental Surgical Unit - Inselspital / Bern Universität. c) General anesthesia as in ICU (Propofol / Fentanil), full monitoring, flow measurements by Doppler (portal vein, hepatic artery, femoral artery, and carotid artery), regional metabolism (O2, CO2, lactate, and glucose, hepatic, renal, cardiac and renal), mitochondrial function (respiration and tissue ATP measurements), and additional serum angiotensin II levels and angiotensin-converting enzyme activity. GRANTS: All experiment expenses will be fully covered by Bern Universität, including partial financial support for the researcher Adriano José Pereira (SFr 4'500.00). Application for complementary financial support requested to FAPESP. PERSPECTIVES: It is intended with the Bern Universität group experience in mitochondrial function studies in sepsis as well in harmful effects of Noradrenalin in sepsis, allied with the requester researcher experience in the study of regional metabolism and flows in sepsis as well in other models of tissue hypoxia, enable proper and definitely answers about the real effects of Angiotensin in sepsis. If the positive effects in renal function be confirmed, the harms to hepatic flow overcame by hepatic artery buffer response, and the effects over other organ functions are minimal, this drug will deserve be tested soon in a clinical trial in human beings. (AU)