Hélène Charbonneau1, Marie Buléon, Vincent Minville, Stanislas Faguer, Jean-Pierre Girolami, Jean-Loup Bascands, Ivan Tack, Nicolas Mayeur. 1. 1Institut National de la Sante et de la Recherche Medicale (INSERM), U1048, Institut des maladies métaboliques et cardiovasculaires, Toulouse, France.2Université Paul Sabatier Toulouse III, Toulouse, France.3EA 4564 "Modélisation de l'agression tissulaire et nociceptive", Université Paul Sabatier, Toulouse, France.4Pôle Anesthésie-Réanimation,CHU Purpan, Toulouse, France.
Abstract
OBJECTIVES: Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice. DESIGN: In vivo study. SETTING: University research unit. SUBJECTS: C57/Bl6 mice. INTERVENTIONS: The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure. MEASUREMENTS AND MAIN RESULTS: During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups. CONCLUSIONS: During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.
OBJECTIVES:Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice. DESIGN: In vivo study. SETTING: University research unit. SUBJECTS: C57/Bl6 mice. INTERVENTIONS: The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure. MEASUREMENTS AND MAIN RESULTS: During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups. CONCLUSIONS: During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.