Efeitos da interação da doxiciclina e adrenomedulina na embolia pulmonar aguda em ovinos anestesiados

As metaloproteinases de matriz extracelular (MMPs) podem limitar a vasodilatação pulmonar e os efeitos inotrópicos positivos promovidos pela adrenomedulina durante a hipertensão pulmonar. O presente estudo teve por objetivo avaliar os efeitos da administração combinada da doxiciclina (inibidor não seletivo das MMPs) e da adrenomedulina sobre as alterações hemodinâmicas observadas durante a embolia pulmonar aguda em ovinos. Alterações hemodinâmicas e respiratórias foram mensuradas em ovinos anestesiados, pré-tratados com doxiciclina (10 mg/kg por via intravenosa), submetidos à EPA induzida pela injeção intravenosa (IV) de microesferas de silicone (500 mg) e posteriormente tratados com solução salina (grupo Dox+PE) ou adrenomedulina (50 ng/kg/min) (grupo Dox+PE+Adm). Os resultados deste estudo foram comparados com grupos históricos recentemente publicados por nosso grupo de pesquisa, realizados sob as mesmas condições experimentais, onde foram utilizados ovinos anestesiados não submetidos a qualquer intervenção (grupo Sham) ou submetidos à EPA e tratados com solução salina (grupo PE) ou com adrenomedulina (50 ng/kg/min) (grupo PE+Adm). Doxiciclina não produziu efeitos adicionais sobre as diminuições significativas no índice de resistência vascular pulmonar e aumento no índice cardíaco (ambos em 25%) observadas com o uso da adrenomedulina (grupo PE+Adm). A administração da adrenomedulina (grupo PE+Adm e Dox+PE+Adm) diminuiu significativamente a pressão arterial média e o índice de resistência vascular sistêmica, levando a uma hipotensão sistêmica moderada. Reduções significativas na pressão parcial de oxigênio arterial foram observadas após a doxiciclina e a EPA, que não foram afetadas pela administração da adrenomedulina. Estes resultados demonstram que a administração combinada da doxiciclina e adrenomedulina não traz benefícios hemodinâmicos adicionais quando comparada ao uso isolado da adrenomedulina, sugerindo que está combinação não se apresenta vantajosa durante a EPA induzida por microesferas.Matrix metalloproteinases (MMPs) may limit severely the pulmonary vasodilatory and inotropic effects of adrenomedullin during pulmonary hypertension. Hemodynamic and respiratory changes were measured in anesthetized bovine pre-treated with doxycycline (10 mg/kg intravenously), subjected to APE induced by intravenous injection of silicone microspheres (500 mg) and subsequently treated with physiological saline (Dox+PE group) or adrenomedullin (50 ng / kg / min) (Dox+PE+ Adm group). The results were compared with historical group recently published by our research group, carried out under the same experimental conditions, where anesthetized sheep were used not subjected to any intervention (Sham group) or subjected to APE, and treated with physiological saline (PE group) or with adrenomedullin (50 ng / kg / min) (PE+Adm Group). Doxycycline produced no effect on significant temporal decreases in pulmonary vascular resistance index and increases in cardiac index (both by 25%) observed with adrenomedullin. The administration of adrenomedullin significantly decreased mean arterial pressure and systemic vascular resistance index, leading to a moderate systemic hypotension. Significant decreases in arterial oxygen partial pressure were observed after doxycycline or APE, but these changes were not affected by adrenomedullin. These results demonstrate that the combined administration of doxycycline and adrenomedullin does not provide additional hemodynamic benefits when compared to isolated use of adrenomedullin, suggesting that this combination does not appear advantageous for the APE-induced microspheres.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Adrenomedullin induces pulmonary vasodilation but does not attenuate pulmonary hypertension in a sheep model of acute pulmonary embolism

The pulmonary vasodilation induced by adrenomedullin may be beneficial in the acute pulmonary embolism (APE) setting. This study examined effects of adrenomedullin in sheep with microsphere-induced APE. Twenty four anesthetized, mechanically ventilated sheep were randomly assigned into 3 groups (n=8 per group): animals not subjected to any intervention (Sham), animals with APE induced by microspheres (500mg, intravenously) treated 30min later by intravenous physiological saline (Emb group) or intravenous adrenomedullin (50ng/kg/min) during 30min (Emb+Adm group). Plasma concentrations of cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Variables did not change over time in sham animals. In both embolized groups, microsphere injection significantly (P<0.05) increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) from baseline by 181% and 111-142%, respectively (% change in mean values). Adrenomedullin significantly decreased PVRI (18%-25%) and significantly increased cardiac index (22%-25%) from values recorded 30min after APE (E30), without modifying MPAP. Adrenomedullin decreased mean arterial pressure (18%-24%) and systemic vascular resistance index (32%-40%). Embolization significantly increased arterial-to-end tidal CO2 gradient, alveolar-to-arterial O2 gradient, and pulmonary shunt fraction from baseline, but these variables were unaffected by adrenomedullin. While adrenomedullin significantly increased plasma cAMP, cGMP levels were unaltered. Adrenomedullin induces systemic and pulmonary vasodilation, possibly via a cAMP mediated mechanism, without modifying the gas exchange impairment associated with APE. The pulmonary anti-hypertensive effect of adrenomedullin may be offset by increases in cardiac index.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP