RESUMEN
INTRODUCTION: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. METHODS: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. RESULTS: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. DISCUSSION/CONCLUSIONS: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.
Asunto(s)
Presión Arterial/efectos de los fármacos , Cistamina/farmacología , Inhibidores Enzimáticos/farmacología , Hipertensión Pulmonar/prevención & control , Hipoxia/tratamiento farmacológico , Proteína Glutamina Gamma Glutamiltransferasa 2/antagonistas & inhibidores , Arteria Pulmonar/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/complicaciones , Hipoxia/enzimología , Hipoxia/fisiopatología , Masculino , Ratones Endogámicos C57BL , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Arteria Pulmonar/enzimología , Arteria Pulmonar/fisiopatología , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/prevención & control , Ratas Wistar , Remodelación Vascular/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
UNLABELLED: Pulmonary hypertension (PH) worsens the prognosis in chronic obstructive pulmonary disease (COPD). The diagnosis of PH is established by right heart catheterisation (RHC), while echocardiography can be used for screening. We aimed to asses the outcome of echocardiographic screening for PH in a group of stable COPD out-patients, and to evaluate NT-proBNP as a first line screening tool. Criteria for PH on echocardiography were a tricuspid regurgitation pressure gradient > 40 mmHg, a tricuspid annular plane systolic excursion < 1.8 cm or right ventricular dilatation. Positively screened patients were asked to undergo RHC. Results (Mean ± SEM): 16 of 117 patients (14%) had PH on echocardiography. They had a higher mortality (hazard ratio for death: 2.7 ± 1.3, p = 0.037) and lower six minute walk test (224 ± 33 vs. 339 ± 15, p = 0.006). NT-proBNP below 95 ng/l excluded PH on echocardiography with a negative predictive value of 100 (95% CI: 89-100%). RHC was obtained in six patients screened positive. In three of these, PH was not confirmed. CONCLUSIONS: Signs of PH on echocardiography as defined here was found in 14% and had prognostic significance in COPD. A value of NT-proBNP less than 95 ng/l may be used to exclude signs of PH.