RESUMEN
Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.
Asunto(s)
Endotelio Vascular/efectos de los fármacos , Ejercicio Físico , Insuficiencia Cardíaca/tratamiento farmacológico , Hiperventilación/etiología , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Ventilación Pulmonar/efectos de los fármacos , Reflejo/efectos de los fármacos , Sulfonas/uso terapéutico , Vasodilatadores/uso terapéutico , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiopatología , Dióxido de Carbono/metabolismo , Estudios de Casos y Controles , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Endotelio Vascular/fisiopatología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Hiperventilación/tratamiento farmacológico , Hiperventilación/metabolismo , Hiperventilación/fisiopatología , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Consumo de Oxígeno/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Purinas/farmacología , Purinas/uso terapéutico , Pruebas de Función Respiratoria , Citrato de Sildenafil , Sulfonas/farmacología , Resultado del Tratamiento , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.
Asunto(s)
Aspirina/uso terapéutico , Fibrinolíticos/uso terapéutico , Infarto del Miocardio/prevención & control , Isquemia Miocárdica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Animales , Arritmias Cardíacas/prevención & control , Aspirina/análogos & derivados , Creatina Quinasa/sangre , GMP Cíclico/sangre , Hemodinámica/efectos de los fármacos , Masculino , Reperfusión Miocárdica , NG-Nitroarginina Metil Éster/farmacología , Peroxidasa/sangre , Ratas , Ratas WistarRESUMEN
BACKGROUND: A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency. METHODS: In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species. RESULTS: The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity. CONCLUSIONS: In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.