RESUMEN
BACKGROUND: Because plasma levels of adenosine are increased in patients with chronic heart failure (CHF), we examined adenosine concentrations in the plasma and heart and assessed the activity of ecto-5'-nucleotidase in the plasma and ventricular myocardium in patients with CHF. METHODS AND RESULTS: We studied 36 patients with CHF (New York Heart Association Class I/II/III/IV, 9/8/12/7). Twenty-five subjects without CHF were used as controls. Both plasma adenosine levels and ecto-5'-nucleotidase activity were significantly higher in patients with CHF (219 +/- 28 nmol/L and 0.72 +/- 0.03 nmoL/mg protein/min, respectively) than in control subjects (71 +/- 8 nmol/L and 0.54 +/- 0.02 nmoL/mg protein/min, respectively). Plasma adenosine levels sampled from the coronary sinus were significantly higher than from the aorta in patients with CHF, but these differences were not observed in control subjects. Ecto-5'-nucleotidase protein levels were markedly increased in the ventricular myocardium in patients with CHF. CONCLUSIONS: These increases in ecto-5'-nucleotidase in the plasma and myocardium may contribute to increased plasma and cardiac adenosine levels. The increased ecto-5'-nucleotidase activity and adenosine levels in blood may become an index of the presence or severity of CHF.
Asunto(s)
5'-Nucleotidasa/sangre , Insuficiencia Cardíaca/enzimología , Miocardio/enzimología , 5'-Nucleotidasa/metabolismo , Adenosina/sangre , Adenosina/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estudios de Casos y Controles , Femenino , Expresión Génica , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/enzimología , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Volumen SistólicoRESUMEN
OBJECTIVES: We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts. BACKGROUND: Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts. METHODS: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery. RESULTS: Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF. CONCLUSIONS: The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.