The myocardial cross-talk between Angiotensin II (Ang II) and Endothelin-1 (ET-1). Role of the reactive oxygen species (ROS)

14. AIELLO EA, VILLA-ABRILLE MC, CORNELLI M, NOLLY A, CINGOLANI HE

Washington, DC, EEUU

Congreso; 59th Annual Fall Conference and Scientific sessions of the Council for High Blood Pressure Research,; 2005

AHA

Many of the effects thought to be due to Ang II are due to the release/formation of ET-1. In isolated rat myocytes, neonates and adults, it has also been demonstrated that Ang II induce release/formation of ET-1. ET-1 in an autocrine fashion triggers intracellular signals leading to an increase in inotropism. Experiments were performed in cat isolated ventricular myocytes in which sarcomere shortening was measured to asses contractility after pharmacological interventions and the effect of Ang II and ET-1 on inotropism were analyzed (all the data are expressed as percentage change from control). A pilot dose-effect curve to Ang II shows that a maximal effect is achieved at 100 nM with an increase of 70.5±7.7% (n=6, p<0.05). The AT1 selective blocker, Losartan (10 mM), abolished this effect (-2.6±6.6%, n=5). The non-specific blocker of the endothelin (ET) receptors TAK044 decreased the maximal effect (Ang II 100 nM) to 43±8.8% (n=6, p<0.05). The effect of 1 nM Ang II (29.2±3.7%, n=11, p<0.05) was completely abolished by AT1 (-6.1±3.5, n=4) or ET receptors (-4.5±4.9, n=6) blockade. These data suggest that the effects of doses of Ang II that increase inotropism in ~30 % (acting through AT1 receptors) are entirely due to ET, whereas at doses inducing higher effects the increase in contractility is also mediated through other mechanisms. The increase in contractility induced by 1 nM Ang II (the ET-sensitive component) was abolished by the ROS scavenger N-(2-mercaptopropionyl)glicine (MPG, 1 mM) (-8.4±3.8%, n=6) indicating that ROS are involved in the cross-talk between Ang II and ET. MPG decreased the effect of 100 nM Ang II in a magnitude similar to TAK044 (30.1±7.1%, n=6, p<0.05). The positive inotropic effect of an equipotent dose of exogenous ET-1 (0.4 nM, 34.5±3.1, n=5, p<0.05) was also inhibited by MPG (10.4±4.2%, n=7, p<0.05), indicating that ROS are targeting ET-1 intracellular signals leading to the increase in contractility. Taking together, the results allow us to conclude that Ang II induces (through its AT1 receptor) release/formation of ET-1 which acting in autocrine fashion on ET receptors of the isolated myocytes produces increase in inotropism through ROS mediated intracellular signals