Angiotensin II- Induced Negative Inotropy in Rat Ventricular Myocytes: Role of Reactive Oxygen Species and p38 MAPK

MARTIN GERARDO VILA PETROFF; PALOMEQUE, JULIETA; LUCIANA SAPIA; ROGER J. HAJJAR; MATTIAZZI, ALICIA

Keystone, Colorado USA

Congreso; 2nd Annual Symposium of the American Heart Association (AHA) Council on basic Cardiovascular Sciencies- Targeting Heart Failure: New Science, New Tools, New Strategies.; 2005

American Heart Association

ANGIOTENSIN II-INDUCED NEGATIVE INOTROPY IN THE RAT HEART: ROLE OF REACTIVE OXYGEN SPECIES AND P38 MAPK.   Vila Petroff M*,, Palomeque J*, Sapia L*, Hajjar RJ#, Mattiazzi A*. #CVRC, MGH, Harvard Boston; *Centro de Invest. Cardiovasculares La Plata Argentina   The octapeptide Angiotensin II (Ang II) can modulate cardiac contractility and is increased in heart failure, where contractile function is impaired. In rat cardiac myocytes, 1 µM Ang II produces a negative inotropic effect (NIE) (24.6 ± 5% reduction). However, the subcellular signaling involved in this effect, remains elusive. We examined the mechanisms and signaling events involved in the reduction in contractile function induced by the peptide in Indo-1-loaded rat cardiomyocytes.  The results showed that the NIE of Ang II was not associated with a parallel decrease in the intracellular Ca2+ transient, indicating that a decrease in myofilament responsiveness to Ca2+ underlies the reduction in contractility. We assessed the role of PKC, tyrosine kinases, reactive oxygen species (ROS) and MAPK's in the NIE of the peptide. Pretreatment of cells with the NAD(P)H oxidase inhibitor, DPI, or with the superoxide scavenger, Tiron, did not affect the Ang II-induced NIE. Moreover, Ang II-induced ROS production could not be detected using the fluorophore CM-H2DCFDA. In contrast, the Ang II induced NIE was abrogated by the inhibitors of PKC (calphostin C), tyrosine kinase (genistein) and p38 MAPK (SB202190). Furthermore, the NIE was significantly exacerbated (60 ± 10% reduction) by p38 MAPK overexpression. These results exclude the participation of ROS in the NIE of the peptide and point to PKC and tyrosine kinase as upstream mediators. Furthermore, they reveal p38 MAPK as the putative effector of the reduction in myofilament responsiveness to Ca2+ and the decrease in contractility induced by the peptide.