BCR-ABL Signaling emerge as potent novel antioxidant therapeutic possibilities

tal models BCR-ABL Signaling of disease. Based on recent studies, pharmacological inhibition of PARP or decomposition of peroxynitrite, which block the peroxynitrite DNA injury poly polymerase pathway emerge as potent novel antioxidant therapeutic possibilities in multiple pathophysiological conditions. Chronic treatment with PARP inhibitors PJ34 and INO 1001 for 2 months in a rodent model has been demonstrated to improve endothelial and cardiac dysfunction associated with aging showing the involvement of the nitro oxidative stress PARP pathway in the pathophysiology of cardiac and vascular aging. Considering the theoretical possibility of acutely interrupting this pathway by pharmacological inhibition of the PARP enzyme, thereby quickly restoring the ATP pools and the normal energy supply of the cells, we investigated in this study whether cardiac and vascular dysfunction at old age may be beneficially affected even by a single treatment course with a potent pharmacological inhibitor of PARP.
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. All procedures PI3-kinase and handling of animals during the investigations were reviewed and approved by the Ethical Committee of the Land Baden Wrttemberg for Animal Experimentation. Young adult and aging male Lewis rats were housed in a room at a constant temperature of 22 2 with 12 hours light/dark cycles and fed a standard laboratory rat diet and water ad libitum. Hemodynamic measurements Young and aging rats were anesthetized with thiopentone sodium, tracheotomized, intubated and artificially ventilated.
Animals were placed on controlled heating pads and core temperature measured via a rectal probe was maintained at 37. The thoracic cavity was opened to permit access to the apex of the heart. All incisions were kept to a minimum to avoid major blood loss. The left ventricle was punctured by a 20 G plastic cannula, through which a 2F microtip pressure volume catheter was inserted into the left ventricular cavity. Mean arterial pressure was measured via the right femoral artery. After stabilization for 5 minutes, the signals were continuously recorded using a pressure volume conductance system coupled to an A/D converter at a sampling rate of 1000 s, stored and displayed on a computer by the IOX Software System.
With the help of a special pressure volume analysis program mean arterial pressure, maximal left ventricular systolic pressure, left ventricular end diastolic pressure and developed pressure were computed and calculated. Left ventricular pressure volume relations were measured by transiently compressing the inferior vena cava. The slope of the left ventricular end systolic pressure volume relationships, preload recruitable stroke work and maximal slope of systolic pressure increment end diastolic volume relation were calculated as load independent indexes of left ventricular contractility. The above detailed left ventricular pressure volume analysis was performed before and 60 minutes after a single dose iv. injection of the potent PARP inhibitor INO 1001. Myocardial INO 1001 concentrations as high as 100 400 nM can be achieved by dosing of the compound in doses similar to this one in rodents. These tissue concentrations are suffic