Ino-1001 a Novel Poly(adp-Ribose) Polymerase (Parp) Inhibitor Improves Cardiac and Pulmonary Function After Crystalloid Cardioplegia and Extracorporal Circulation

Abstract

Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.

A New, Potent Poly(ADP-ribose) Polymerase Inhibitor Improves Cardiac and Vascular Dysfunction Associated with Advanced Aging

“…Young adult (3 months old) and aging (24 months old) Fischer rats obtained from the National Institute on Aging were treated for 2 months with vehicle, or the potent isoindolinone-based PARP inhibitor INO-1001, 30 mg/kg/orally (Inotek Pharmaceuticals, Beverly, MA) (Du et al, 2003;Khan et al, 2003;Shimoda et al, 2003;Murakami et al, 2004;Szabó et al, 2004b). In cell-free PARP assay using NAD ϩ and purified PARP enzyme, INO-1001 inhibited PARP activity in a dose-dependent manner with an EC 50 of 3 nM.…”

“…The EC 50 of the prototypical PARP inhibitor 3-aminobenzamide was 200 M. Peroxynitrite-and hydrogen peroxide-induced oxidation of dihydrorhodamine-123 were unaffected by INO-1001 in the concentration range up to 10 mM, indicating that the compound does not act as an antioxidant. The chosen dose of INO-1001 (30 mg/kg/orally) was found to effectively inhibit PARP activation in previous studies in various tissues including myocardium and vasculature (Du et al, 2003;Khan et al, 2003;Shimoda et al, 2003;Murakami et al, 2004;Szabó et al, 2004b). Rats were housed two to three per cage, fed a standard laboratory diet and water ad libitum, and maintained on a 12-h light/dark cycle.…”

Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury

“…After 60 minutes, the aortic crossclamp was released, and the reperfusion phase was initiated. Each animal underwent 60 minutes of cardiac ischemia and 60 minutes of reperfusion 16 (see the online-only Data Supplement).…”

“…Heart rate (HR), mean arterial pressure (MAP), cardiac output, coronary blood flow, and PV loop-derived (conductance catheter) contractility indexes were assessed at baseline and at 60 minutes of reperfusion 16 (see the online-only Data Supplement).…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…1A) [58]. The beneficial effects of INO-1001 were also shown in a dog model of cardioplegic arrest and extracorporeal circulation [59] and a rat model of obliterative bronchiolitis occurring after lung transplantation [60]. Allografted airways treated with INO-1001 demonstrated attenuated NF-B nuclear translocation and reduced transcription of tumour necrosis factor (TNF)-, indicating proinflammatory effects of PARP-1 activation [60].…”