Radikal Therapeutics (RTX) is developing a novel K+-ATP channel opener (R-801) for the prevention of radiocontrast media (CM) induced nephropathy (CIN), a devastating complication developing in >25% of diabetics with significant preexisting renal dysfunction. The high incidence of atherosclerosis in this population frequently necessitates angiographic procedures of the coronary and peripheral vasculature, wherein large quantities of CM are utilized;thus, risk of CIN is a major concern. R-801 is a bifunctional small molecule, formed from the covalent linkage of: 1) the non-selective K+-ATP channel opener pinacidil, and 2) a pyrrolidine nitroxide that acts as a superoxide dismutase mimetic, a catalase mimic, and a peroxynitrite decomposition catalyst. R-801 behaves as a mitochondrial-selective K+-ATP channel opener, providing profound cytoprotection without induction of hyperglycemia and diastolic hypotension. The addition of the redox catalytic function provides R-801 with the capacity to neutralize not only reactive oxygen species generated by CM administration but also the removal of superoxide anion generated by mitoK+-ATP channel mediated inhibition of the first component of the electron transport chain. Taken together, R-801 represents the first agent intended to safely exploit K+-ATP channel activation as a clinical prophylactic for CIN. In support of this approach, in a rodent model of renal ischemia/reperfusion injury R- 801 profoundly reduced the elevation in BUN and creatinine, blocked neutrophil inflammation, and prevented histologic evidence of necrosis. Similar benefits have been observed in other rodent redox models, including myocardial ischemia/reperfusion injury and chlorine inhalational lung injury. We now propose to establish the dose-response of R-801 in a classic model of CIN and to validate its mechanism of action.
Aim #1 : Establish the pharmacodynamic (PD) profile of R-801 in preventing tissue injury in a rodent model of CIN. Rats will be subjected to dehydration, prostaglandin synthetase inhibition, and an intravenous challenge of CM. A sham injury group will be compared to treatment with R-801, pinacidil, or R-801 given in combination with a mitoK+-ATP channel inhibitor (5-hydroxydecanoate). We expect that R- 801 will exhibit dose-dependent superiority to pinacidil and vehicle control, as shown by: 1) Reduced tissue injury, manifested by the level of tissue necrosis (histology score), lipid peroxidation (malondialdehyde, F21-isoprostane), PMN infiltration (myeloperoxidase), apoptosis (TUNEL staining), 3-nitrotyrosine (a measure of ONOO- formation), poly(ADP-ribose) (a measure of PARP activity);and 2) Improved renal function, reflected by the concentration of urinary Kidney Injury Molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). We expect that the efficacy of R-801 will be attenuated by 5- hydroxydecanoate, demonstrating the centrality of mitoK+-ATP channel activation to its mechanism of cytoprotection.
Radiocontrast imaging is an invaluable and frequently used diagnostic modality, but its use is complicated by the subsequent development of kidney injury, often to the extent of requiring dialysis, particularly in populations at greatest risk, such as th elderly, diabetic, and those with preexisting renal impairment. There are no approved pharmaceutical therapies to prevent this complication. We are developing a novel prophylactic agent that protects the kidney from radiocontrast administration by directly protecting kidney cells from injury. We now propose to test this agent in a clinically-relevant small animal model of radiocontrast-induced kidney failure.
