This project seeks to develop safer, more effective and enduring: 1) nitrate therapy for angina and congestive heart failure using nitroglycerin (GTN) or isosorbide mononitrate (ISMN) and 2) statin therapy [pravastatin (PRA) or simvastatin (SIM)] for unstable angina and stroke, by their combination with L-arginine (L-arginine). Nitrovasodilators are highly effective acutely, but their usefulness for chronic therapy is limited due to the rapid development of tolerance to their vasodilating effects. NitrOSystems, Inc. has discovered an additional endothelial cell (EC)-dependent mechanism of GTN-induced vasodilation and tolerance and that tolerance can be prevented by treatment with supplemental L-arginine. Data show that GTN activates EC nitric oxide synthase (eNOS) to produce NO from its substrate L-arginine. It is known that the intracellular supply of L-arginine can become limiting in diseases characterized by vascular dysfunction, that diminished availability of L-arginine as a substrate for eNOS can result in EC damage due to formation of superoxide anion (SOA) and other reactive oxygen species and that treatment with supplemental L-arginine can prevent EC dysfunction. Statins or HMG CoA reductase inhibitors, by mechanisms unrelated to lowering lipids, activate eNQS and inhibit platelet aggregation. Formation of SOA is also increased by statins. It is hypothesized that sustained elevated extracellular levels of L-arginine are required for optimal therapeutic effects of nitrates and the statins and that supplemental L-arginine will potentiate drug actions by reducing formation of SOA.
Specific aims are to: 1. Determine the ability of GTN, ISMN, PRA, SIM to activate NOS and produce SOA in EC and the ability of supplemental L-arginine to prevent SOA formation. 2. Determine the ability of supplemental L-arginine to prevent SOA formation and nitrite tolerance in animals. 3. Develop an IV formulation of GTN in combination with L-arginine and an oral combined sustained release formulation of ISMN and L-arginine. 4. Develop an oral combined sustained release formulation of SIM and L-arginine.
