Neuropeptides, Free Radical Stress and Antioxidants in Models of Mg-Deficient Cardiomyopathy

Dietary Mg-deficiency in rodents induces a pro-oxidant/proinflammatory condition in vivo characterized by enhanced free radical (lipid radicals and nitric oxide) production, accumulation of oxidation products and pro-oxidant metals, depletion of endogenous antioxidants, and elevated circulating levels of inflammatory mediators. Untreated, this condition leads to cardiomyopathy, as well as reduced myocardial tolerance to imposed oxidative stresses (lipid hydroperoxide exposure; ischemia/reperfusion). The early detection of elevated circulating substance P levels (by dietary day 3) in this model led to the hypothesis that this neuropeptide may trigger subsequent inflammatory and pro-oxidant events in vivo. Treatment in vivo with substance P receptor antagonists (or with select antioxidants) provided substantial protection against pro-oxidant stress, evidenced by the attenuation of blood glutathione loss and cardiac lesion formation in vivo, and postischemic injury in vitro. The protection provided by the receptor antagonists demonstrates a direct contribution of early substance P-mediated inflammation in the subsequent development of the Mg-deficient cardiomyopathy and reduced tolerance to postischemic oxidative stress.