Substance P receptor blockade attenuates oxidative stress, endotoxemia and cardiac dysfunction in Mg‐deficient rats

The impact of the substance P (SP) receptor blocker (SPRB), L‐703,606 (1 mg/kg/day s.c. pellet), on oxidative stress, plasma endotoxin (LPS) and cardiac function was examined in dietary Mg‐deficient (MgD, 9% RDA) rats. Rats were fed MgD or Mg‐sufficient (MgS, 100% RDA) diets for 5 wks. Echocardiography was performed and blood assessed for SP, RBC glutathione, isoprostane, PMN basal superoxide production and LPS. Mg‐deficiency led to significant (p<0.05) LV systolic dysfunction (depressed ejection fraction [LVEF, 6 %]; fractional shortening [%FS, 17 %]; aortic pressure maximum [Pmax, 19 %]). Mitral valve E/A ratio (E/A) was reduced 28%, suggesting diastolic dysfunction. Dysfunction was associated with 42 % lower RBC glutathione, and elevations in SP (6.52‐fold), isoprostane (2‐fold), PMN superoxide (3.86‐fold), and LPS (3‐fold) vs MgS. Concurrent SPRB led to partial protection against oxidative stress (43 – 53% improved), lowered LPS to control levels, and improved cardiac function 42 – 57%. The severity of dysfunction correlated well with alterations in circulating LPS levels (r=−0.713 to −0.782 for LPS vs E/A, Pmax, LVEF & %FS). Since SPRB does not alter plasma SP levels, but does inhibit its bioactivity, the partial significant protection by the SPRB suggests a causal role for SP in development of oxidative injury, endotoxemia and cardiac dysfunction during Mg‐deficiency. Support: NIH RO1 HL‐62282.