Suppression of neutrophil and endothelial activation by substance P receptor blockade in the Mg-deficient rat.
The regulatory role of substance-P (SP) on neutrophil and endothelium activation as well as nitric oxide (NO) production induced by Mg-deficiency was examined. Male Sprague-Dawley rats (180 g) were fed either a Mg-deficient (MgD) or Mg-sufficient (MgS) diet for 3 weeks. Enriched neutrophil fractions (> 85%) isolated from whole blood of the Mg-deficient rats displayed an 11-fold (p < 0.001) higher basal superoxide anion producing activity (assayed as SOD-inhibitable cytochrome c reduction) compared to that obtained from the MgS rats. Treatment of the MgD rats with the specific SP-receptor (SPR) blocker, L-703,606 (1 mg/kg/day as s.c. implanted sustained-release pellets) attenuated the superoxide anion producing activity by 75% (p < 0.025). In parallel, circulating prostacyclin (PGI2) level (assayed as 6-keto-PGF-1alpha) was elevated 13-fold in the MgD rats, but was reduced 90% by L-703,606 treatment. Concomitantly, plasma NO products (nitrate + nitrite), which increased 2.2-fold during Mg-deficiency, were completely suppressed by the SPR blockade. When the isolated hearts were subjected to ischemia/ reperfusion stress, NO products were elevated 2.4-fold in the effluent of the MgD group compared to MgS; such heightened NO release was also attenuated after in vivo treatment with the SPR blocker. In conclusion, SP plays a direct role in promoting activation of the neutrophil and endothelium as well as induction of NO production; these processes might participate in the oxidative stress that contributes to the depletion of blood glutathione and cardiac pathology.
Mak
I Tong
IT
The George Washington University Medical Center, Department of Physiology and Experimental Medicine, Washington, DC 20037, USA. itmak@gwu.edu
Kramer
Jay H
JH
Weglicki
William B
WB
D000818:Animals; D000838:Anions; D042783:Endothelial Cells / Q000166:cytology*; D011464:Epoprostenol / Q000378:metabolism; D005978:Glutathione / Q000097:blood; D008274:Magnesium / Q000378:metabolism; D008275:Magnesium Deficiency; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010477:Perfusion; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides
D000838:Anions; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; D013481:Superoxides; C076851:L 703606; D009569:Nitric Oxide; D011464:Epoprostenol; D005978:Glutathione; D008274:Magnesium