Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats.
Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF-kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate.
Ndisang
Joseph Fomusi
JF
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. joseph.ndisang@.usask.ca
Jadhav
Ashok
A
D000818:Animals; D001120:Arginine / Q000494:pharmacology / Q000627:therapeutic use*; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003900:Desoxycorticosterone; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006418:Heme / Q000494:pharmacology / Q000627:therapeutic use*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology; D008901:Mineralocorticoids; D016328:NF-kappa B / Q000378:metabolism; D009942:Organometallic Compounds; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
D019332:Endothelin-1; D008901:Mineralocorticoids; D016328:NF-kappa B; D009942:Organometallic Compounds; D017673:Sodium Chloride, Dietary; C476530:tricarbonylchloro(glycinato)ruthenium(II); C075750:8-epi-prostaglandin F2alpha; D003900:Desoxycorticosterone; D006418:Heme; D015544:Inositol 1,4,5-Trisphosphate; D001120:Arginine; D015237:Dinoprost; D006419:Heme Oxygenase (Decyclizing); D010738:Type C Phospholipases; D006152:Cyclic GMP; C048849:heme arginate; D002118:Calcium