title: Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo.
abstract: The enzyme heme oxygenase, which exists in inducible (HO-1) and constitutive (HO-2) isoforms, catalyzes the degradation of heme to biliverdin and CO in mammalian tissues. CO has been implicated in the control of vascular tone in a manner similar to that for NO. In the present study, we investigated the contribution of the heme oxygenase/CO pathway to the modulation of acute hypertensive responses in vivo induced by (1) alphaalphaHb, a chemically modified hemoglobin known to scavenge NO, and (2) NG-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries and veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of alphaalphaHb (8% solution) or L-NAME (30 micromol/kg) [corrected] produced an acute and significant increase in mean arterial pressure (P<0.05) in rats at 5 days after catheter implantation. In contrast, no change in blood pressure was observed when alphaalphaHb or L-NAME was infused 1 day after the surgical intervention. The suppression of the hypertensive response observed at 1 day after surgery correlated with a significant (P<0.05) HO-1 expression in aorta, heart, and liver as well as increased aortic CO production and cGMP levels. At 1 day after surgery, pretreatment of animals with the heme oxygenase inhibitor zinc protoporphyrin IX (50 micromol/kg IP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both alphaalphaHb and L-NAME. These results provide evidence for a crucial role of the heme oxygenase/CO pathway in the regulation of blood pressure under stress conditions in vivo.
authors.affiliation: Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK. r.motterlini@ic.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Motterlini
authors.forename: A
authors.initials: A
authors.lastname: Gonzales
authors.forename: R
authors.initials: R
authors.lastname: Foresti
authors.forename: J E
authors.initials: JE
authors.lastname: Clark
authors.forename: C J
authors.initials: CJ
authors.lastname: Green
authors.forename: R M
authors.initials: RM
authors.lastname: Winslow
mesh_terms: D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002248:Carbon Monoxide / Q000378:metabolism*; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006454:Hemoglobins / Q000494:pharmacology; D006973:Hypertension / Q000517:prevention & control*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011183:Postoperative Complications / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D006454:Hemoglobins; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019331:NG-Nitroarginine Methyl Ester