© 1998 American Heart Association, Inc.
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Heme Oxygenase-1–Derived Carbon Monoxide Contributes to the Suppression of Acute Hypertensive Responses In Vivo
From the Vascular Biology Unit (R.M., R.F., J.E.C., C.J.G.), Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK, and the Department of Medicine (A.G., R.M.W.), VA Medical Center, University of California San Diego, La Jolla, Calif.
Correspondence to Dr Roberto Motterlini, Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, HA1 3UJ UK. E-mail r.motterlini{at}ic.ac.uk
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) 
Hb, 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 Hb
(8% solution) or L-NAME (30 mmol/kg) 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 Hb 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 µmol/kg IP)
markedly decreased aortic CO and cGMP levels and completely restored
the vasoconstrictor effects of both Hb 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.
Key Words: surgical stress • hemoglobin-based blood substitute • carbon monoxide • bilirubin • cGMP
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