Abstract
Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.
Footnotes
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This work was supported in part by National Institutes of Health Grants DK55601 and HL31069 (to N.G.A.), R01-25394 (to J.C.M.), PPG-HL34300 (to J.C.M. and N.G.A.), and HL59884 and HL03674 (to A.O.O.) and by a grant from the Italian Ministry of Instruction, University, and Research (to D.S. and A.G.).
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DOI: 10.1124/jpet.103.057315.
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ABBREVIATIONS: HO, heme-oxygenase; HO-2, constitutive heme-oxygenase; HO-1, inducible heme-oxygenase; l-NAME, NG-nitro-l-arginine methyl ester; CO, carbon monoxide; NO, nitric oxide; NOS, nitric-oxide synthase; CCl4, carbon tetrachloride; SnMP, tin-mesoporphyrin/stannous-mesoporphyrin; SMV, superior mesenteric vasculature; HHO-1, human HO-1; PE, phenylephrine; ET-1, endothelin-1; pfu, plaque-forming units; RT, reverse transcription; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; eNOS, endothelial nitric oxide synthase.
- Received July 21, 2003.
- Accepted October 30, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Role of the Heme Oxygenases in Abnormalities of the Mesenteric Circulation in Cirrhotic Rats
