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Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase‐1
Author(s) -
Sammut Ivan A.,
Foresti Roberta,
Clark James E.,
Exon David J.,
Vesely Martin J. J.,
Sarathchandra Padmini,
Green Colin J.,
Motterlini Roberto
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702212
Subject(s) - vascular tone , oxygenase , carbon monoxide , tone (literature) , heme oxygenase , chemistry , medicine , cardiology , biochemistry , heme , vasodilation , enzyme , philosophy , linguistics , catalysis
1 The contribution of haeme oxygenase‐derived carbon monoxide (CO) to the regulation of vascular tone in thoracic aorta was investigated following induction of the inducible isoform of haeme oxygenase (HO‐1). 2 Isometric smooth muscle contractions were recorded in isolated rat aortic ring preparations. Rings were incubated in the presence of the nitric oxide (NO) donor S‐nitroso‐N‐acetyl penicillamine (SNAP, 500 μ m ) for 1 h, then repetitively washed and maintained for a further 4 h prior to producing a concentration‐response curve to phenylephrine (PE, 1–3000 n m ). 3 Treatment with SNAP resulted in increased mRNA and protein expression of aortic HO‐1 and was associated with a significant suppression of the contractile response to PE ( P <0.05 vs control). Immunohistochemical staining procedures revealed marked HO‐1 expression in the endothelial layer and, to a lesser extent, in smooth muscle cells. 4 Induction of HO‐1 in SNAP‐treated rings was associated with a higher 14 CO release compared to control, as measured by scintillation counting after incubation of aortas with [2‐ 14 C]‐ L ‐glycine, the precursor of haeme. Guanosine 3′,5′‐monophosphate (cyclic GMP) content was also greatly enhanced in aortas expressing high levels of HO‐1. 5 Incubation of aortic rings with the NO synthase inhibitor, N G ‐monomethyl‐ L ‐arginine (100 μ m ), significantly ( P <0.05) increased the contractile response to PE in controls but failed to restore PE‐mediated contractility in SNAP‐treated rings. In contrast, the selective inhibitor of haeme oxygenase, tin protoporphyrin IX (SnPP‐IX, 10 μ m ), restored the pressor response to PE in SNAP‐treated rings whilst markedly reducing CO and cyclic GMP production. 6 We conclude that up‐regulation of the HO‐1/CO pathway significantly contributes to the suppression of aortic contractility to PE. This effect appears to be mediated by the elevation of cyclic GMP levels and can be reversed by inhibition of the haeme oxygenase pathway.British Journal of Pharmacology (1998) 125 , 1437–1444; doi: 10.1038/sj.bjp.0702212