Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1

1 The contribution of haeme oxygenase-derived carbon monoxide (CO) to the r egulation of vascular tone in thoracic aorta was investigated following ind uction 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 oxid e (NO) donor S-nitroso-N-acetyl penicillamine (SNAP, 500 mu M) for 1 h, the n repetitively washed and maintained for a further 4 h prior to producing a concentration-response curve to phenylephrine (PE, 1-3000 nM). 3 Treatment with SNAP resulted in increased mRNA and protein expression of aortic HO-1 and was associated with a significant suppression of the contra ctile response to PE (P<0.05 vs control). Immunohistochemical staining proc edures revealed marked HO-1 expression in the endothelial layer and, to a l esser extent, in smooth muscle cells. 4 Induction of HO-I in SNAP-treated rings was associated with a higher (CO) -C-14 release compared to control, as measured by scintillation counting af ter incubation of aortas with [2-C-14]-L-glycine, the precursor of haeme. G uanosine 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 mu M), significantly (P<0.05) increased the contractile re sponse to PE in controls but failed to restore PE-mediated contractility in SNAP-treated rings. In contrast, the selective inhibitor of haeme oxygenas e, tin protoporphyrin IX (SnPP-IX, 10 mu M), restored the presser response to PE in SNAP-treated rings whilst markedly reducing CO and cyclic GMP prod uction. 6 We conclude that up-regulation of the HO-1/CO pathway significantly contr ibutes to the suppression of aortic contractility to PE. This effect appear s to be mediated by the elevation of cyclic GMP levels and can be reversed by inhibition of the haeme oxygenase pathway.