среда, 5 марта 2008 г.

Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouse

PROMOTES NITRIC OXIDE FUNCTION IN THE DUCTUS ARTERIOSUS IN THE MOUSE D Sodini, B Baragatti,, S Barogi,, V E Laubach and F Coceani, 1Scuola Superiore Sant'Anna, Pisa, Italy 2Institute of Clinical Physiology CNR, Pisa, Italy 3Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA Correspondence: Dr F Coceani, Scuola Superiore Sant'Anna, Piazza Martiri della Libert 33, Pisa 56127, Italy.Received 4 December 2007; Accepted 15 January 2008; Published online 25 February 2008.Background And Purpose: Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E2 in concert with nitric oxide (NO) and carbon monoxide (CO).Have previously found that NO activity increases upon deletion of either COX.We have examined whether COX inhibition by indomethacin mimics COX deletion in promoting NO.Experiments were performed _in vitro_ and _in vivo_ with wild-type (WT) and eNOS-/-, near-term mouse foetuses.Was given p.To the mother as single (acute treatment) or repeated (daily for 3 days; chronic treatment) doses within a therapeutic range (2 mg kg-1).Indomethacin promoted eNOS mRNA expression in the WT ductus.Drug enhanced the contraction of the isolated ductus to the NOS inhibitor, _N_G-nitro-L-arginine methyl ester, and its effect augmented with the length of treatment.Such enhancement was seen with the eNOS-/- ductus.Indomethacin also increased, albeit marginally, the contraction of the WT ductus to the CO synthesis inhibitor, zinc protoporphyrin.Given acutely or chronically, indomethacin induced a little narrowing of the ductus antenatally and had no effect on postnatal closure of the vessel.Implications: We conclude that activation of NO and, to a much lesser degree, CO mechanisms is an integral part of the indomethacin effect on the ductus.
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