Istituto di Fisiologia Clinica     
Baragatti B., Brizzi F., Barogi S., Laubach V., Sodini D., Shesely E., Regan R., Coceani F. Interactions between NO, CO and an endotheliumderived hyperpolarizing factor (EDHF) in maintaining patency of the ductus arteriosus in the mouse. In: British Journal of Pharmacology, vol. 151 pp. 54 - 62. nature, 2007.
Background and purpose: Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E2, possibly along with nitric oxide (NO) and carbon monoxide (CO), and cyclooxygenase (COX) deletion upregulates NO. Here, we have examined enzyme source and action of NO for ductus patency and whether NO and CO are upregulated by deletion of, respectively, heme oxygenase 2 (HO-2) and COX1 or COX2. Experimental approach: Experiments were performed in vitro and in vivo with wild-type and gene-deleted, near-term mouse fetuses. Key results: NG-nitro-L-arginine methyl ester (L-NAME) contracted the isolated ductus and its effect was reduced by eNOS, but not iNOS, deletion. L-NAME contraction was not modified by HO-2 deletion. Zinc protoporphyrin (ZnPP) also contracted the ductus, an action unaffected by deletion of either COX isoform. Bradykinin (BK) relaxed indomethacin-contracted ductus similarly in wild-type and eNOS=/= or iNOS=/=. BK relaxation was suppressed by either L-NAME or ZnPP. However, it reappeared with combined L-NAME and ZnPP to subside again with Kū increase or Kū channel inhibition. In vivo, the ductus was patent in wild-type and NOS-deleted fetuses. Likewise, no genotype-related difference was noted in postnatal closure. Conclusions and implications: NO, formed mainly via eNOS, regulates ductal tone. NO and CO cooperatively mediate BKinduced relaxation in the absence of PGE2. However, in the absence of PGE2, NO and CO, BK induces a relaxant substance behaving as an endothelium-derived hyperpolarizing factor. Ductus patency is, therefore, sustained by a cohort of agents with PGE2 and NO being preferentially coupled for reciprocal compensation.
Subject ductus arteriosus
nitric oxide

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