Interactions between NO, CO and an endothelium-derived hyperpolarizing factor (EDHF) in maintaining patency of the ductus arteriosus in the mouse.
OBJECTIVE
Prenatal patency of ductus arteriosus is maintained by prostaglandin (PG) E(2), 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.


METHODS
Experiments were performed in vitro and in vivo with wild-type and gene-deleted, near-term mouse fetuses.


RESULTS
N(G)-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 K(+) increase or K(+) 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
NO, formed mainly via eNOS, regulates ductal tone. NO and CO cooperatively mediate BK-induced relaxation in the absence of PGE(2). However, in the absence of PGE(2), 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 PGE(2) and NO being preferentially coupled for reciprocal compensation.
Baragatti
B
B
Scuola Superiore Sant'Anna, Pisa, Italy.
Brizzi
F
F
Barogi
S
S
Laubach
V E
VE
Sodini
D
D
Shesely
E G
EG
Regan
R F
RF
Coceani
F
F
D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D002248:Carbon Monoxide / Q000502:physiology*; D004374:Ductus Arteriosus, Patent / Q000209:etiology*; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000502:physiology
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D001920:Bradykinin