Role of carbon monoxide in electrically induced non‐adrenergic, non‐cholinergic relaxations in the guinea‐pig isolated whole trachea

Background and purpose:

Nitric oxide (NO) and vasoactive intestinal peptide (VIP) are considered transmitters of non‐adrenergic, non‐cholinergic (NANC) relaxations in guinea‐pig trachea, whereas the role of carbon monoxide (CO) is unknown. This study was designed to assess the participation of CO, and to investigate the localization of haem oxygenase‐2 (HO‐2), the CO‐producing enzyme, in tracheal neurons.

Experimental approach:

NANC responses to electrical field stimulation (EFS) at 3 and 10 Hz were evaluated in epithelium‐free whole tracheal segments as intraluminal pressure changes. Drugs used were: L‐nitroarginine methyl ester (L‐NAME, 100 μM) to inhibit NO synthase (NOS), α‐chymotrypsin (2 U ml⁻¹) to inactivate VIP, zinc protoporphyrin‐IX (ZnPP‐IX, 10 μM) to inhibit HO‐2, and 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μM), a soluble guanylyl cyclase inhibitor. For immunohistochemistry, tissues were exposed to antibodies to PGP 9.5, a general neuronal marker, HO‐2 and NOS, and processed with an indirect immunofluorescence method.

Key results:

α‐Chymotrypsin did not affect NANC relaxations. ODQ inhibited NANC responses by about 60%, a value similar to that obtained by combining L‐NAME and ZnPP‐IX. The combination of ODQ, L‐NAME and ZnPP‐IX reduced the responses by 90%. Subpopulations of HO‐2 positive neurons containing NOS were detected in tracheal sections.

Conclusions and Implications:

In the guinea‐pig trachea, NANC inhibitory responses at 3 and 10 Hz use NO and CO as main transmitters. Their participation is revealed following inhibition of NOS, HO‐2 and soluble guanylyl cyclase. The involvement of CO as a relaxing transmitter paves the way for novel therapeutic approaches in the treatment of airway obstruction.

DOI: 10.1038/sj.bjp.0706968

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