Abstract
The effect of the novel, selective, soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one (ODQ) on the nitric oxide component of the nonadrenergic, noncholinergic relaxation in guinea pig trachea was examined. Relaxant responses to field stimulation (1-16 Hz, 8 V, 1 ms for 15 s) in the presence of indomethacin (3 μM), atropine (1 μM), propranolol (1 μM), α-chymotrypsin (2 U/ml) and histamine (3 μM) were partially inhibited by 0.1 μM ODQ and almost abolished by 1 μM ODQ. In addition, relaxations to the nitric oxide donor 3-morpholinosyndnonimine-N-ethylcarbamide were partially inhibited by 0.1 μM ODQ and abolished by 1 μM ODQ. Relaxations to 3-morpholinosyndnonimine-N-ethylcarbamide in human bronchus were also substantially inhibited by ODQ (1–10 μM). By contrast, relaxations elicited by the stable 3′,5′-cyclic monophosphate analog 8-bromoguanosine-3′,5′-cyclic monophosphate and by isoproterenol were unaffected by 1 μM ODQ in guinea pig trachea and by 10 μM ODQ in human bronchus. These results suggest that relaxant responses to endogenously released or exogenously added nitric oxide in guinea pig trachea and human bronchus are mediated via the activation of soluble guanylyl cyclase and the formation of guanosine-3′,5′-cyclic monophosphate.
Footnotes
-
Send reprint requests to: James L. Ellis, CytoMed Incorporated, 840 Memorial Drive, Cambridge, MA 02139.
-
↵1 Supported by grant HL 48680 from the National Heart, Lung and Blood Institute of the National Institutes of Health.
- Abbreviations:
- ODQ
- 1H-[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one
- NO
- nitric oxide
- NANC
- nonadrenergic, noncholinergic
- SIN-1
- 3-morpholinosyndnonimine-N-ethylcarbamide
- cGMP
- guanosine-3′,5′-cyclic monophosphate
- 8Br-cGMP
- 8-bromoguanosine-3′,5′-cyclic monophosphate
- VIP
- vasoactive intestinal polypeptide
- DMSO
- dimethyl sulfoxide
- Received June 17, 1996.
- Accepted November 11, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
