Abstract
The potency of the nitric oxide (NO) donors glyceryltrinitrate (GTN) and 3-morpholinosydnonimine was compared in human dorsal hand veins, the radial artery, and the forearm resistance vessels. NO donors were more potent in veins and the radial artery (vessels with minimal basal NO-mediated dilatation) than in the resistance vascular bed (where basal NO is a major determinant of vascular tone). In contrast, 8-bromoguanosine 3′,5′-cyclic monophosphate (a cGMP mimetic) was approximately equipotent in resistance arteries and veins and was less potent in the radial artery. Inhibition of phosphodiesterase V with dipyridamole did not alter the arteriovenous profile of GTN. Increasing the local concentration of NO in veins (by infusing sodium nitroprusside) reduced their sensitivity to GTN but not to 8-bromoguanosine 3′,5′-cyclic monophosphate. Conversely, reducing endogenous NO production in the resistance vasculature led to time-dependent increases in the response to GTN. These data suggest that soluble guanylate cyclase rather than cGMP-dependent protein kinase or phosphodiesterase V is the site in the second messenger pathway that determines the arteriovenous profile of NO donors. Moreover, the sensitivity of soluble guanylate cyclase to NO donors might be regulated by the ambient concentration of NO, with increased local NO down-regulating the dilator response to NO donors.
Footnotes
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Send reprint requests to: Dr. R J. MacAllister, Centre for Clinical Pharmacology, The Wolfson Institute for Biomedical Research, University College London, 3rd Floor, The Rayne Institute, 5 University St., London, WC1E 6JJ UK. E-mail: rmgzrjm{at}ucl.ac.uk
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↵1 This work was supported by the British Heart Foundation and the Special Trustees of the Middlesex Hospital, University College Hospital and University College London Medical School.
- Abbreviations:
- PDE V
- phosphodiesterase type V
- G kinase
- cGMP-dependent protein kinase
- SNP
- sodium nitroprusside
- AUC
- area under the dilatation/time curve
- GTN
- glyceryltrinitrate
- SIN-1
- 3-morpholinosydnonimine
- sGC
- soluble guanylate cyclase
- 8-Br-GMP
- 8-bromoguanosine 3′,5′-cyclic monophosphate
- NE
- norepinephrine
- l-NMMA
- NG-monomethyl-l-arginine
- Received August 3, 1998.
- Accepted March 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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