Glyceryl trinitrate-induced vasodilation is inhibited by ultraviolet irradiation despite enhanced nitric oxide generation: evidence for formation of a nitric oxide conjugate.
Our objective was to determine whether a stabilized form of nitric oxide (NO) such as an S-nitrosothiol, rather than NO itself, is the vasoactive metabolite produced when glyceryl trinitrate (GTN) interacts with vascular smooth muscle. In a control study, NO formation was measured by a chemiluminescence-headspace gas method during the incubation of a prototype S-nitrosothiol, namely, S-nitroso-N-acetylpenicillamine (SNAP), in Krebs' solution. NO formation from SNAP was increased when the incubation was carried out in the presence of UV light, indicating that homolytic photolysis of the S-nitrosothiol had occurred. When GTN was incubated with bovine pulmonary artery (BPA) in the absence of UV light, NO was not measurable until 5 min of incubation. By contrast, in the presence of UV light, NO was measurable as early as 0.5 min, and by 5 min, it was higher than that observed in the absence of UV light. BPA rings were relaxed with SNAP and GTN in the absence of UV light, and EC50 values of 0.24 +/- 0.28 microM and 10 +/- 6 nM, respectively, were observed. In the presence of UV light, the vasodilator response of BPA to SNAP and GTN was attenuated, and EC50 values of 2.7 +/- 3.0 microM and 49 +/- 23 nM, respectively, were observed. Our results are consistent with the idea that GTN biotransformation by vascular smooth muscle results in the production of a stabilized form of NO, possibly an S-nitrosothiol, and that degradation of this metabolite by UV light results in NO formation accompanied by decreased vasodilation.
Hussain
A S
AS
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
Crispino
N H
NH
McLaughlin
B E
BE
Brien
J F
JF
Marks
G S
GS
Nakatsu
K
K
D000818:Animals; D001711:Biotransformation; D002417:Cattle; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009126:Muscle Relaxation / Q000528:radiation effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology / Q000528:radiation effects; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000528:radiation effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine; D014466:Ultraviolet Rays; D014664:Vasodilation / Q000187:drug effects* / Q000528:radiation effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005996:Nitroglycerin; D010396:Penicillamine