Cytochrome P-450 2C9 exerts a vasoconstrictor influence on coronary resistance vessels in swine at rest and during exercise.
A significant endothelium-dependent vasodilation persists after inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) in the coronary vasculature, which has been linked to the activation of cytochrome P-450 (CYP) epoxygenases expressed in endothelial cells and subsequent generation of vasodilator epoxyeicosatrienoic acids. Here, we investigated the contribution of CYP 2C9 metabolites to regulation of porcine coronary vasomotor tone in vivo and in vitro. Twenty-six swine were chronically instrumented. Inhibition of CYP 2C9 with sulfaphenazole (5 mg/kg iv) alone had no effect on bradykinin-induced endothelium-dependent coronary vasodilation in vivo but slightly attenuated bradykinin-induced vasodilation in the presence of combined NOS/COX blockade with N(ω)-nitro-L-arginine (20 mg/kg iv) and indomethacin (10 mg/kg iv). Sulfaphenazole had minimal effects on coronary resistance vessel tone at rest or during exercise. Surprisingly, in the presence of combined NOS/COX blockade, a significant coronary vasodilator response to sulfaphenzole became apparent, both at rest and during exercise. Subsequently, we investigated in isolated porcine coronary small arteries (∼250 μm) the possible involvement of reactive oxygen species (ROS) in the paradoxical vasoconstrictor influence of CYP 2C9 activity. The vasodilation by bradykinin in vitro in the presence of NOS/COX blockade was markedly potentiated by sulfaphenazole under control conditions but not in the presence of the ROS scavenger N-(2-mercaptoproprionyl)-glycine. In conclusion, CYP 2C9 can produce both vasoconstrictor and vasodilator metabolites. Production of these metabolites is enhanced by combined NOS/COX blockade and is critically dependent on the experimental conditions. Thus production of vasoconstrictors slightly outweighed the production of vasodilators at rest and during exercise. Pharmacological stimulation with bradykinin resulted in vasodilator CYP 2C9 metabolite production when administered in vivo, whereas vasoconstrictor CYP 2C9 metabolites, most likely ROS, were dominant when administered in vitro.
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School Erasmus University Rotterdam, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Zhichao
Z
Zhou
Veemal
V
Hemradj
Vincent J
VJ
de Beer
Fen
F
Gao
Maaike
M
Hoekstra
Daphne
D
Merkus
Dirk J
DJ
Duncker
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006940:Hyperemia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009129:Muscle Tonus / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012146:Rest / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D014655:Vascular Resistance / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D001920:Bradykinin