Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries.
The perivascular sensory nerve (PvN) Ca(2+)-sensing receptor (CaR) is implicated in Ca(2+)-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries, which involves the vascular endogenous cannabinoid system. We determined the effect of inhibition of diacylglycerol (DAG) lipase (DAGL), phospholipase A(2) (PLA(2)), and cytochrome P-450 (CYP) on Ca(2+)-induced relaxation of PE-contracted rat mesenteric arteries. Our findings indicate that Ca(2+)-induced vasorelaxation is not dependent on the endothelium. The DAGL inhibitor RHC 802675 (1 microM) and the CYP and PLA(2) inhibitors quinacrine (5 microM) (EC(50): RHC 802675 2.8 +/- 0.4 mM vs. control 1.4 +/- 0.3 mM; quinacrine 4.8 +/- 0.4 mM vs. control 2.0 +/- 0.3 mM; n = 5) and arachidonyltrifluoromethyl ketone (AACOCF(3), 1 microM) reduced Ca(2+)-induced relaxation of mesenteric arteries. Synthetic 2-arachidonoylglycerol (2-AG) and glycerated epoxyeicosatrienoic acids (GEETs) induced concentration-dependent relaxation of isolated arteries. 2-AG relaxations were blocked by iberiotoxin (IBTX) (EC(50): control 0.96 +/- 0.14 nM, IBTX 1.3 +/- 0.5 microM) and miconazole (48 +/- 3%), and 11,12-GEET responses were blocked by IBTX (EC(50): control 55 +/- 9 nM, IBTX 690 +/- 96 nM) and SR-141716A. The data suggest that activation of the CaR in the PvN network by Ca(2+) leads to synthesis and/or release of metabolites of the CYP epoxygenase pathway and metabolism of DAG to 2-AG and subsequently to GEETs. The findings indicate a role for 2-AG and its metabolites in Ca(2+)-induced relaxation of resistance arteries; therefore this receptor may be a potential target for the development of new vasodilator compounds for antihypertensive therapy.
Awumey
Emmanuel M
EM
Cardiovascular Disease Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA. eawumey@nccu.edu
Hill
Sylvie K
SK
Diz
Debra I
DI
Bukoski
Richard D
RD
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008825:Miconazole / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D010455:Peptides; D064801:Phospholipase A2 Inhibitors; D010880:Piperidines; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D044169:Receptors, Calcium-Sensing; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C081565:arachidonyltrifluoromethane; D010656:Phenylephrine; C064719:iberiotoxin; D008825:Miconazole; C094503:glyceryl 2-arachidonate; D003577:Cytochrome P-450 Enzyme System; D008071:Lipoprotein Lipase; D054467:Phospholipases A2; D015126:8,11,14-Eicosatrienoic Acid; D011796:Quinacrine; D000109:Acetylcholine; D000077285:Rimonabant; D002118:Calcium