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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/H2363    most recent 01042.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Awumey, E. M. Articles by Bukoski, R. D. PubMed PubMed Citation Articles by Awumey, E. M. Articles by Bukoski, R. D.

Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca²⁺-induced relaxation of rat mesenteric arteries

Emmanuel M. Awumey,¹ Sylvie K. Hill,¹ Debra I. Diz,² and Richard D. Bukoski^1,

¹Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham; and ²Hypertension and Vascular Research Center and Department of Physiology and Pharmacology, Wake Forest University Medical School, Winston Salem, North Carolina

Submitted 7 September 2007 ; accepted in final form 25 March 2008

The perivascular sensory nerve (PvN) Ca²⁺-sensing receptor (CaR) is implicated in Ca²⁺-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 A₂ (PLA₂), and cytochrome P-450 (CYP) on Ca²⁺-induced relaxation of PE-contracted rat mesenteric arteries. Our findings indicate that Ca²⁺-induced vasorelaxation is not dependent on the endothelium. The DAGL inhibitor RHC 802675 (1 µM) and the CYP and PLA₂ inhibitors quinacrine (5 µM) (EC₅₀: 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 (AACOCF₃, 1 µM) reduced Ca²⁺-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) (EC₅₀: control 0.96 ± 0.14 nM, IBTX 1.3 ± 0.5 µM) and miconazole (48 ± 3%), and 11,12-GEET responses were blocked by IBTX (EC₅₀: control 55 ± 9 nM, IBTX 690 ± 96 nM) and SR-141716A. The data suggest that activation of the CaR in the PvN network by Ca²⁺ 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 Ca²⁺-induced relaxation of resistance arteries; therefore this receptor may be a potential target for the development of new vasodilator compounds for antihypertensive therapy.

Ca²⁺-sensing receptor; arachidonic acid; vasorelaxation