© 1999 American Heart Association, Inc.
Original Contribution |
Nitric Oxide–Independent Relaxations to Acetylcholine and A23187 Involve Different Routes of Heterocellular Communication
Role of Gap Junctions and Phospholipase A2
From the Departments of Diagnostic Radiology (I.R.H., A.T.C., T.M.G.) and Medical Biochemistry (W.H.E.), Cardiovascular Sciences Research Group, University of Wales College of Medicine, Cardiff, United Kingdom.
Correspondence to Prof Tudor M. Griffith, Department of Diagnostic Radiology, Cardiovascular Sciences Research Group, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK. E-mail griffith{at}cardiff.ac.uk
Abstract—NO- and prostanoid-independent relaxations are generally assumed to be mediated by an endothelium-derived hyperpolarizing factor (EDHF) that has been postulated to be an arachidonic acid metabolite. Recent evidence also suggests that direct heterocellular gap junctional communication (GJC) between endothelium and smooth muscle contributes to NO-independent relaxations. In the present study we have investigated the contribution of phospholipase A2 (PLA2)-linked metabolites and GJC to EDHF-type relaxations in rabbit mesenteric artery. In isolated rings preconstricted with 10 µmol/L phenylephrine in the presence of NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin, acetylcholine (ACh) and the Ca2+ ionophore A23187 evoked relaxations that were markedly attenuated by the Ca2+-dependent PLA2 inhibitors 2-(p-amylcinnamoyl)amino-4-chlorobenzoic acid (3 µmol/L) and arachidonyl trifluoromethyl ketone (3 µmol/L), but were potentiated by the sulfhydryl agent thimerosal (300 nmol/L). In intact rings, relaxations to ACh were attenuated synergistically by L-NAME and Gap 27 peptide, an inhibitor of GJC, whereas ACh-evoked relaxations of "sandwich" preparations were unaffected by the peptide but were abolished by L-NAME. In both ring and sandwich preparations A23187-induced relaxations were attenuated by inhibition of PLA2 but were insensitive to L-NAME and Gap 27 peptide. We conclude that EDHF-type relaxations of rabbit mesenteric artery to ACh and A23187 depend on a common pathway that involves activation of PLA2. In the case of ACh, relaxation requires transfer of a factor or factors from the endothelium to smooth muscle via gap junctions, whereas A23187 permits release directly into the extracellular space.
Key Words: EDHF • phospholipase A2 • gap junction • acetylcholine • A23187
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