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PHARMACOLOGY
5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation
Department of Diagnostic Radiology, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom
Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved March 21, 2005 (received for review December 1, 2004)
We have investigated the ability of 5-methyltetrahydrofolate (5-MTHF) and tetrahydrobiopterin (BH4) to modulate nitric oxide (NO)-independent vascular relaxations that are mediated by the sequential spread of endothelial hyperpolarization through the wall of the rabbit iliac artery by means of myoendothelial and homocellular smooth muscle gap junctions. Relaxations and subintimal smooth muscle hyperpolarizations evoked by cyclopiazonic acid were depressed by the gap junction inhibitor 2-aminoethoxydiphenyl borate, whose effects were prevented by 5-MTHF and BH4, but not by their oxidized forms folic acid and 7,8-dihydrobiopterin. Analogously, 5-MTHF and BH4, but not folic acid or 7,8-dihydrobiopterin, attenuated the depression of subintimal hyperpolarization by a connexin-mimetic peptide targeted against Cx37 and Cx40 (37,40Gap 26) and the depression of subadventitial hyperpolarization by a peptide targeted against Cx43 (43Gap 26), thus reflecting the known differential expression of Cx37 and Cx40 in the endothelium and Cx43 in the media of the rabbit iliac artery. The inhibitory effects of 2-aminoethoxydiphenyl borate and 37,40Gap 26 against subintimal hyperpolarization were prevented by catalase, which destroys H2O2. 5-MTHF and BH4 thus appear capable of modulating electrotonic signaling by means of myoendothelial and smooth muscle gap junctions by reducing oxidant stress, potentially conferring an ability to reverse the endothelial dysfunction found in disease states through mechanisms that are independent of NO.
connexin | folic acid | methotrexate | gap junction | endothelium-derived hyperpolarizing factor
Abbreviations: EDHF, endothelium-derived hyperpolarizing factor; 5-MTHF, 5-methyltetrahydrofolate; BH4, tetrahydrobiopterin; BH2, 7,8-dihydrobiopterin; (6R), (6R)-5,6,7,8; APB, 2-aminoethoxydiphenyl borate; L-NAME; NG-nitro-L-arginine methyl ester; CPA, cyclopiazonic acid; FA, folic acid.
* To whom correspondence should be addressed. E-mail: griffith{at}cardiff.ac.uk.
© 2005 by The National Academy of Sciences of the USA
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