5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation.
We have investigated the ability of 5-methyltetrahydrofolate (5-MTHF) and tetrahydrobiopterin (BH(4)) 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 BH(4), but not by their oxidized forms folic acid and 7,8-dihydrobiopterin. Analogously, 5-MTHF and BH(4), but not folic acid or 7,8-dihydrobiopterin, attenuated the depression of subintimal hyperpolarization by a connexin-mimetic peptide targeted against Cx37 and Cx40 ((37,40)Gap 26) and the depression of subadventitial hyperpolarization by a peptide targeted against Cx43 ((43)Gap 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 (37,40)Gap 26 against subintimal hyperpolarization were prevented by catalase, which destroys H(2)O(2). 5-MTHF and BH(4) 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.
Griffith
Tudor M
TM
Department of Diagnostic Radiology, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. griffith@cardiff.ac.uk
Chaytor
Andrew T
AT
Bakker
Linda M
LM
Edwards
David H
DH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004566:Electrodes; D004583:Electrons; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D005492:Folic Acid / Q000494:pharmacology; D017629:Gap Junctions; D006454:Hemoglobins; D007083:Iliac Artery / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D016877:Oxidants; D011817:Rabbits; D015398:Signal Transduction; D013763:Tetrahydrofolates / Q000494:pharmacology; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
D000975:Antioxidants; D001708:Biopterins; D001896:Boron Compounds; D002118:Calcium; D017630:Connexins; D005492:Folic Acid; D006454:Hemoglobins; D007211:Indoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D016877:Oxidants; D013763:Tetrahydrofolates; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein; C017226:7,8-dihydrobiopterin; C109986:2-aminoethoxydiphenyl borate; C003402:sapropterin; C005984:5-methyltetrahydrofolate; C000543:cyclopiazonic acid