title: Role of voltage-dependent potassium channels and myo-endothelial gap junctions in 4-aminopyridine-induced inhibition of acetylcholine relaxation in rat carotid artery.
abstract: The present study examined the role of voltage-gated potassium (K(v)) channels and myo-endothelial gap junctions in 4-aminopyridine-induced inhibition of acetylcholine-evoked endothelium-dependent relaxation and NO release in the rat carotid artery. The acetylcholine-induced relaxation was drastically inhibited by 94% and 82%, respectively in the presence of either 100 microM N(G)-nitro-l-arginine methyl ester (L-NAME) or 10 microM 1H-[1,2,4]oxadiazolo[4,3,a]quinoxalin-1-one (ODQ), while it was abolished following endothelium removal. 4-aminopyridine (1 mM), a preferential blocker of the K(v) channels significantly decreased the vasodilator potency, as well as efficacy of acetylcholine (pD(2) 5.7+/-0.09, R(max) 86.1+/-3.5% versus control 6.7+/-0.10 R(max) 106+/-3.5%, n=6), but had no effect on the relaxations elicited by either sodium nitroprusside (SNP) or 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP). 4-AP (1 mM) also inhibited acetylcholine (3 microM)-stimulated nitrite release in the carotid artery segments (99.4+/-4.93 pmol/mg tissue weight wt; n=6 versus control 123.8+/-7.43 pmol/mg tissue weight wt, n=6). 18alpha-glycyrrhetinic acid (18alpha-GA, 5 microM), a gap junction blocker, completely prevented the inhibition of acetylcholine-induced relaxation, as well as nitrite release by 4-AP. In the pulmonary artery, however antagonism of acetylcholine-evoked relaxation by 4-AP was not reversed by 18alpha-GA. These results suggest that 4-AP-induced inhibition of endothelium-dependent relaxation and NO release involves electrical coupling between vascular smooth muscle and endothelial cells via myo-endothelial gap junctions in the rat carotid artery, but not in the pulmonary artery. Further, direct activation of 4-AP-sensitive vascular K(v) channels by endothelium-derived NO is not evident in the carotid blood vessel, while this appears to be an important mechanism of acetylcholine-induced relaxation in the pulmonary artery.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, India-243122.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Gupta
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Subramani
authors.forename: Marie Dennis Marcus
authors.initials: MD
authors.lastname: Leo
authors.forename: Anurag S
authors.initials: AS
authors.lastname: Sikarwar
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.forename: Vellanki Ravi
authors.initials: VR
authors.lastname: Prakash
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D014665:Vasodilator Agents; D015761:4-Aminopyridine; D000109:Acetylcholine