title: Enhanced phenylephrine-induced rhythmic activity in the atherosclerotic mouse aorta via an increase in opening of KCa channels: relation to Kv channels and nitric oxide.
abstract: 1. Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E degrees xLDLR degrees ) develop atherosclerosis. The aim of this study was to investigate changes in endothelium-dependent vasodilation and vasomotion in thoracic aortic rings of E degrees xLDLR degrees mice. 2. K+-induced contractions of the aorta from E degrees xLDLR degrees mice were stronger than those from control mice. The sensitivity of E degrees xLDLR degrees aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine-induced, but not sodium nitroprusside-induced, relaxations of E degrees xLDLR degrees aorta was decreased. 3. PE induced rhythmic activity in both E degrees xLDLR degrees and control aorta but the amplitude was larger in E degrees xLDLR degrees than in control mice. PE-induced rhythmic activity in both E degrees xLDLR degrees and control aorta was augmented by increase in extracellular Ca2+-concentration, but was abolished by removal of the endothelium, the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor LY-83583, high K+ solution and ryanodine. 4. 4-Aminopyridine, a voltage-dependent potassium (KV) channel blocker, increased basal tension and induced rhythmic activity in E degrees xLDLR degrees aorta but not in control aorta. 5. The Ca2+-activated potassium (KCa) channel blockers tetraethylammonium and charybdotoxin abolished PE-induced rhythmic activity in E degrees xLDLR degrees aorta. 6. In conclusion, opening of Kv channels in E degrees xLDLR degrees mice aorta is reduced and it is susceptible to be depolarized resulting in Ca2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca2+-entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of KCa channels by NO via a cyclic GMP-dependent mechanism.
authors.affiliation: Department of Medicine, Division of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.forename: P
authors.initials: P
authors.lastname: Thorén
authors.forename: G
authors.initials: G
authors.lastname: Caligiuri
authors.forename: G K
authors.initials: GK
authors.lastname: Hansson
authors.forename: J
authors.initials: J
authors.lastname: Pernow
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001161:Arteriosclerosis / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007213:Indomethacin / Q000494:pharmacology; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D012433:Ryanodine; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D010042:Ouabain; D002772:Cholera Toxin; D015761:4-Aminopyridine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000109:Acetylcholine; D005905:Glyburide; D002118:Calcium; D007213:Indomethacin