title: Effects of exercise training and hypercholesterolemia on adenosine activation of voltage-dependent K+ channels in coronary arterioles.
abstract: Coronary arterioles from hypercholesterolemic swine display attenuated adenosine-mediated vasodilatation that is attributable to the elimination of voltage-dependent K(+) (Kv) channel stimulation. For the present study, we tested the hypotheses that exercise training would correct impaired adenosine-induced dilatation in coronary arterioles from hypercholesterolemic pigs through restoration of adenosine activation of Kv channels and that vasodilatation to the receptor-independent adenylyl cyclase activator, forskolin, would also be attenuated in arterioles from hypercholesterolemic pigs. Pigs were randomly assigned to a control (NC) or high-fat, high-cholesterol (HC) diet for 20 wk. Four weeks after the diet was initiated, pigs from both groups were assigned to exercise training (Ex; 5 days/wk for 16 wk) or sedentary (Sed) protocols, resulting in four groups of pigs: NC-Sed, NC-Ex, HC-Sed, and HC-Ex. Arterioles ( approximately 150 mum) from both HC-Sed and HC-Ex pigs displayed impaired adenosine-mediated dilatation that was attributable to the elimination of 4-aminopyridine (4-AP; 1 mM)-sensitive Kv channel activation compared with NC counterparts. Arteriolar smooth muscle whole cell Kv currents were significantly reduced in HC-Sed compared with NC-Sed, although HC-Ex and NC-Ex did not differ. Forskolin-mediated dilatation was attenuated by 4-AP (1 mM) and in a concentration-dependent manner by tetraethylammonium (TEA; 0.1-1 mM) in NC-Sed but not HC-Sed. Further, TEA-sensitive Kv currents were diminished in cells of HC-Sed compared with NC-Sed pigs. Quantitative RT-PCR revealed similar expression levels of Kv3.1 and 3.3 in arterioles of NC-Sed and HC-Sed swine with undetectable expression of Kv1.1, 3.2, and 3.4. Taken together, these results suggest that hypercholesterolemia-mediated attenuation of adenosine-induced vasodilatation in coronary arterioles is not corrected by exercise training and is likely attributable to an impairment in the pathway coupling adenylyl cyclase with a highly TEA-sensitive Kv channel isoform(s).
authors.affiliation: Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas, USA. CHeaps@cvm.tamu.edu
authors.forename: Cristine L
authors.initials: CL
authors.lastname: Heaps
authors.forename: Elise C
authors.initials: EC
authors.lastname: Jeffery
authors.forename: Glen A
authors.initials: GA
authors.lastname: Laine
authors.forename: Elmer M
authors.initials: EM
authors.lastname: Price
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Bowles
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002791:Cholesterol, Dietary / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006937:Hypercholesterolemia / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010805:Physical Conditioning, Animal / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013556:Swine, Miniature; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002791:Cholesterol, Dietary; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D005576:Colforsin; D019789:Tetraethylammonium; D015761:4-Aminopyridine; D000241:Adenosine