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Vol. 282, Issue 3, 1473-1479, 1997

Role of Nitric Oxide and Ca++-Dependent K+ Channels in Mediating Heterogeneous Microvascular Responses to Acetylcholine in Different Vascular Beds1

Shawn G. Clark and Leslie C. Fuchs

Vascular Biology Center and Department of Pharmacology, Medical College of Georgia, Augusta, Georgia

Endothelium-derived relaxing factors may differentially modulate vascular tone and relaxation in arteries from specific vascular beds. We evaluated the role of nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor in determining basal tone and acetylcholine (ACh)-induced relaxation of coronary (Cor), skeletal muscle (Ske) and mesenteric (Mes) small arteries (150-250 µm) isolated from male Golden Syrian hamsters (16-17 weeks). Intraluminal diameter (ID) was recorded in vessels maintained at a constant pressure of 40 mm Hg. Charybdotoxin (0.1 µM), a blocker of large Ca++-dependent K+ channels (BKCa), decreased base-line ID by 33 ± 4% and 15 ± 4% in Cor and Mes small arteries, respectively. Neither the nitric oxide synthase (NOS) inhibitor, Nomega -nitro-L-arginine (LNA, 0.1 mM), indomethacin (10-5 M) nor apamin (0.5 µM), which blocks small Ca++-dependent K+ channels (SKCa), affected ID. Maximal relaxation to ACh was significantly reduced by LNA in Cor arteries preconstricted with the thromboxane A2 analog, U46619. LNA shifted the dose-response curve to the right without altering maximal relaxation to ACh in Mes arteries and had no effect on relaxation to ACh in Ske arteries relaxation. A high extracellular K+ concentration (25-50 mM) largely reduced relaxation to ACh in Ske and Mes and abolished relaxation in Cor arteries, whereas indomethacin had no effect on any vessel. Blockade of both BKCa and SKCa channels with a combination of charybdotoxin and apamin abolished relaxation to ACh in Cor, but had no effect in Mes or Ske arteries. Collectively, these results indicate that ACh-induced relaxation is mediated by both NO and an endothelium-derived hyperpolarizing factor that opens K+ channels independently of NO or PGI2 in Cor and Mes arteries. Relaxation of Ske arteries is completely due to a NO and PGI2-independent opening of K+ channels. Relaxation to ACh is mediated by KCa channels in Cor arteries, and by other types of K+ channels in Ske and Mes arteries. Additionally, BKCa channels regulate basal tone in Cor and Mes, but not Ske arteries. These results indicate that arteries of similar size use different mechanisms of endothelium-dependent regulation of vascular tone and relaxation which are dependent on the vascular bed.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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