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CARDIOVASCULAR |
1 The John B. Pierce Laboratory, 290 Congress Avenue, New Haven, CT 06519, USA
2 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
3 Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
4 Department of Molecular, Cellular and Developmental Biology, New Haven, CT 06520, USA
5 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
6 Dalton Cardiovascular Research Center, Columbia, MO 65211, USA
Conducted vasodilatation (CVD) reflects the initiation and rapid (>mm s–1) spread of hyperpolarization along the endothelium and into smooth muscle. The ion channels that initiate CVD remain unclear as do signalling pathways that may complement electromechanical relaxation. Using isolated pressurized (75 mmHg; 37°C) feed arteries (n
= 63; diameter: rest: 53 ± 2 µm, maximal: 98 ± 2 µm) from hamster retractor skeletal muscle, we investigated the contribution of calcium-activated potassium channels (KCa) and endothelium-derived autacoids to CVD. Local delivery (1 µm micropipette tip; 500–2000 ms pulse) of acetylcholine (ACh) at the downstream end initiated a local increase in endothelial cell [Ca2+]i (Fura-PE3; 
ratio 340/380 nm = 0.215 ± 0.032) that preceded CVD along the entire vessel. During local perifusion with KCa antagonists, iberiotoxin (5 µM) had no effect, but charybdotoxin (CTX, 5 µM) + apamin (APA, 10 µM) abolished CVD reversibly. Remarkably, this local inhibition of KCa unmasked a ‘slow-conducted vasodilatation’ (SCVD) that spread >1200 µm at 
21 µm s–1 (n
= 27). Recorded 500 µm upstream from the ACh stimulus, a rise in endothelial cell [Ca2+]i (ratio 340/380 nm) = 0.146 ± 0.017; P < 0.05) preceded SCVD (diameter = 14 ± 3 µm) by 10 s. Before KCa inhibition, antagonism of nitric oxide synthase (N
-nitro-L-arginine, 250 µM; L-NNA) and cyclooxygenase (indomethacin, 5 µM; INDO) had no effect on the amplitude of CVD yet response duration decreased by one-third (P < 0.05). During local CTX + APA perifusion, L-NNA + INDO abolished SCVD while conducted [Ca2+]i responses remained intact. Thus, ACh triggers electromechanical relaxation of smooth muscle cells along the vessel initiated by local KCa, and the ensuing ‘wave’ of Ca2+ along the endothelium releases autacoids to promote pharmacomechanical relaxation.
(Received 7 November 2006;
accepted after revision 28 November 2006;
first published online 30 November 2006)
Corresponding author S. S. Segal, Ph. D.: Department of Medical Pharmacology and Physiology, School of Medicine, 1 Hospital Drive, MA415 Medical Sciences Building, University of Missouri – Columbia, Columbia, MO 65212, USA. Email: segalss{at}health.missouri.edu
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