Electromechanical and pharmacomechanical signalling pathways for conducted vasodilatation along endothelium of hamster feed arteries

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Abstract

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; Δratio 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 (Δratio 340/380 nm) = 0.146 ± 0.017; P < 0.05) preceded SCVD (Δdiameter = 14 ± 3 μm) by ∼10 s. Before KCa inhibition, antagonism of nitric oxide synthase (Nω-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.

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