Twenty-four-hour exposure to altered blood flow modifies endothelial Ca2+-activated K+ channels in rat mesenteric arteries.
We tested the hypothesis that changes in arterial blood flow modify the function of endothelial Ca2+-activated K+ channels [calcium-activated K+ channel (K(Ca)), small-conductance calcium-activated K+ channel (SK3), and intermediate calcium-activated K+ channel (IK1)] before arterial structural remodeling. In rats, mesenteric arteries were exposed to increased [+90%, high flow (HF)] or reduced blood flow [-90%, low flow (LF)] and analyzed 24 h later. There were no detectable changes in arterial structure or in expression level of endothelial nitric-oxide synthase, SK3, or IK1. Arterial relaxing responses to acetylcholine and 3-oxime-6,7-dichlore-1H-indole-2,3-dione (NS309; activator of SK3 and IK1) were measured in the absence and presence of endothelium, NO, and prostanoid blockers, and 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo [b,n] [1,5,12,16]tetraazacyclotricosine-5,13-diium dibromide (UCL 1684; inhibitor of SK3) or 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; inhibitor of IK1). In LF arteries, endothelium-dependent relaxation was markedly reduced, due to a reduction in the endothelium-derived hyperpolarizing factor (EDHF) response. In HF arteries, the balance between the NO/prostanoid versus EDHF response was unaltered. However, the contribution of IK1 to the EDHF response was enhanced, as indicated by a larger effect of TRAM-34 and a larger residual NS309-induced relaxation in the presence of UCL 1684. Reduction of blood flow selectively blunts EDHF relaxation in resistance arteries through inhibition of the function of K(Ca) channels. An increase in blood flow leads to a more prominent role of IK1 channels in this relaxation.
Hilgers
Rob H P
RH
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Janssen
Ger M J
GM
Fazzi
Gregorio E
GE
De Mey
Jo G R
JG
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009119:Muscle Contraction; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010091:Oximes / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D011921:Rats, Inbred WKY; D018160:Receptors, Cytoplasmic and Nuclear / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000071756:Soluble Guanylyl Cyclase; D013152:Splanchnic Circulation; D013314:Stress, Mechanical
C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496901:Kcnn3 protein, rat; C491575:Kcnn4 protein, rat; D010091:Oximes; D024681:Potassium Channels, Calcium-Activated; D018160:Receptors, Cytoplasmic and Nuclear; D051640:Small-Conductance Calcium-Activated Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D000109:Acetylcholine