Disruption of endothelial caveolae is associated with impairment of both NO- as well as EDHF in acetylcholine-induced relaxation depending on their relative contribution in different vascular beds.
Caveolae represent an important structural element involved in endothelial signal-transduction. The present study was designed to investigate the role of caveolae in endothelium-dependent relaxation of different vascular beds. Caveolae were disrupted by cholesterol depletion with filipin (4x10(-6) g L(-1)) or methyl-beta-cyclodextrin (MCD; 1x10(-3) mol L(-1)) and the effect on endothelium-dependent relaxation was studied in rat aorta, small renal arteries and mesenteric arteries in the absence and presence of L-NMMA. The contribution of NO and EDHF, respectively, to total relaxation in response to acetylcholine (ACh) gradually changed from aorta (71.2+/-6.1% and 28.8+/-6.1%), to renal arteries (48.6+/-6.4% and 51.4+/-6.4%) and to mesenteric arteries (9.1+/-4.0% and 90.9+/-4.1%). Electron microscopy confirmed filipin to decrease the number of endothelial caveolae in all vessels studied. Incubation with filipin inhibited endothelium-dependent relaxation induced by cumulative doses of ACh (3x10(-9)-10(-4) mol L(-1)) in all three vascular beds. In aorta, treatment with either filipin or MCD only inhibited the NO component, whereas in renal artery both NO and EDHF formation were affected. In contrast, in mesenteric arteries, filipin treatment only reduced EDHF formation. Disruption of endothelial caveolae is associated with the impairment of both NO and EDHF in acetylcholine-induced relaxation.
Xu
Y
Y
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, University of Groningen, University Medical Center Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands. y.xu@med.umcg.nl
Henning
R H
RH
van der Want
J J L
JJ
van Buiten
A
A
van Gilst
W H
WH
Buikema
H
H
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001158:Arteries / Q000378:metabolism / Q000648:ultrastructure; D001685:Biological Factors / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005372:Filipin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001685:Biological Factors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D047392:beta-Cyclodextrins; C067410:endothelium-dependent hyperpolarization factor; C108732:methyl-beta-cyclodextrin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D005372:Filipin; D000109:Acetylcholine