Different modulation by Ca2+-activated K+ channel blockers and herbimycin of acetylcholine- and flow-evoked vasodilatation in rat mesenteric small arteries.
1. The present study addressed whether endothelium-dependent vasodilatation evoked by acetylcholine and flow are mediated by the same mechanisms in isolated rat mesenteric small arteries, suspended in a pressure myograph for the measurement of internal diameter. 2. In pressurized arterial segments contracted with U46619 in the presence of indomethacin, shear stress generated by the flow evoked relaxation. Thus, in endothelium-intact segments low (5.1+/-0.6 dyn cm(-2)) and high (19+/-2 dyn cm(-2)) shear stress evoked vasodilatations that were reduced by, respectively, 68+/-11 and 68+/-8% (P<0.05, n=7) by endothelial cell removal. Acetylcholine (0.01-1 microM) evoked concentration-dependent vasodilatation that was abolished by endothelial cell removal. 3. Incubation with indomethacin alone did not change acetylcholine and shear stress-evoked vasodilatation, while the combination of indomethacin with the nitric oxide (NO) synthase inhibitor, N(G),N(G)-asymmetric dimethyl-L-arginine (ADMA 1 mM), reduced low and high shear stress-evoked vasodilatation with, respectively, 52+/-15 and 58+/-10% (P<0.05, n=9), but it did not change acetylcholine-evoked vasodilatation. 4. Inhibition of Ca(2+)-activated K(+) channels with a combination of apamin (0.5 microM) and charybdotoxin (ChTX) (0.1 microM) did not change shear stress- and acetylcholine-evoked vasodilatation. In the presence of indomethacin and ADMA, the combination of apamin (0.5 microM) and ChTx (0.1 microM) increased contraction induced by U46619, but these blockers did not change the vasodilatation evoked by shear stress. In contrast, acetylcholine-evoked vasodilatation was abolished by the combination of apamin and charybdotoxin. 5. In the presence of indomethacin, the tyrosine kinase inhibitor, herbimycin A (1 microM), inhibited low and high shear stress-evoked vasodilatation with, respectively, 32+/-12 and 68+/-14% (P<0.05, n=8), but it did not change vasodilatation induced by acetylcholine. In the presence of indomethacin and ADMA, herbimycin A neither changed shear stress nor acetylcholine-evoked vasodilatation. 6. The present study suggests that Ca(2+)-activated K(+) channels sensitive for the combination of apamin and ChTx are involved in acetylcholine-evoked, mainly non-NO nonprostanoid factor-mediated, vasodilatation, while an Src tyrosine kinase plays a role for flow-evoked NO-mediated vasodilatation in rat mesenteric small arteries.
Department of Pharmacology, University of Aarhus, 8000 Aarhus C, Denmark.
Michael
M
Thorsgaard
Vanesa
V
Lopez
Niels H
NH
Buus
Ulf
U
Simonsen
D000109:Acetylcholine / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D016227:Benzoquinones; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017828:Rifabutin / Q000031:analogs & derivatives; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D000109:Acetylcholine