Components of acetylcholine-induced dilation in isolated rat arterioles.
Acetylcholine-induced dilation was studied in cannulated resistance arteries of rat cremaster muscle. Pressurized arteriolar segments (internal diameter: 175 +/- 2 microm) developed spontaneous tone (90 +/- 2 microm). Application of acetylcholine (0.1 and 0.3 microM) resulted in a transient dilation followed by a steady-state dilatory response. In the presence of N(G)-nitro-L-arginine (L-NNA) approximately 70% of the transient dilation was resistant to nitric oxide inhibition, whereas the steady-state response was abolished. Further experiments using 0.1 microM acetylcholine (no L-NNA present) were aimed to inhibit synthesis or action of the mediator of the transient component (amplitude: 39 +/- 2.8 microm). A high-potassium buffer (30-50 mM) abolished this transient dilation (1.3 +/- 1.3 microm), suggesting that the dilation is mediated by an endothelium-derived hyperpolarizing factor (EDHF). This putative EDHF-mediated dilation is strongly reduced by cytochrome P-450 inhibitors miconazole (11 +/- 1.3 microm) and SKF-525a (4.8 +/- 4.5 microm). The transient component is inhibited by tetraethylammonium but not by glibenclamide, indicating it is mediated by opening of Ca2+-activated K+ channels. Interestingly, inhibition of the transient component was followed by a subsequent decrease of the nitric oxide-mediated part of the response to acetylcholine. Thus a transient dilation, mediated by a cytochrome P-450 metabolite, precedes and possibly stimulates nitric oxide-mediated dilation in acetylcholine-induced dilation.
Bakker
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EN
Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands.
Sipkema
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D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001685:Biological Factors / Q000008:administration & dosage / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019789:Tetraethylammonium / Q000494:pharmacology; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001685:Biological Factors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C067410:endothelium-dependent hyperpolarization factor; D019335:Nitroarginine; D009569:Nitric Oxide; D019789:Tetraethylammonium; D000109:Acetylcholine; D011188:Potassium; D005905:Glyburide