Acetylcholine-induced systemic vasodilation resistant to NG-nitro-L-arginine in an anaesthetized rats.
1. The effects of NG-nitro-L-arginine (L-NNA; 20 mg/kg bodyweight (BW), i.v.) and metyrapone (300 mg/kg BW, s.c.) on acetylcholine (ACh)-induced depressor responses were investigated in anaesthetized rats. 2. Acetylcholine (0.05, 0.5, 5 micrograms/kg BW, i.v.) dose-dependently evoked a sharp fall in mean blood pressure (BP) followed by a slow recovery under control conditions. 3. Basal BP level was elevated when rats were treated with L-NNA, indicating endogenous nitric oxide (NO) participated in BP regulation. However, pretreatment with L-NNA did not attenuate but rather augmented the ACh-induced maximum vasodilation. In contrast, the time for recovery of mean BP to the pre-ACh administration level was shortened by L-NNA. These observations suggested that ACh-induced vasodilation consisted of two phases: a sharp and transient fall (phase 1) that was resistant to L-NNA followed by a longer depressor response (phase 2) that was suppressed by L-NNA. 4. To examine whether augmentation of phase 1 by L-NNA resulted from the elevation of basal BP, an appropriate dose of phenylephrine was infused to obtain similar BP elevation. Phenylephrine infusion augmented the phase 1 in a similar manner to L-NNA pretreatment but showed little effect on phase 2, supporting the selective inhibition of phase 2 by L-NNA. 5. The s.c. pretreatment with metyrapone for 3 days failed to attenuate phase 1. Thus, the involvement of endothelium-derived hyperpolarizing factor that could be formed by a metyrapone-sensitive oxidase in phase 1 was unlikely. 6. These results suggest that some factor(s), which is not inhibitable by L-NNA or metyrapone, may induce the phase 1 depressor response to ACh while NO is responsible for the phase 2 response. The mechanism inducing the phase 1 response remains to be identified.
Department of Pharmacology, Shimane Medical University, Izumo, Japan. phamcL29@shimane-med.ac.jp
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Kakizoe
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Wang
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Kobayashi
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Shimoura
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Okunishi
D000109:Acetylcholine / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D001685:Biological Factors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; C067410:endothelium-dependent hyperpolarization factor; D010656:Phenylephrine; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D008797:Metyrapone