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Acetylcholine-induced relaxation and hyperpolarization in small bovine adrenal cortical arteries: Role of cytochrome P450 metabolites

Endocrinology, ISSN: 0013-7227, Vol: 145, Issue: 10, Page: 4532-4539
2004
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The present study characterizes the vascular responses of isolated small bovine adrenal cortical arteries to acetylcholine, an endogenous neurotransmitter in the adrenal gland. Acetylcholine (10 to 10 M) elicited a concentration-dependent relaxation, with a maximal relaxation of 96 ± 1% and EC of 4.2 nM. The relaxation was abolished by endothelial removal and attenuated by the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA, 30 μM) but not by the cyclooxygenase inhibitor indomethacin (10 μM). The maximal relaxation and EC of acetylcholine in the presence of L-NA were 87 ± 4% and 22 nM, respectively. The acetylcholine-induced, indomethacin- and L-NA-resistant relaxation was eliminated by high K and markedly inhibited by the cytochrome P450 inhibitors SKF 525A (10 μM) and miconazole (10 μM). The maximal relaxations and ECs with SKF 525A and miconazole were 56 ± 8 and 72 ± 2% and 0.8 and 0.5 μM, respectively. In indomethacin- and L-NA-treated arteries, acetylcholine induced a smooth muscle hyperpolarization, which was blocked by SKF 525A (3 ± 1 mV vs. 15 ± 2 mV of control). Arachidonic acid (10 to 10 M) and 14,15-epoxyeicosatrienoic acid (14,15-EET, 10 to 10 M), a cytochrome P450 metabolite of arachidonic acid, also evoked relaxations in small adrenal arteries, with maximal relaxations of 56 ± 4 and 90 ± 5%, respectively. The arachidonic acid-induced relaxation was blocked by SKF 525A. Using high-pressure liquid chromatography and gas chromatography/mass spectrometry analysis, EETs were identified in small adrenal arteries. These results demonstrate that acetylcholine is a potent vasodilator of small adrenal cortical arteries. The acetylcholine-induced relaxation is largely mediated by an endothelium-dependent hyperpolarization mechanism, presumably through cytochrome P450 metabolites of arachidonic acid.

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