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Acetylcholine-induced relaxation and hyperpolarization in small bovine adrenal cortical arteries: role of cytochrome P450 metabolites. Endocrinology 2004 Oct;145(10):4532-9 PMID: 15231705

Pubmed ID

15231705

Abstract

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(-10) to 10(-6) m) elicited a concentration-dependent relaxation, with a maximal relaxation of 96 +/- 1% and EC50 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 microm) but not by the cyclooxygenase inhibitor indomethacin (10 microm). The maximal relaxation and EC50 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 microm) and miconazole (10 microm). The maximal relaxations and EC50s with SKF 525A and miconazole were 56 +/- 8 and 72 +/- 2% and 0.8 and 0.5 microm, 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(-9) to 10(-5) m) and 14,15-epoxyeicosatrienoic acid (14,15-EET, 10(-9) to 10(-5) 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.

Author List

Zhang DX, Gauthier KM, Campbell WB

Authors

William B. Campbell PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-4644284906   8 Citations

MESH terms used to index this publication - Major topics in bold

Acetylcholine
Adrenal Cortex
Animals
Arachidonic Acid
Arteries
Cattle
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Drug Resistance
Electrophysiology
Enzyme Inhibitors
In Vitro Techniques
Indomethacin
Muscle, Smooth, Vascular
Nitroarginine
Vasodilation
Vasodilator Agents
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e