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. 1997 Dec 1;100(11):2793–2799. doi: 10.1172/JCI119826

Importance of endothelium-derived hyperpolarizing factor in human arteries.

L Urakami-Harasawa 1, H Shimokawa 1, M Nakashima 1, K Egashira 1, A Takeshita 1
PMCID: PMC508484  PMID: 9389744

Abstract

The endothelium plays an important role in maintaining the vascular homeostasis by releasing vasodilator substances, including prostacyclin (PGI2), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Although the former two substances have been investigated extensively, the importance of EDHF still remains unclear, especially in human arteries. Thus we tested our hypothesis that EDHF plays an important role in human arteries, particularly with reference to the effect of vessel size, its vasodilating mechanism, and the influences of risk factors for atherosclerosis. Isometric tension and membrane potentials were recorded in isolated human gastroepiploic arteries and distal microvessels (100-150 microm in diameter). The contribution of PGI2, NO, and EDHF to endothelium-dependent relaxations was analyzed by inhibitory effects of indomethacin, NG-nitro- L-arginine, and KCl, respectively. The nature of and hyperpolarizing mechanism by EDHF were examined by the inhibitory effects of inhibitors of cytochrome P450 pathway and of various K channels. The effects of atherosclerosis risk factors on EDHF-mediated relaxations were also analyzed. The results showed that (a) the contribution of EDHF to endothelium-dependent relaxations is significantly larger in microvessels than in large arteries; (b) the nature of EDHF may not be a product of cytochrome P450 pathway, while EDHF-induced hyperpolarization is partially mediated by calcium-activated K channels; and (c) aging and hypercholesterolemia significantly impair EDHF-mediated relaxations. These results demonstrate that EDHF also plays an important role in human arteries.

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Selected References

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  1. Bauersachs J., Hecker M., Busse R. Display of the characteristics of endothelium-derived hyperpolarizing factor by a cytochrome P450-derived arachidonic acid metabolite in the coronary microcirculation. Br J Pharmacol. 1994 Dec;113(4):1548–1553. doi: 10.1111/j.1476-5381.1994.tb17172.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Campbell W. B., Gebremedhin D., Pratt P. F., Harder D. R. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res. 1996 Mar;78(3):415–423. doi: 10.1161/01.res.78.3.415. [DOI] [PubMed] [Google Scholar]
  3. Candia S., Garcia M. L., Latorre R. Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel. Biophys J. 1992 Aug;63(2):583–590. doi: 10.1016/S0006-3495(92)81630-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohen R. A., Vanhoutte P. M. Endothelium-dependent hyperpolarization. Beyond nitric oxide and cyclic GMP. Circulation. 1995 Dec 1;92(11):3337–3349. doi: 10.1161/01.cir.92.11.3337. [DOI] [PubMed] [Google Scholar]
  5. Corriu C., Félétou M., Canet E., Vanhoutte P. M. Inhibitors of the cytochrome P450-mono-oxygenase and endothelium-dependent hyperpolarizations in the guinea-pig isolated carotid artery. Br J Pharmacol. 1996 Feb;117(4):607–610. doi: 10.1111/j.1476-5381.1996.tb15233.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cowan C. L., Steffen R. P. Lysophosphatidylcholine inhibits relaxation of rabbit abdominal aorta mediated by endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor independent of protein kinase C activation. Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2290–2297. doi: 10.1161/01.atv.15.12.2290. [DOI] [PubMed] [Google Scholar]
  7. Eizawa H., Yui Y., Inoue R., Kosuga K., Hattori R., Aoyama T., Sasayama S. Lysophosphatidylcholine inhibits endothelium-dependent hyperpolarization and N omega-nitro-L-arginine/indomethacin-resistant endothelium-dependent relaxation in the porcine coronary artery. Circulation. 1995 Dec 15;92(12):3520–3526. doi: 10.1161/01.cir.92.12.3520. [DOI] [PubMed] [Google Scholar]
  8. Fujii K., Ohmori S., Tominaga M., Abe I., Takata Y., Ohya Y., Kobayashi K., Fujishima M. Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery. Am J Physiol. 1993 Aug;265(2 Pt 2):H509–H516. doi: 10.1152/ajpheart.1993.265.2.H509. [DOI] [PubMed] [Google Scholar]
  9. Fujii K., Tominaga M., Ohmori S., Kobayashi K., Koga T., Takata Y., Fujishima M. Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ Res. 1992 Apr;70(4):660–669. doi: 10.1161/01.res.70.4.660. [DOI] [PubMed] [Google Scholar]
  10. Hecker M., Bara A. T., Bauersachs J., Busse R. Characterization of endothelium-derived hyperpolarizing factor as a cytochrome P450-derived arachidonic acid metabolite in mammals. J Physiol. 1994 Dec 1;481(Pt 2):407–414. doi: 10.1113/jphysiol.1994.sp020449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mantelli L., Amerini S., Ledda F. Roles of nitric oxide and endothelium-derived hyperpolarizing factor in vasorelaxant effect of acetylcholine as influenced by aging and hypertension. J Cardiovasc Pharmacol. 1995 Apr;25(4):595–602. doi: 10.1097/00005344-199504000-00013. [DOI] [PubMed] [Google Scholar]
  12. Murphy M. E., Brayden J. E. Apamin-sensitive K+ channels mediate an endothelium-dependent hyperpolarization in rabbit mesenteric arteries. J Physiol. 1995 Dec 15;489(Pt 3):723–734. doi: 10.1113/jphysiol.1995.sp021086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Najibi S., Cohen R. A. Enhanced role of K+ channels in relaxations of hypercholesterolemic rabbit carotid artery to NO. Am J Physiol. 1995 Sep;269(3 Pt 2):H805–H811. doi: 10.1152/ajpheart.1995.269.3.H805. [DOI] [PubMed] [Google Scholar]
  14. Najibi S., Cowan C. L., Palacino J. J., Cohen R. A. Enhanced role of potassium channels in relaxations to acetylcholine in hypercholesterolemic rabbit carotid artery. Am J Physiol. 1994 May;266(5 Pt 2):H2061–H2067. doi: 10.1152/ajpheart.1994.266.5.H2061. [DOI] [PubMed] [Google Scholar]
  15. Nakashima M., Mombouli J. V., Taylor A. A., Vanhoutte P. M. Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest. 1993 Dec;92(6):2867–2871. doi: 10.1172/JCI116907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pascoal I. F., Umans J. G. Effect of pregnancy on mechanisms of relaxation in human omental microvessels. Hypertension. 1996 Aug;28(2):183–187. doi: 10.1161/01.hyp.28.2.183. [DOI] [PubMed] [Google Scholar]
  17. Reinhart P. H., Chung S., Levitan I. B. A family of calcium-dependent potassium channels from rat brain. Neuron. 1989 Jan;2(1):1031–1041. doi: 10.1016/0896-6273(89)90227-4. [DOI] [PubMed] [Google Scholar]
  18. Rosolowsky M., Campbell W. B. Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid. Am J Physiol. 1993 Feb;264(2 Pt 2):H327–H335. doi: 10.1152/ajpheart.1993.264.2.H327. [DOI] [PubMed] [Google Scholar]
  19. Shimokawa H., Takeshita A. Endothelium-dependent regulation of the cardiovascular system. Intern Med. 1995 Oct;34(10):939–946. doi: 10.2169/internalmedicine.34.939. [DOI] [PubMed] [Google Scholar]
  20. Shimokawa H., Yasutake H., Fujii K., Owada M. K., Nakaike R., Fukumoto Y., Takayanagi T., Nagao T., Egashira K., Fujishima M. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol. 1996 Nov;28(5):703–711. doi: 10.1097/00005344-199611000-00014. [DOI] [PubMed] [Google Scholar]
  21. Tagawa H., Shimokawa H., Tagawa T., Kuroiwa-Matsumoto M., Hirooka Y., Takeshita A. Short-term estrogen augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women. J Cardiovasc Pharmacol. 1997 Oct;30(4):481–488. doi: 10.1097/00005344-199710000-00012. [DOI] [PubMed] [Google Scholar]
  22. Wallerstedt S. M., Bodelsson M. Endothelium-dependent relaxation by substance P in human isolated omental arteries and veins: relative contribution of prostanoids, nitric oxide and hyperpolarization. Br J Pharmacol. 1997 Jan;120(1):25–30. doi: 10.1038/sj.bjp.0700879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Weintraub N. L., Joshi S. N., Branch C. A., Stephenson A. H., Sprague R. S., Lonigro A. J. Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid. Hypertension. 1994 Jun;23(6 Pt 2):976–981. doi: 10.1161/01.hyp.23.6.976. [DOI] [PubMed] [Google Scholar]
  24. Zygmunt P. M., Högestätt E. D. Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery. Br J Pharmacol. 1996 Apr;117(7):1600–1606. doi: 10.1111/j.1476-5381.1996.tb15327.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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