Vasorelaxant effect of fluoxetine in isolated rat aorta

흰쥐 대동맥에서 fluoxetine의 혈관 이완 효과

  • Kim, Shang-Jin (Bio-Safety Research Institute, Chonbuk National University) ;
  • Kang, Hyung-sub (Bio-Safety Research Institute, Chonbuk National University) ;
  • Kim, Jin-shang (Bio-Safety Research Institute, Chonbuk National University)
  • 김상진 (전북대학교 생체안전성연구소) ;
  • 강형섭 (전북대학교 생체안전성연구소) ;
  • 김진상 (전북대학교 생체안전성연구소)
  • Accepted : 2004.08.25
  • Published : 2004.12.30

Abstract

The vasorelaxant effect of serotonin reuptake inhibitor fluoxetine was investigated in rat isolated thoracic aorta. Fluoxetine induced a concentration-dependent relaxation in aorta precontracted with phenylephrine (PE) and KCl. These relaxations were suppressed by removal of the endothelium (-E) or pretreatment of nitric oxide synthase inhibitors, N(G)-nitro-L-arginine (L-NNA) and N(omega)-nitro-Larginine methyl ester (L-NAME), guanylate cyclase inhibitors, methylene blue (MB) and 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), and $Ca^{2+}$ channel blockers, nifedipine and verapamil, in PE-precontracted +E rings. However, fluoxetine-induced relaxations were not suppressed by pretreatment of $K^{+}$ channel blockers, tetrabutylammonium and glibenclamide, in PE-precontracted endothelium intact (+E) rings. The fluoxetine-induced relaxations were not suppressed by removal of the endothelium or pretreatment of LNNA and MB in KCl-precontracted +E rings. Also, fluoxetine inhibited PE-induced sustained contraction in +E rings. These inhibitory effects of fluoxetine on contractions could be reversed by removal of the endothelium or pretreatment of L-NNA, L-NAME, MB, ODQ, nifedipine and verapamil, but not by pretreatment of etrabutylammonium and glibenclamide. These findings suggest that the vasorelaxant effect of fluoxetine is modulated by intracellular $Ca^{2+}$ with an involvement of endothelial NO-cGMP pathway and also may be related to the inhibition of $Ca^{2+}$ entry through voltage-gated channel.

Acknowledgement

Supported by : 전북대학교

References

  1. Brayden, J. E. Potassium channels in vascular smooth muscle. Clin. Exp. Pharmacol. Physiol. 1996, 23, 1069-1076
  2. Busch, L., Wald, M., Sterin-Borda, L. and Borda, E. Fluoxetine modulates norepinephrine contractile effect on rat vas deferens. Pharmacol. Res. 2000, 41, 39-45
  3. Carvajal, J. A., Germain, A. M., Huidobro-Toro, J. P. and Weiner, C. P. Molecular mechanism of cGMPmediated smooth muscle relaxation. J. Cell Physiol. 2000, 184, 409-420
  4. Cauvin, C., Loutzenhiser, R. and van Breemen, C. Mechanism of calcium-antagonist induced vasodilation. Annu. Rev. Pharmacol. 1983, 23, 373-396
  5. Ellis, E. S., Byrne, C., Murphy, O. E., Tilford, N. S. and Baxter, G. S. Mediation by 5-hydroxytryptamine 2B receptors of endothelium-dependent relaxation in rat jugular vein. Br. J. Pharmacol. 1995, 114, 400-404
  6. Fernandez del Pozo, B., Perez-Vizcaino, F., Fernandez, C., Zaragoza, F. and Tamargo, J. Effects of several class I antiarrhythmic drugs on isolated rat aortic vascular smooth muscle. Gen. Pharmacol. 1997, 29, 539-543
  7. Garcia-Colunga, J., Awad, J. N. and Miledi, R. Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac). Proc. Natl. Acad. Sci. USA. 1997, 94, 2041-2044
  8. Glusa, E. and Pertz, H. H. Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors. Br. J. Pharmacol. 2000, 130, 692-698
  9. Huang, Y. Inhibitory effect of noradrenalin uptake inhibitors on contractions of rat aortic smooth muscle. Br. J. Pharmacol. 1996, 117, 533-539
  10. Hudgins, P. M. and Weiss, G. B. Differential effects of calcium removal upon vascular smooth muscle contraction induced by norepinephrine, histamine and potassium. J. Pharmacol. Exp. Ther. 1968, 159, 91-97
  11. Jagadesh, S. R. and Subhash, M. N. Effect of antidepressants on intracellular $Ca^{2+}$ mobilization in human frontal cortex. Biol. Psychiatery. 1998, 44, 617-621
  12. Karaki, H., Ozaki, H., Hori, M., Mitsui-Saito, M., Amano, K., Harada, K., Miyamoto, S., Nakazawa, H., Won, K. J. and Sato, K. Calcium movements, distribution, and functions in smooth muscle. Pharmacol. Rev. 1997, 49, 157-230
  13. Lavoie, P. A., Beauchamp, G. and Elie, R. Atypical antidepressants inhibit depolarization-induced calcium uptake in rat hippocampus synaptosomes. Can. J. Physiol. Pharmacol. 1997, 75, 983-987
  14. Leung, E., Walsh, L. K., Pulido-Rios, M. T. and Eglen, R. M. Characterization of putative 5-$HT_7$ receptors mediating direct relaxation in Cynomolgus monkey isolated jugular vein. Br. J. Pharmacol. 1996, 117, 926-930
  15. Li, Q., Brownfield, M. S., Battaglia, G., Cabrera, T. M., Levy, A. D., Rittenhouse, P. A. and van de Kar, L. D. Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). J. Pharmacol. Exp. Ther. 1993, 266, 836-844
  16. Lucchelli, A., Santagostino-Barbone, M. G., Masoero, E., Baiardi, P. and Tonini, M. Influence of fluoxetine and litoxetine on 5-$HT_4$ receptor-mediated relaxation in the rat isolated oesophagus. Fundam. Clin. Pharmacol. 1999, 13, 330-336
  17. McLean, P. G. and Coupar, I. M. Characterisation of a postjunctional 5-$HT_7$-like and a prejunctional 5-$HT_3$ receptor mediating contraction of rat isolated jejunum. Eur. J. Pharmacol. 1996, 312, 215-225
  18. Nakajima, T., Hazama, H., Hamada, E., Wu, S. N., Igarashi, K., Yamashita, T., Seyama, Y., Omata, M. and Kurachi, Y. Endothelin-1 and vasopressin activate Ca(2+)-permeable non-selective cation channels in aortic smooth muscle cells: mechanism of receptormediated $Ca^{2+}$ influx. J. Mol. Cell Cardiol. 1996, 28, 707-722
  19. Ni, Y. G. and Miledi, R. Blockage of 5-$HT_{2C}$ serotonin receptors by fluoxetine (Prozac). Proc. Natl. Acad. Sci. USA. 1997, 94, 2036-2040
  20. Pacher, P., Ungvari, Z., Kecskemeti, V. and Koller, A. Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal muscle arterioles. Possible role of altered $Ca^{2+}$ sensitivity. Br. J. Pharmacol. 1999, 127, 740-746
  21. Pacher, P., Ungvari, Z., Kecskemeti, V., Friedmann, T. and Furst, S. Serotonin reuptake inhibitors fluoxetine and citalopram relax intestinal smooth muscle. Can. J. Physiol. Pharmacol. 2001, 79, 580-584
  22. Pancrazio, J. J., Kamatchi, G. L., Roscoe, A. K. and Lynch, C. 3rd. Inhibition of neuronal $Na^+$ channels by antidepressant drugs. J. Pharmacol. Exp. Ther. 1998, 284, 208-214
  23. Pitt, B. R., Weng, W., Steve, A. R., Blakely, R. D., Reynolds, I. and Davies, P. Serotonin increases DNA synthesis in rat proximal and distal pulmonary vascular smooth muscle cells in culture. Am. J. Physiol. 1994, 266, L178-186
  24. Reeves, J. J., Bunce, K. T. and Humphrey, P. P. Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus. Br. J. Pharmacol. 1991, 103, 1067-1072
  25. Somlyo, A. P. and Himpens, B. Cell calcium and its regulation in smooth muscle. FASEB J. 1989, 3, 2266-2276
  26. Taggart, M. J., Menice, C. B., Morgan, K. G. and Wray, S. Effect of metabolic inhibition on intracellular $Ca^{2+}$, phosphorylation of myosin regulatory light chain and force in rat smooth muscle. J. Physiol. 1997, 499, 485-496
  27. Terron, J. A. Antagonism of the relaxant 5-HT receptor in the dog basilar artery by the high-affinity 5-$HT_7$ receptor ligand, LY215840. Proc. West Pharmacol. Soc. 1998, 41, 129-130
  28. Terron, J. A. and Falcon-Neri, A. Pharmacological evidence for the 5-$HT_7$ receptor mediating smooth muscle relaxation in canine cerebral arteries. Br. J. Pharmacol. 1999, 127, 609-616
  29. Tuladhar, B. R., Costall, B. and Naylor, R. J. Pharmacological characterization of the 5-hydroxytryptamine receptor mediating relaxation in the rat isolated ileum. Br. J. Pharmacol. 1996, 119, 303-310
  30. Tytgat, J., Maertens, C. and Daenens, P. Effect of fluoxetine on a neuronal voltage-dependent potassium channel. Br. J. Pharmacol. 1997, 122. 1417-1424
  31. Ungvari, Z., Pacher, P. and Koller, A. Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic tone by reducing smooth muscle [$Ca^{2+}$]i. J. Cardiovasc. Pharmacol. 2000, 35, 849-854
  32. Ungvari, Z., Pacher, P., Kecskemeti, V. and Koller, A. Fluoxetine dilates isolated small cerebral arteries of rats and attenuates constrictions to serotonin, norepinephrine, and a voltage-dependent Ca(2+) channel opener. Stroke. 1999, 30, 1949-1954
  33. Velasco, A., Alamo, C., Hervas, J. and Carvajal, A. Effects of fluoxetine hydrochloride and fluvoxamine maleate on different preparations of isolated guinea pig and rat organ tissues. Gen. Pharmacol. 1997, 28, 509-512
  34. Vila, J. M., Medina, P., Segarra, G., Lluch, P., Pallardo, F., Flor, B. and Lluch, S. Relaxant effects of antidepressants on human isolated mesenteric arteries. Br. J. Clin. Pharmacol. 1999, 48, 223-229
  35. Villazon, M., Padin, J. F., Cadavid, M. I., Enguix, M, J., Tristan, H., Orallo, F. and Loza, M. I. Functional characterization of serotonin receptors in rat isolated aorta. Biol. Pharm. Bull. 2002, 25, 584-590