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Volume 14, Issue 2 (2-2016)
IJRM 2016, 14(2): 109-116 |
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Sandoughdaran S, Sadeghipour H, Sadeghipour H R. Effect of acute lithium administration on penile erection: involvement of nitric oxide system. IJRM 2016; 14 (2) :109-116
URL: http://ijrm.ir/article-1-722-en.html
URL: http://ijrm.ir/article-1-722-en.html
1- Department of Radiation Oncology, Shohada-e-Tajrish Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2- Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
3- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran , sadeghipour@tums.ac.ir
2- Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
3- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran , sadeghipour@tums.ac.ir
Abstract: (3391 Views)
Background: Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown.
Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction.
Materials and Methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium.
Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001).
Conclusion: These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.
Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction.
Materials and Methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium.
Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001).
Conclusion: These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.
Type of Study: Original Article |
References
1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349-352.
2. Ghadirian AM, Annable L, Belanger MC. Lithium, benzodiazepines, and sexual function in bipolar patients. Am J Psychiatry 1992; 149: 801-805. [DOI:10.1176/ajp.149.6.801]
3. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition-recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23: 346-388. [DOI:10.1177/0269881109102919]
4. Young AH, Hammond JM. Lithium in mood disorders: increasing evidence base, declining use? Br J Psychiatry 2007; 191: 474-476. [DOI:10.1192/bjp.bp.107.043133]
5. Frye MA, Yatham L, Ketter TA, Goldberg J, Suppes T, Calabrese JR, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatrica Scand 2009; 120: 10-13. [DOI:10.1111/j.1600-0447.2008.01343.x]
6. Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach: Part I: Clinical efficacy in bipolar disorder. CNS Drugs 2009; 23: 225-240. [DOI:10.2165/00023210-200923030-00004]
7. Vieta E, Calabrese JR, Hennen J, Colom F, Martinez-Aran A, Sanchez-Moreno J, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar I manic patients during treatment with olanzapine: analysis of pooled data. J Clin Psychiatry 2004; 65: 1420-1428. [DOI:10.4088/JCP.v65n1019]
8. Aizenberg D, Sigler M, Zemishlany Z, Weizman A. Lithium and male sexual function in affective patients. Clin Neuropharmacol 1996; 19: 515-519. [DOI:10.1097/00002826-199619060-00005]
9. Ghadirian AM, Annable L, Belanger MC. Lithium, benzodiazepines, and sexual function in bipolar patients. Am J Psychiatry 1992; 149: 801-805. [DOI:10.1176/ajp.149.6.801]
10. Kristensen E, Jorgensen P. Sexual function in lithium-treated manic-depressive patients. Pharmacopsychiatry 1987; 20: 165-167. [DOI:10.1055/s-2007-1017096]
11. Zuncheddu C, Carpiniello B. [Sexual dysfunctions and bipolar disorder: a study of patients submitted to a long- term lithium treatment]. Clin Ter 2006; 157: 419-424. (In Italian)
12. Blay SL, Ferraz MP, Calil HM. Lithium-induced male sexual impairment: two case reports. J Clin Psychiatry 1982; 43: 497-498.
13. Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature 1989; 341: 197-205. [DOI:10.1038/341197a0]
14. Williams RS, Harwood AJ. Lithium therapy and signal transduction. Trends Pharmacol Sci 2000; 21: 61-64. [DOI:10.1016/S0165-6147(99)01428-5]
15. Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 2003; 24: 441-443. [DOI:10.1016/S0165-6147(03)00206-2]
16. Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, et al. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 2008; 132: 125-136. [DOI:10.1016/j.cell.2007.11.041]
17. Anai H, Ueta Y, Serino R, Nomura M, Nakashima Y, Yamashita H. Activation of hypothalamic neuronal nitric oxide synthase in lithium-induced diabetes insipidus rats. Psychoneuroendocrinology 2001; 26: 109-120. [DOI:10.1016/S0306-4530(00)00030-5]
18. Weerasinghe GR, Rapoport SI, Bosetti F. The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A2 or lipoxygenase/cytochrome P450 pathways. Brain Res Bull 2004; 63: 485-489. [DOI:10.1016/j.brainresbull.2004.04.005]
19. Paoletti AM, Piccirilli S, Costa N, Rotiroti D, Bagetta G, Nistico G. Systemic administration of N omega-nitro-L-arginine methyl ester and indomethacin reduces the elevation of brain PGE2 content and prevents seizures and hippocampal damage evoked by LiCl and tacrine in rat. Exp Neurol 1998; 149: 349-355. [DOI:10.1006/exnr.1997.6741]
20. Ghasemi M, Karimollah AR, Dehpour AR. Nitric oxide involvement in the effect of acute lithium administration on the nonadrenergic noncholinergic-mediated relaxation of rat gastric fundus. Nitric Oxide 2007; 17: 152-159. [DOI:10.1016/j.niox.2007.08.002]
21. Talab SS, Emami H, Elmi A, Nezami BG, Assa S, Deroee AF, et al. Chronic lithium treatment protects the rat kidney against ischemia/reperfusion injury: the role of nitric oxide and cyclooxygenase pathways. Eur J Pharmacol 2010; 647:171-177. [DOI:10.1016/j.ejphar.2010.08.036]
22. Szabo C. Physiological and pathophysiological roles of nitric oxide in the central nervous system. Brain Res Bull 1996; 41: 131-141. [DOI:10.1016/0361-9230(96)00159-1]
23. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992; 257: 401-403. [DOI:10.1126/science.1378650]
24. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170: 843-850. [DOI:10.1016/0006-291X(90)92168-Y]
25. Sadeghipour H, Dehghani M, Ghasemi M, Riazi K, Asadi S, Ebrahimi F, et al. The nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum was impaired in chronic lithium-treated rats: improvement with l-arginine. Eur J Pharmacol 2008; 586: 300-305. [DOI:10.1016/j.ejphar.2008.02.054]
26. Sadeghipour H, Ghasemi M, Ebrahimi F, Dehpour AR. Effect of lithium on endothelium-dependent and neurogenic relaxation of rat corpus cavernosum: role of nitric oxide pathway. Nitric Oxide 2007; 16: 54-63. [DOI:10.1016/j.niox.2006.05.004]
27. Sadeghipour H, Ghasemi M, Nobakht M, Ebrahimi F, Dehpour AR. Effect of chronic lithium administration on endothelium-dependent relaxation of rat corpus cavernosum: the role of nitric oxide and cyclooxygenase pathways. BJU Int 2007; 99: 177-182. [DOI:10.1111/j.1464-410X.2006.06530.x]
28. Berendsen HH, Broekkamp CL. Drug-induced penile erections in rats: indications of serotonin1B receptor mediation. Eur J Pharmacol 1987; 135: 279-287. [DOI:10.1016/0014-2999(87)90676-5]
29. Heaton JP, Varrin SJ, Morales A. The characterization of a bio-assay of erectile function in a rat model. J Urol 1991; 145: 1099-1102. [DOI:10.1016/S0022-5347(17)38543-9]
30. Hull EM, Lumley LA, Matuszewich L, Dominguez J, Moses J, Lorrain DS. The roles of nitric oxide in sexual function of male rats. Neuropharmacology 1994; 33: 1499-1504. [DOI:10.1016/0028-3908(94)90054-X]
31. Moreland RB, Nakane M, Donnelly-Roberts DL, Miller LN, Chang R, Uchic ME, et al. Comparative pharmacology of human dopamine D(2)-like receptor stable cell lines coupled to calcium flux through Galpha(qo5). Biochem Pharmacol 2004; 68: 761-772. [DOI:10.1016/j.bcp.2004.05.019]
32. Bitran D, Hull EM. Pharmacological analysis of male rat sexual behavior. Neurosci Biobehav Rev 1987; 11: 365-389. [DOI:10.1016/S0149-7634(87)80008-8]
33. Pomerantz SM. Apomorphine facilitates male sexual behavior of rhesus monkeys. Pharmacol Biochem Behav 1990; 35: 659-664. [DOI:10.1016/0091-3057(90)90304-Z]
34. Lorimy F, Loo H, Deniker P. [Clinical effects of long-term lithium treatment on sleep, appetite and sexuality]. L'Encephale 1977; 3: 227-239. (In French)
35. Zarate CA, Jr. Antipsychotic drug side effect issues in bipolar manic patients. J Clin Psychiatry 2000; 61 (Suppl.): 52-61.
36. Ables AZ, Baughman OL, 3rd. Antidepressants: update on new agents and indications. Am Fam Phys 2003; 67: 547-554.
37. Price LH, Heninger GR. Lithium in the treatment of mood disorders. N Engl J Med 1994; 331: 591-598. [DOI:10.1056/NEJM199409013310907]
38. Azadzoi KM, Master TA, Siroky MB. Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. J Androl 2004; 25: 382-388. [DOI:10.1002/j.1939-4640.2004.tb02804.x]
39. Podlasek CA, Zelner DJ, Bervig TR, Gonzalez CM, McKenna KE, McVary KT. Characterization and localization of nitric oxide synthase isoforms in the BB/WOR diabetic rat. J Urol 2001; 166: 746-755. [DOI:10.1016/S0022-5347(05)66054-5]
40. Musicki B, Ross AE, Champion HC, Burnett AL, Bivalacqua TJ. Posttranslational modification of constitutive nitric oxide synthase in the penis. J Androl 2009; 30: 352-362. [DOI:10.2164/jandrol.108.006999]
41. Mulhall JP, Muller A, Donohue JF, Mullerad M, Kobylarz K, Paduch DA, et al. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate. J Sex Med 2008; 5: 1126-1136. [DOI:10.1111/j.1743-6109.2008.00794.x]
42. Garthwaite J. Concepts of neural nitric oxide-mediated transmission. Eur J Neuroscience 2008; 27: 2783-2802. [DOI:10.1111/j.1460-9568.2008.06285.x]
43. Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of sildenafil citrate on human hemodynamics. AM J Cardiol 1999; 83: 13C-20C. [DOI:10.1016/S0002-9149(99)00043-0]
44. Dehpour AR, Aghadadashi H, Ghafourifar P, Roushanzamir F, Ghahremani MH, Meysamee F, et al. Effect of chronic lithium administration on endothelium-dependent relaxation in rat aorta. Clin Exp Pharmacol Physiol 2000; 27: 55-59. [DOI:10.1046/j.1440-1681.2000.03205.x]
45. Wegener G, Volke V, Bandpey Z, Rosenberg R. Nitric oxide modulates lithium-induced conditioned taste aversion. Behav Brain Res 2001; 118: 195-200. [DOI:10.1016/S0166-4328(00)00329-6]
46. Maruta S, Suzuki E, Yokoyama M, Sato T, Inada K, Watanabe S, et al. Effects of intraperitoneally injected lithium, imipramine and diazepam on nitrate levels in rat amygdala. Psychiatry Clin Neurosci 2005; 59: 358-361. [DOI:10.1111/j.1440-1819.2005.01383.x]
47. Dehpour AR, Sadr SS, Nouroddini M, Shadan F, Nourozi A, Farahani M, et al. Comparison of simultaneous administration of lithium with L-NAME or L-arginine on morphine withdrawal syndrome in mice. Hum Psychopharmacol 2000; 15: 87-93.
https://doi.org/10.1002/(SICI)1099-1077(200003)15:2<87::AID-HUP147>3.0.CO;2-8 [DOI:10.1002/(SICI)1099-1077(200003)15:23.0.CO;2-8]
48. Wegener G, Bandpey Z, Heiberg IL, Volke V, Trabace L, Rosenberg R, et al. Combined chronic treatment with citalopram and lithium does not modify the regional neurochemistry of nitric oxide in rat brain. J Physiol Pharmacol 2004; 55: 575-586.
49. Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR. Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. Eur Neuropsychopharmacol 2008; 18: 323- 332. [DOI:10.1016/j.euroneuro.2007.07.011]
50. Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR. A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test. Behav Brain Res 2009; 200: 76-82. [DOI:10.1016/j.bbr.2008.12.032]
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