Investigating the Effect of Serotonin II and III Receptor Inhibitors on the Chronotropic Changes of the Heart to Isoproterenol in Rat Models of Biliary Cirrhosis
-
Sahar Asvar
,
Farahnaz Jazaeri
,
Mohammad Abdullah Algazo
,
Razieh Mohammad Jafari
,
Ahmad Reza Dehpour
Abstract
Cirrhotic patients have hyperdynamic circulation and at-rest tachycardia, and agents that activate the sympathetic pathway, such as physical practice and pharmacologic stimulations, compared with the normal population, cannot cause enough increase in heartbeat, a condition known as cirrhotic cardiomyopathy. Concerning the presentation of 5-HT2 & 5-HT3 receptors in rat hearts, we used Ketanserin as a 5-HT2 receptor inhibitor & Tropisetron as a 5-HT3 receptor inhibitor to evaluate chronic therapeutic effects of 5-HT2 & 5-HT3 antagonists on the cardiac chronotropic response of cirrhotic rats to adrenergics. Cirrhosis was induced by surgical ligation of the bile duct in Male Wistar rats, and another group remained sham. A week after bile duct ligation or sham surgery, the subjects were given an intraperitoneal injection of either saline or Tropisetron (2 mg/kg). In other BDL & Sharm groups, the subjects were given an intraperitoneal injection of either saline or Ketanserin (6 mg/kg) every other 3 days in the last 3 weeks. Four weeks after bile duct ligation or sham surgery, the atria were isolated and chronotropic responsiveness to Isoproterenol was assessed using a standard organ bath. Our data showed that chronic treatment with Tropisetron (5-HT3 antagonist) in cirrhotic rats could decrease the cardiac chronotropic response. Chronic treatment with Tropisetron can cause a significant decrease in cardiac chronotropic response to Isoproterenol in healthy and cirrhotic rats, even lower than that in cirrhotic rats (without any special treatment). Chronic treatment with Ketanserin cannot change their impaired chronotropic response to Isoproterenol.
1. Bacon B. Cirrhosis and its complications. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principle of Internal Medicine. 17th ed. New York, United States: McGraw Hill; 2008:1971-4.
2. Mani AR, Ippolito S, Ollosson R, Moore KP. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 2006;43:847-56.
3. Saxena PR, Villalón CM. Cardiovascular effects of serotonin agonists and antagonists. J Cardiovasc Pharmacol 1990;15:S17-34.
4. Sirek A, Sirek O. Serotonin: a review. Can Med Assoc J 1970;102:846-9.
5. Cerrito E, Lazzaro M, Gaudio E, Arminio P, Aloisi G. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci 1993;53:209-15.
6. Ouadid H, Seguin J, Dumuis A, Bockaert J, Nargeot J. Serotonin increases calcium current in human atrial myocytes via the newly described 5-hydroxytryptamine4 receptors. Mol Pharmacol 1992;41:346-51.
7. Ciurzynska G, Deptuch T, Kurenko-Deptuch M, Wojtecka-Lukasik E, Witanowska A, Maslinska D, et al. Influence of serotonin and selective 5-HT2 and 5-HT3 receptor agonists on the haemodynamics of the isolated, constant pressure perfused rat heart. Inflamm Res 2005;54:S72-3.
8. Jacob G, Bishara B, Lee SS, Hilzenart N, Bomzon A. Cardiovascular responses to serotonin in experimental liver disease. Hepatology 1991;14:1235-42.
9. Papadimas GK, Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Skaltsas SD, Hereti RI, et al. Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver. Liver Int 2006;26:352-61.
10. Alimoradi H, Barzegar-Fallah A, Hassanzadeh G, Mohammadi-Rick S, Asadi F, Delfan B, et al. The cardioprotective effects of an antiemetic drug, tropisetron, on cardiomyopathy related to doxorubicin. Cardiovasc Toxicol 2012;12:318-25.
11. Gholami M, Mazaheri P, Mohamadi A, Dehpour T, Safari F, Hajizadeh S, et al. Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats. Shock 2012;37:219-27.
12. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol 2010;53:179-90.
13. Kaumann AJ. Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors. Naunyn Schmiedebergs Arch Pharmacol 1990;342:619-22.
14. Fozard J, Mwaluko G. Mechanism of the indirect sympathomimetic effect of 5-hydroxytrypt-amine on the isolated heart of the rabbit. Br J Pharmacol 1976;57:115-25.
15. Zaizen H, Imanishi S, Nasu M, Arita M. Diverse inotropic effects of 5-hydroxytryptamine in heart muscles of various mammalian species. Heart Vessels 1996;11:10-7.
16. Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-HT 4-like receptor in human right atrium. Naunyn Schmiedebergs Arch Pharmacol 1991;344:150-9.
17. Läer S, Remmers F, Scholz H, Stein B, Ulrich Müller F, Neumann J. Receptor mechanisms involved in the 5‐HT‐induced inotropic action in the rat isolated atrium. Br J Pharmacol 1998;123:1182-8.
18. Mertens MJ, Pfaffendorf M, Van Zwieten PA. Impaired vasodilator and chronotropic responses to 5-hydroxytryptamine in two models of hypertension-associated cardiac hypertrophy. Blood Press 1992;1:254-9.
19. Nishio H, Fujii A, Nakata Y. Re-examination for pharmacological properties of serotonin-induced tachycardia in isolated guinea-pig atrium. Behav Brain Res 1995;73:301-4.
20. El Rawadi C, Haddad R, Davy M, Midol-Monnet M, Cohen Y. Role of 5-HT2 receptors in the positive chronotropic action of serotonin on the isolated atria in rats. C R Seances Soc Biol Fil 1993;187:390-7.
21. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1. Am J Physiol Regul Integr Comp Physiol 2008;294:R1825-31.
22. Liu FC, Yu HP, Hwang TL, Tsai YF. Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression. PLoS One 2012;7:e53203.
23. Liu FC, Liu FW, Yu HP. Ondansetron attenuates hepatic injury via p38 MAPK-dependent pathway in a rat haemorrhagic shock model. Resuscitation 2011;82:335-40.
24. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 2005;111:1601-10.
25. Sauter KA, Wood LJ, Wong J, Iordanov M, Magun BE. Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome: Progress at a snail's pace. Cancer Biol Ther 2011;11:1008-16.
26. Fiebich B, Akundi R, Lieb K, Candelario‐Jalil E, Gmeiner D, Haus U, et al. Antiinflammatory effects of 5‐HT3 receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes. Scand J Rheumatol Suppl 2004;33:28-32.
27. Kalivendi SV, Konorev EA, Cunningham S, Vanamala SK, Kaji EH, Joseph J, et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J 2005;389:527-39.
28. de la Vega L, Muñoz E, Calzado MA, Lieb K, Candelario-Jalil E, Gschaidmeir H, et al. The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. Biochem Pharmacol 2005;70:369-80.
29. Rahimian R, Dehpour AR, Fakhfouri G, Khorramizadeh MR, Ghia JE, Seyedabadi M, et al. Tropisetron upregulates cannabinoid CB1 receptors in cerebellar granule cells: possible involvement of calcineurin. Brain Res 2011;1417:1-8.
30. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology 2010;115:155-62.
31. Krayer O. The history of the Bezold-Jarisch effect. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1961;240:361-8.
32. Sévoz C, Nosjean A, Callera JC, Machado B, Hamon M, Laguzzi R. Stimulation of 5-HT3 receptors in the NTS inhibits the cardiac Bezold-Jarisch reflex response. Am J Physiol 1996;271:H80-H7.
33. Cummings SA, Kaumann AJ, Groszmann RJ. Comparison of the hemodynamic responses to ketanserin and prazosin in portal hypertensive rats. Hepatology 1988;8:1112-5.
34. Mastaï R, Rocheleau B, Huet PM. Serotonin blockade in conscious, unrestrained cirrhotic dogs with portal hypertension. Hepatology 1989;9:265-8.
35. Ghia M, Mereto E, Mattioli F, Dagnino F, Testa R. Splanchnic haemodynamic effects of ketanserin in anaesthetized cirrhotic rats. Pharmacol Res 1992;26:173-8.
36. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-7.
37. Watanabe M, Murata S, Hashimoto I, Nakano Y, Ikeda O, Aoyagi Y, et al. Platelets contribute to the reduction of liver fibrosis in mice. J Gastroenterol Hepatol 2009;24:78-89.
38. Fausto N. Liver regeneration. J Hepatol 2000;32:19-31.
39. Tomikawa M, Hashizume M, Highashi H, Ohta M, Sugimachi K. The role of the spleen, platelets, and plasma hepatocyte growth factor activity on hepatic regeneration in rats. J Am Coll Surg 1996;182:12-6.
40. Nagao Y, Akahoshi T, Kamori M, Uehara H, Hashimoto N, Kinjo N, et al. Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis. Hepatol Res 2011;41:784-94.
2. Mani AR, Ippolito S, Ollosson R, Moore KP. Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis. Hepatology 2006;43:847-56.
3. Saxena PR, Villalón CM. Cardiovascular effects of serotonin agonists and antagonists. J Cardiovasc Pharmacol 1990;15:S17-34.
4. Sirek A, Sirek O. Serotonin: a review. Can Med Assoc J 1970;102:846-9.
5. Cerrito E, Lazzaro M, Gaudio E, Arminio P, Aloisi G. 5HT2-receptors and serotonin release: their role in human platelet aggregation. Life Sci 1993;53:209-15.
6. Ouadid H, Seguin J, Dumuis A, Bockaert J, Nargeot J. Serotonin increases calcium current in human atrial myocytes via the newly described 5-hydroxytryptamine4 receptors. Mol Pharmacol 1992;41:346-51.
7. Ciurzynska G, Deptuch T, Kurenko-Deptuch M, Wojtecka-Lukasik E, Witanowska A, Maslinska D, et al. Influence of serotonin and selective 5-HT2 and 5-HT3 receptor agonists on the haemodynamics of the isolated, constant pressure perfused rat heart. Inflamm Res 2005;54:S72-3.
8. Jacob G, Bishara B, Lee SS, Hilzenart N, Bomzon A. Cardiovascular responses to serotonin in experimental liver disease. Hepatology 1991;14:1235-42.
9. Papadimas GK, Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Skaltsas SD, Hereti RI, et al. Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver. Liver Int 2006;26:352-61.
10. Alimoradi H, Barzegar-Fallah A, Hassanzadeh G, Mohammadi-Rick S, Asadi F, Delfan B, et al. The cardioprotective effects of an antiemetic drug, tropisetron, on cardiomyopathy related to doxorubicin. Cardiovasc Toxicol 2012;12:318-25.
11. Gholami M, Mazaheri P, Mohamadi A, Dehpour T, Safari F, Hajizadeh S, et al. Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats. Shock 2012;37:219-27.
12. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol 2010;53:179-90.
13. Kaumann AJ. Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors. Naunyn Schmiedebergs Arch Pharmacol 1990;342:619-22.
14. Fozard J, Mwaluko G. Mechanism of the indirect sympathomimetic effect of 5-hydroxytrypt-amine on the isolated heart of the rabbit. Br J Pharmacol 1976;57:115-25.
15. Zaizen H, Imanishi S, Nasu M, Arita M. Diverse inotropic effects of 5-hydroxytryptamine in heart muscles of various mammalian species. Heart Vessels 1996;11:10-7.
16. Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ. A 5-HT 4-like receptor in human right atrium. Naunyn Schmiedebergs Arch Pharmacol 1991;344:150-9.
17. Läer S, Remmers F, Scholz H, Stein B, Ulrich Müller F, Neumann J. Receptor mechanisms involved in the 5‐HT‐induced inotropic action in the rat isolated atrium. Br J Pharmacol 1998;123:1182-8.
18. Mertens MJ, Pfaffendorf M, Van Zwieten PA. Impaired vasodilator and chronotropic responses to 5-hydroxytryptamine in two models of hypertension-associated cardiac hypertrophy. Blood Press 1992;1:254-9.
19. Nishio H, Fujii A, Nakata Y. Re-examination for pharmacological properties of serotonin-induced tachycardia in isolated guinea-pig atrium. Behav Brain Res 1995;73:301-4.
20. El Rawadi C, Haddad R, Davy M, Midol-Monnet M, Cohen Y. Role of 5-HT2 receptors in the positive chronotropic action of serotonin on the isolated atria in rats. C R Seances Soc Biol Fil 1993;187:390-7.
21. Hsu JT, Kan WH, Hsieh CH, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1. Am J Physiol Regul Integr Comp Physiol 2008;294:R1825-31.
22. Liu FC, Yu HP, Hwang TL, Tsai YF. Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression. PLoS One 2012;7:e53203.
23. Liu FC, Liu FW, Yu HP. Ondansetron attenuates hepatic injury via p38 MAPK-dependent pathway in a rat haemorrhagic shock model. Resuscitation 2011;82:335-40.
24. Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 2005;111:1601-10.
25. Sauter KA, Wood LJ, Wong J, Iordanov M, Magun BE. Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome: Progress at a snail's pace. Cancer Biol Ther 2011;11:1008-16.
26. Fiebich B, Akundi R, Lieb K, Candelario‐Jalil E, Gmeiner D, Haus U, et al. Antiinflammatory effects of 5‐HT3 receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes. Scand J Rheumatol Suppl 2004;33:28-32.
27. Kalivendi SV, Konorev EA, Cunningham S, Vanamala SK, Kaji EH, Joseph J, et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J 2005;389:527-39.
28. de la Vega L, Muñoz E, Calzado MA, Lieb K, Candelario-Jalil E, Gschaidmeir H, et al. The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. Biochem Pharmacol 2005;70:369-80.
29. Rahimian R, Dehpour AR, Fakhfouri G, Khorramizadeh MR, Ghia JE, Seyedabadi M, et al. Tropisetron upregulates cannabinoid CB1 receptors in cerebellar granule cells: possible involvement of calcineurin. Brain Res 2011;1417:1-8.
30. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology 2010;115:155-62.
31. Krayer O. The history of the Bezold-Jarisch effect. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1961;240:361-8.
32. Sévoz C, Nosjean A, Callera JC, Machado B, Hamon M, Laguzzi R. Stimulation of 5-HT3 receptors in the NTS inhibits the cardiac Bezold-Jarisch reflex response. Am J Physiol 1996;271:H80-H7.
33. Cummings SA, Kaumann AJ, Groszmann RJ. Comparison of the hemodynamic responses to ketanserin and prazosin in portal hypertensive rats. Hepatology 1988;8:1112-5.
34. Mastaï R, Rocheleau B, Huet PM. Serotonin blockade in conscious, unrestrained cirrhotic dogs with portal hypertension. Hepatology 1989;9:265-8.
35. Ghia M, Mereto E, Mattioli F, Dagnino F, Testa R. Splanchnic haemodynamic effects of ketanserin in anaesthetized cirrhotic rats. Pharmacol Res 1992;26:173-8.
36. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-7.
37. Watanabe M, Murata S, Hashimoto I, Nakano Y, Ikeda O, Aoyagi Y, et al. Platelets contribute to the reduction of liver fibrosis in mice. J Gastroenterol Hepatol 2009;24:78-89.
38. Fausto N. Liver regeneration. J Hepatol 2000;32:19-31.
39. Tomikawa M, Hashizume M, Highashi H, Ohta M, Sugimachi K. The role of the spleen, platelets, and plasma hepatocyte growth factor activity on hepatic regeneration in rats. J Am Coll Surg 1996;182:12-6.
40. Nagao Y, Akahoshi T, Kamori M, Uehara H, Hashimoto N, Kinjo N, et al. Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis. Hepatol Res 2011;41:784-94.
| Files | ||
| Issue | Vol 61 No 7 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v61i7.14498 | |
| Keywords | ||
| Serotonin Cardiac Chronotropic Response Biliary Cirrhosis Serotonin II and III Receptor Antagonists Cirrhotic Cardiomyopathy | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Asvar S, Jazaeri F, Algazo M, Mohammad Jafari R, Dehpour AR. Investigating the Effect of Serotonin II and III Receptor Inhibitors on the Chronotropic Changes of the Heart to Isoproterenol in Rat Models of Biliary Cirrhosis. Acta Med Iran. 2023;61(7):424-431.
