Effects of Treatment with a 5-HT4 Receptor Antagonist in Heart Failure

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2006 Dec 13

PMID 17160012

Citations 16

Authors

J A K Birkeland

I Sjaastad

T Brattelid

E Qvigstad

E R Moberg

K A Krobert

R Bjornerheim

T Skomedal

O M Sejersted

J-B Osnes

F O Levy

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats.

Experimental Approach: Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR.

Key Results: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl).

Conclusions And Implications: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.

Citing Articles

Role of Vasoactive Hormone-Induced Signal Transduction in Cardiac Hypertrophy and Heart Failure.

Dhalla N, Mota K, Elimban V, Shah A, de Vasconcelos C, Bhullar S Cells. 2024; 13(10.

PMID: 38786079 PMC: 11119949. DOI: 10.3390/cells13100856.

Serotonin Receptors in Myocardial Infarction: Friend or Foe?.

Bahr F, Ricke-Hoch M, Ponimaskin E, Muller F ACS Chem Neurosci. 2024; 15(8):1619-1634.

PMID: 38573542 PMC: 11027101. DOI: 10.1021/acschemneuro.4c00031.

Cardiac Roles of Serotonin (5-HT) and 5-HT-Receptors in Health and Disease.

Neumann J, Hofmann B, Dhein S, Gergs U Int J Mol Sci. 2023; 24(5).

PMID: 36902195 PMC: 10003731. DOI: 10.3390/ijms24054765.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

Barnes N, Ahern G, Becamel C, Bockaert J, Camilleri M, Chaumont-Dubel S Pharmacol Rev. 2020; 73(1):310-520.

PMID: 33370241 PMC: 7770494. DOI: 10.1124/pr.118.015552.

Serotonin: a platelet hormone modulating cardiovascular disease.

Rieder M, Gauchel N, Bode C, Duerschmied D J Thromb Thrombolysis. 2020; 52(1):42-47.

PMID: 33155668 PMC: 8282555. DOI: 10.1007/s11239-020-02331-0.

References

Bristow M . beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000; 101(5):558-69. DOI: 10.1161/01.cir.101.5.558. View

Ishikawa Y, Sorota S, Kiuchi K, Shannon R, Komamura K, Katsushika S . Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs. J Clin Invest. 1994; 93(5):2224-9. PMC: 294370. DOI: 10.1172/JCI117219. View

Houser S, Piacentino 3rd V, Weisser J . Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000; 32(9):1595-607. DOI: 10.1006/jmcc.2000.1206. View

Sjaastad I, Sejersted O, Ilebekk A, Bjornerheim R . Echocardiographic criteria for detection of postinfarction congestive heart failure in rats. J Appl Physiol (1985). 2000; 89(4):1445-54. DOI: 10.1152/jappl.2000.89.4.1445. View

Omerovic E, Bollano E, Mobini R, Madhu B, Kujacic V, Soussi B . Selective beta(1)-blockade improves cardiac bioenergetics and function and decreases neuroendocrine activation in rats during early postinfarct remodeling. Biochem Biophys Res Commun. 2001; 281(2):491-8. DOI: 10.1006/bbrc.2001.4336. View

Lowes B, Gilbert E, Abraham W, Minobe W, Larrabee P, Ferguson D . Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med. 2002; 346(18):1357-65. DOI: 10.1056/NEJMoa012630. View

Ponimaskin E, Profirovic J, Vaiskunaite R, Richter D, Voyno-Yasenetskaya T . 5-Hydroxytryptamine 4(a) receptor is coupled to the Galpha subunit of heterotrimeric G13 protein. J Biol Chem. 2002; 277(23):20812-9. DOI: 10.1074/jbc.M112216200. View

Sjaastad I, Schiander I, Sjetnan A, Qvigstad E, Bokenes J, Sandnes D . Increased contribution of alpha 1- vs. beta-adrenoceptor-mediated inotropic response in rats with congestive heart failure. Acta Physiol Scand. 2003; 177(4):449-58. DOI: 10.1046/j.1365-201X.2003.01063.x. View

Spindler M, Engelhardt S, Niebler R, Wagner H, Hein L, Lohse M . Alterations in the myocardial creatine kinase system precede the development of contractile dysfunction in beta(1)-adrenergic receptor transgenic mice. J Mol Cell Cardiol. 2003; 35(4):389-97. DOI: 10.1016/s0022-2828(03)00015-4. View

10.

Kaumann A, Sanders L . 5-Hydroxytryptamine causes rate-dependent arrhythmias through 5-HT4 receptors in human atrium: facilitation by chronic beta-adrenoceptor blockade. Naunyn Schmiedebergs Arch Pharmacol. 1994; 349(4):331-7. DOI: 10.1007/BF00170877. View

11.

Hoyer D, Clarke D, Fozard J, Hartig P, Martin G, Mylecharane E . International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994; 46(2):157-203. View

12.

Vaughan D, Pfeffer M . Post-myocardial infarction ventricular remodeling: animal and human studies. Cardiovasc Drugs Ther. 1994; 8(3):453-60. DOI: 10.1007/BF00877922. View

13.

Sanders L, Lynham J, Bond B, Del Monte F, Harding S, Kaumann A . Sensitization of human atrial 5-HT4 receptors by chronic beta-blocker treatment. Circulation. 1995; 92(9):2526-39. DOI: 10.1161/01.cir.92.9.2526. View

14.

Sanbe A, Takeo S . Long-term treatment with angiotensin I-converting enzyme inhibitors attenuates the loss of cardiac beta-adrenoceptor responses in rats with chronic heart failure. Circulation. 1995; 92(9):2666-75. DOI: 10.1161/01.cir.92.9.2666. View

15.

Gaster L, Joiner G, King F, Wyman P, Sutton J, Bingham S . N-[(1-butyl-4-piperidinyl)methyl]-3,4dihydro-2H-[1,3]oxazino[3,2- a]indole10-carboxamide hydrochloride: the first potent and selective 5-HT4 receptor antagonist amide with oral activity. J Med Chem. 1995; 38(24):4760-3. DOI: 10.1021/jm00024a002. View

16.

Engelhardt S, Bohm M, Erdmann E, Lohse M . Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure. J Am Coll Cardiol. 1996; 27(1):146-54. DOI: 10.1016/0735-1097(95)00425-4. View

17.

Laser A, Neubauer S, Tian R, Hu K, Gaudron P, Ingwall J . Long-term beta-blocker treatment prevents chronic creatine kinase and lactate dehydrogenase system changes in rat hearts after myocardial infarction. J Am Coll Cardiol. 1996; 27(2):487-93. DOI: 10.1016/0735-1097(95)00458-0. View

18.

Sanders L, Lynham J, Kaumann A . Chronic beta 1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: rôle of cyclic nucleotides. Naunyn Schmiedebergs Arch Pharmacol. 1996; 353(6):661-70. DOI: 10.1007/BF00167185. View

19.

Sigmund M, Jakob H, Becker H, Hanrath P, Schumacher C, Eschenhagen T . Effects of metoprolol on myocardial beta-adrenoceptors and Gi alpha-proteins in patients with congestive heart failure. Eur J Clin Pharmacol. 1996; 51(2):127-32. DOI: 10.1007/s002280050172. View

20.

Nicolosi G, Latini R, Marino P, Maggioni A, Barlera S, Franzosi M . The prognostic value of predischarge quantitative two-dimensional echocardiographic measurements and the effects of early lisinopril treatment on left ventricular structure and function after acute myocardial infarction in the GISSI-3 Trial. Gruppo.... Eur Heart J. 1996; 17(11):1646-56. DOI: 10.1093/oxfordjournals.eurheartj.a014747. View