mdl-100907 and Heart-Failure

The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice.. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues.. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro.. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

Topics: Animals; Endomyocardial Fibrosis; Heart; Heart Failure; Hemodynamics; Male; Mice; Mice, Inbred C57BL; Myocardium; Protective Agents; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Ventricular Dysfunction, Right

By mimicking sympathetic stimulation in vivo, we previously reported that mice globally lacking serotonin 5-HT(2B) receptors did not develop isoproterenol-induced left ventricular hypertrophy. However, the exact cardiac cell type(s) expressing 5-HT(2B) receptors (cardiomyocytes versus noncardiomyocytes) involved in pathological heart hypertrophy was never addressed in vivo. We report here that mice expressing the 5-HT(2B) receptor solely in cardiomyocytes, like global 5-HT(2B) receptor-null mice, are resistant to isoproterenol-induced cardiac hypertrophy and dysfunction, as well as to isoproterenol-induced increases in cytokine plasma-levels. These data reveal a key role of noncardiomyocytes in isoproterenol-induced hypertrophy in vivo. Interestingly, we show that primary cultures of angiotensinogen null adult cardiac fibroblasts are releasing cytokines on stimulation with either angiotensin II or serotonin, but not in response to isoproterenol stimulation, demonstrating a critical role of angiotensinogen in adrenergic-dependent cytokine production. We then show a functional interdependence between AT(1)Rs and 5-HT(2B) receptors in fibroblasts by revealing a transinhibition mechanism that may involve heterodimeric receptor complexes. Both serotonin- and angiotensin II-dependent cytokine production occur via a Src/heparin-binding epidermal growth factor-dependent transactivation of epidermal growth factor receptors in cardiac fibroblasts, supporting a common signaling pathway. Finally, we demonstrate that 5-HT(2B) receptors are overexpressed in hearts from patients with congestive heart failure, this overexpression being positively correlated with cytokine and norepinephrine plasma levels. Collectively, these results reveal for the first time that interactions between AT(1) and 5-HT(2B) receptors coexpressed by noncardiomyocytes are limiting key events in adrenergic agonist-induced, angiotensin-dependent cardiac hypertrophy. Accordingly, antagonists of 5-HT(2B) receptors might represent novel therapeutics for sympathetic overstimulation-dependent heart failure.

Topics: Adult; Angiotensin II; Animals; Cells, Cultured; Cytokines; ErbB Receptors; Female; Fibroblasts; Heart Failure; Heparin-binding EGF-like Growth Factor; Humans; Hypertrophy, Left Ventricular; Intercellular Signaling Peptides and Proteins; Isoproterenol; Male; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Myocardium; Myocytes, Cardiac; Norepinephrine; Protein Interaction Mapping; Receptor, Angiotensin, Type 1; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Signal Transduction; src-Family Kinases

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Cardiomegaly; Cytokines; Drug Delivery Systems; ErbB Receptors; Fibroblasts; Heart Failure; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Isoproterenol; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Transgenic; Myocardium; Rats; Receptor, Angiotensin, Type 1; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Signal Transduction

A relationship between morphofunctional changes in the heart and predominance of adrenergic or serotoninergic influences on the strength of myocardial contraction in the right atrium was revealed in patients with chronic heart failure. During left ventricular hypertrophy, the strength of myocardial contraction in response to serotonin exceeded that induced by epinephrine and was realized via 5-HT2 receptors.

Topics: Adrenergic Agonists; Epinephrine; Heart Failure; Humans; Hypertrophy, Left Ventricular; Middle Aged; Myocardial Contraction; Piperazines; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents

Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-HT(2A) and 5-HT(4) receptors. Human ventricle is similarly responsive to 5-HT through 5-HT(4) receptors. We studied isolated ventricular cardiomyocytes to clarify the effects of 5-HT on intracellular Ca(2+) handling. Left-ventricular cardiomyocytes were isolated from male Wistar rats 6 wk after induction of postinfarction CHF. Contractile function and Ca(2+) transients were measured in field-stimulated cardiomyocytes, and L-type Ca(2+) current (I(Ca,L)) and sarcoplasmic reticulum (SR) Ca(2+) content were measured in voltage-clamped cells. Protein phosphorylation was measured by Western blotting or phosphoprotein gel staining. 5-HT(4)- and 5-HT(2A)-receptor stimulation induced a positive inotropic response of 33 and 18% (both P < 0.05) and also increased the Ca(2+) transient (44 and 6%, respectively; both P < 0.05). I(Ca,L) and SR Ca(2+) content increased only after 5-HT(4)-receptor stimulation (57 and 65%; both P < 0.05). Phospholamban serine(16) (PLB-Ser(16)) and troponin I phosphorylation increased by 26 and 13% after 5-HT(4)-receptor stimulation (P < 0.05). 5-HT(2A)-receptor stimulation increased the action potential duration and did not significantly change the phosphorylation of PLB-Ser(16) or troponin I, but it increased myosin light chain 2 (MLC2) phosphorylation. In conclusion, the positive inotropic response to 5-HT(4) stimulation results from increased I(Ca,L) and increased phosphorylation of PLB-Ser(16), which increases the SR Ca(2+) content. 5-HT(4) stimulation is thus, like beta-adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-HT(2A)-receptor stimulation, previously studied in acute CHF, induces a positive inotropic response also in chronic CHF, probably mediated by MLC2 phosphorylation.

Topics: Action Potentials; Adrenergic beta-Agonists; Animals; Calcium Channels, L-Type; Calcium Signaling; Calcium-Binding Proteins; Cardiac Myosins; Cardiotonic Agents; Coronary Vessels; Disease Models, Animal; Heart Failure; Indoles; Isoproterenol; Ketanserin; Ligation; Male; Myocardial Contraction; Myocardial Infarction; Myocytes, Cardiac; Myosin Light Chains; Phosphorylation; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin, 5-HT4; Sarcoplasmic Reticulum; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Sulfonamides; Time Factors; Troponin I; Ventricular Function

Serotonin via serotonin 2B receptors (SR2BR) regulates cardiac embryonic development and adult heart functions. However, the role of SR2BR in the failing heart due to pressure overload is not well understood.. Wistar rats of aortic banding and neonatal cardiomyocyte with mechanical stretch were used as cardiomyopathy models.. After two weeks of aortic banding surgery, serum serotonin, mRNA and protein expression of SR2BR increased significantly. The selective SR2BR antagonist, SB215505 (SB), significantly reduced the increase in heart weight, decreased heart wall thickness, left ventricular mass and the expression of the brain natriuretic peptide (BNP) but did not attenuate the up-regulation of SR2BR protein expression in rats after aortic banding for three weeks. After following in vitro mechanical stretch of cardiomyocytes and incubation with serotonin 1 muM, the level of SR2BR and BNP protein increased time-dependently. When transfected by specific siRNA of SR2BR or pretreated with caffeic acid phenethyl ester in cardiomyocytes, the increase of nuclear factor-kappaB (NF-kappaB) translocation and BNP protein induced by serotonin incubation plus mechanical stretch were both reversed.. SR2BR expression is involved in pressure-induced cardiomyopathy and its downstream signaling may involve NF-kappaB to modulate BNP expression in cardiomyocyte.

Topics: Animals; Animals, Newborn; Aorta; Caffeic Acids; Constriction, Pathologic; Heart Failure; Hypertrophy, Left Ventricular; Indoles; Models, Animal; Myocytes, Cardiac; Natriuretic Peptide, Brain; NF-kappa B; Phenylethyl Alcohol; Quinolines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2B; RNA Interference; RNA, Small Interfering; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Stress, Mechanical; Ventricular Remodeling