Pneumologie 2011; 65 - P307
DOI: 10.1055/s-0031-1272119

Terguride attenuates myocardial remodelling and diastolic dysfunction in the pressure overloaded right heart

DR Krompiec 1, W Janssen 2, S Savai Pullamsetti 1, Y Schymura 2, H Luitel 1, HA Ghofrani 1, N Weissmann 1, F Grimminger 1, R Reiter 3, W Seeger 1, RT Schermuly 1
  • 1University of Gießen, Lung Centre
  • 2Max Planck Institute for Heart and Lung Research, Bad Nauheim
  • 3Ergonex Pharma, Appenzell, Switzerland

Rationale:

Sustained right ventricular (RV) pressure overload causes myocardial remodelling and heart failure. However, little is known about the role of serotonin (5-hydroxytryptamine, 5-HT) and its receptors in RV hypertrophy due to RV pressure overload. We therefore investigated the effects of the 5-HT2a- and 5-HT2b-receptor antagonist terguride on myocardial hypertrophy and fibrosis, as well as diastolic function in RV pressure overload.

Methods:

Pulmonary artery banding (PAB) was applied to male C57Bl6N-mice with a hemoclip to an outer diameter of 0.35mm. Sham mice underwent the same procedure except for PAB. Terguride (0,2mg/kg bid i.p.) was administered from day 7 to day 21. RV functionality was visualized by Magnetic Resonance Imaging (MRI) and fibrosis was determined by collagen staining. At day 21, RV hemodynamic parameters and RV hypertrophy were measured. Gene expression was investigated by quantitive realtime PCR.

Results:

5-HT2b mRNA expression was twofold upregulated in right ventricles (RVs) of PAB mice compared to sham. PAB caused a threefold increase in RV systolic pressure, a significantly elevated RV to left ventricle plus septum (RV/(LV+S)) ratio and increased RV collagen content compared to sham mice. Terguride significantly reversed the elevation of RV systolic pressure. The RV/(LV+S) ratio and the RV mass normalized to bodyweight were significantly reduced by terguride, along with a reduced mRNA expression of the hypertrophic marker atrial natriuretic peptide (ANP). Furthermore, terguride significantly reduced mRNA expression of collagen I and collagen II in RVs, as well as collagen I and collagen III deposition.

Conclusions:

Pulmonary artery banding (PAB) causes severe myocardial hypertrophy and fibrosis. Treatment with the 5-HT2a- and 5-HT2b-receptor antagonist terguride reduces myocardial hypertrophy and fibrosis. Terguride may offer a novel therapeutic option in right heart hypertrophy.