Impaired response to ETB receptor stimulation in heart failure: Functional evidence of endocardial endothelial dysfunction?

• Type: Article in International Scientific Journal
• Date: 2006

Authors

Bras Silva, C (Author) FCNAUP; Fontes Sousa, AP (Author) Other; Moura, C (Author) Other; Areias, JC (Author) FMUP; Leite Moreira, AF (Author) FMUP

Journal

Title: Experimental Biology and Medicine

Vol. 231

Pages: 893-898

ISSN: 1535-3702

Publisher: SAGE

Indexing

ISI Web of Knowledge - 11 Citations

Scopus - 15 Citations

Scientific classification

FOS: Medical and Health sciences > Other medical sciences

Other information

Authenticus ID: P-004-KD1

Abstract (EN): Inotropic effects of selective ETB receptor stimulation depend on the functional integrity of the endocardial endothelium (EE), which is negative when it is intact and positive when it is damaged. These results have been attributed to the existence of two subtypes of ETB receptors in the heart: (i) ETB1, located on the EE, decreases inotropy; (ii) ETB2, located on myocardial cells, increases inotropy. In the present study we investigated the functional integrity of the EE in a heart failure (HF) model (doxorubicin-induced cardiomyopathy) by evaluating the contractile response to ETB1 receptor stimulation. New Zealand White rabbits were treated with doxorubicin (DOX-HF, 1 mg/kg, iv, twice weekly for 8 weeks) or with saline. Contractile effects of increasing doses of a selective agonist of enclothelial ETB receptors, IRL-1620 (10(-9) to 10(-6) M), were studied in papillary muscles (Krebs-Ringer: 1.8 mM CaCl2, 35 degrees C) from control (n = 10) and DOX-HF rabbits (n = 7). Isotonic and isometric twitches were recorded and analyzed. Reported parameters included active tension (AT) and maximum velocities of tension rise (dT/ dt(max)) and decline (dT/dt(min)). On echocardiography DOX-HF rabbits had increased left ventricular (LV) end-diastolic and end-systolic diameters and reduced ejection fraction (52% +/- 2% vs. 61% +/- 1%). Contrary to control papillary muscles, DOX-HF muscles showed a steady decrease in contractility between 1 and 4 Hz. In the control group, IRL-1620 induced dose-dependent negative inotropic and lusitropic effects that decreased at 10(-6) M. 26% +/- 3%, AT; 17% +/- 3%, dT/dt(max); and 16% +/- 5%q dT/dt(min). In the DOX-HF group, these effects were significantly reduced. At the same concentration, IRL-1620 decreased AT (8% +/- 3%) and dT/dt(max) (8% +/- 3%), without significantly affecting dT/dt(min). This study showed an impaired response to endothelial ETB receptor stimulation, providing for the first time strong evidence of the occurrence of EE dysfunction in the failing heart and further highlighting the potential use of ETB receptor stimulation as a marker of EE function.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 6