Modulation of the myocardial effects of selective ETB receptor stimulation and its implications for heart failure [Modulação dos efeitos miocárdicos da estimulação selectiva dos receptores ETB e suas implicações na insuficiência cardíaca]

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Bras Silva, C (Author) FCNAUP; Leite Moreira, AF (Author) Other

Journal

Title: Revista Portuguesa de Cardiologia

Vol. 24 No. 11

Pages: 1125-1133

ISSN: 0870-2551

Publisher: Sociedade Portuguesa De Cardiologia

Indexing

ISI Web of Knowledge

Scopus - 6 Citations

Other information

Authenticus ID: P-007-ECY

Abstract (EN): Introduction: Endothelin-1 (ET-1) acts on two types of receptors, ET A and ETB. Recent functional studies suggest the existence of two ETB receptor subtypes in the heart: ETB1, located on endocardial endothelial cells and responsible for negative inotropisin, and ETB2, located on myocardial cells and responsible for positive inotropism. The aim of the present study was to investigate the mechanisms underlying the myocardial effects of selective ETB receptor stimulation. Methods: The study was performed on right papillary muscles from New Zealand white rabbits (n = 39; Krebs-Ringer; 1.8 mM CaCL2; 35°C). The effects of sarafotoxin S6c (SRTXc, ETB agonist; 0.2¿ M) were evaluated in muscles with: (i) intact endocardial endothelium (EE) (n = 6); (ii) damaged EE (Triton X100; 0.5%; n = 6); (iii) intact EE, in the presence of NG-nitro-L-arginine (L-NNA, nitric oxide synthase inhibitor; n = 6); (iv) intact EE, in the presence of indomethacin (INDO, cyclooxygenase inhibitor; n = 6); (v) intact EE, in the presence of BQ-123 (ETA antagonist; n = 7); and (vi) damaged EE, in the presence of BQ-123 (n = 8). Only significant results (mean ± SEM, p < 0.05) are given, expressed as % change from baseline. Results: In muscles with intact EE, SRTXc alone induced negative inotropic and lusitropic effects, decreasing active tension (AT) by 11.0 ± 5.6%, maximum velocity of tension rise (dT/dtmax) by 11.2 ± 5.9% and maximum velocity of tension decline (dT/dtmin) by 11.5 ± 6.2%. However, after removal of EE, or in the presence of L-NNA or INDO, SRTXc increased AT by 35.2 ± 11.7%, 22.8 ± 2.9% and 15.2 ± 3.4%, dT/dtmax by 29.5 ± 7.9%, 20.1 ± 2.1% and 13.3 ± 5.0%, and dT/dt min by 28.2 ± 8.1%, 21.2 ± 3.8% and 12.3 ± 2.2%, respectively. In muscles with intact EE and in the presence of BQ-123, the negative inotropic and lusitropic effects of SRTXc were enhanced: AT decreased by 27.0 ± 7.4%, dT/dtmax by 13.3 ± 4.9% and dT/dt min by 31.1 ± 7.9%. On the other hand, the positive inotropic and lusitropic effects of SRTXc in the absence of intact EE were reversed in the presence of ETA blockade: AT decreased by 9.0 ± 1.8%, dT/dtmax by 4.1 ± 3.5% and dT/dtmin by 8.1 ± 3.6%. Conclusions: The present study shows that the inotropic and lusilropic effects mediated by ETB receptors are modulated by endocardial endothelium and by ETA receptor activity. These results may have pathophysiological and therapeutic implications in heart failure, a condition in which ET-1 levels are increased and endothelial dysfunction may be present.

Language: English

Type (Professor's evaluation): Scientific