Myocardial Dysfunction and Neurohumoral Activation Without Remodeling in the Left Ventricle of Monocrotaline-Induced Pulmonary Hypertensive Rat

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

Authors

Lourenço, AP (Author) FMUP; Roncon-Albuquerque R, Jr. (Author) Other; Brás-Silva, C (Author) FMUP; Faria, B (Author) Other; Wieland, J (Author) Other; Henriques-Coelho, T (Author) FMUP; Correia-Pinto, J (Author) Other; Leite-Moreira, AF (Author) Other

Journal

Title: American Journal of Physiology - Heart and Circulatory Physiology

Vol. 291 No. 4

Pages: H1587-H1594

ISSN: 0363-6135

Publisher: American Physiological Society

Indexing

ISI Web of Science

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences

Other information

Abstract (EN): In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

Language: English

Type (Professor's evaluation): Scientific