Reverse myocardial effects of intermedin in pressure-overloaded hearts: role of endothelial nitric oxide synthase activity

• Tipo: Artigo em Revista Científica Internacional
• Data: 2013

Autores

Pires, AL (Autor) Outra; Pinho, M (Autor) Outra; Alves, BS (Autor) Outra; Pinho, S (Autor) Outra; Sena, C (Autor) Outra; Seica, RM (Autor) Outra; Leite-Moreira AF (Autor) FMUP

Revista

Título: JOURNAL OF PHYSIOLOGY-LONDON

Vol. 591

Páginas: 677-687

ISSN: 0022-3751

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 6 Citações

Scopus - 6 Citações

Outras Informações

ID Authenticus: P-002-0PZ

DOI: 10.1113/jphysiol.2012.240812

Abstract (EN): Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD147) and 40 amino acids (IMD847). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD147 (1010 to106m) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-l-arginine, l-NAME), and respective controls (Sham and Ctrl). In TAC and l-NAME rats, exogenous administration of IMD147 elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD147 induced a negative inotropic response without a significant effect on relaxation. Both TAC and l-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD147 induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177, indicating enhanced eNOS activity. In TAC and l-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD147 was blunted. In addition, the distinct myocardial response to IMD147 was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD147 induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD147 induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD147 neurohumoral stimulation due to impairment of eNOS activation in TAC and l-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD147 in normal and hypertrophic hearts, but also highlight the potential pathophysiological relevance of cardiac endothelial dysfunction in neurohumoral myocardial action.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11