Reverse myocardial effects of intermedin in pressure‐overloaded hearts: role of endothelial nitric oxide synthase activity
Authors: Pires Ana Luísa , Pinho Marta , Alves Bárbara Silvana , Pinho Sónia , Sena Cristina , Seica Raquel Maria , Leite‐Moreira Adelino F. 
Published: November 2012

Key points

Intermedin (IMD) is a cardiac endogenous peptide upregulated in several models of heart disease.

We show a depressant effect of IMD1−47 on contractility of the normal myocardium, mediated by increased nitric oxide (NO) production due to endothelial nitric oxide synthase (eNOS) phosphorylation.

In rat models of cardiac hypertrophy or NO deficiency, IMD1−47 enhances contractility and hastens relaxation associated with phospholamban phosphorylation.

This opposing response in normal and diseased myocardium is due to impairment of IMD1−47‐induced eNOS phosphorylation.

The results reveal distinct myocardial effects and subcellular mechanisms for IMD1−47 in the hypertrophic heart, suggesting a key role of cardiac endothelial dysfunction with potential pathophysiological relevance.

Abstract  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 (IMD1−47) and 40 amino acids (IMD8−47). 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 IMD1−47 (10−10 to10−6 m) 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 IMD1−47 elicited concentration‐dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD1−47 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), IMD1−47 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 IMD1−47 was blunted. In addition, the distinct myocardial response to IMD1−47 was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD1−47 induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD1−47 induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD1−47 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 IMD1−47 in normal and hypertrophic hearts, but also highlight the potential pathophysiological relevance of cardiac endothelial dysfunction in neurohumoral myocardial action.