Revisiting the slow force response: The role of the PKG signaling pathway in the normal and the ischemic heart

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Abstract

Introduction The myocardial response to acute stretch consists of a two-phase increase in contractility: an acute increase by the Frank-Starling mechanism and a gradual and time-dependent increase in force generated known as the slow force response (SFR). The SFR is actively modulated by different signaling pathways, but the role of protein kinase G (PKG) signaling is unknown. In this study we aim to characterize the role of the PKG signaling pathway in the SFR under normal and ischemic conditions. Methods Rabbit papillary muscles were stretched from 92 to 100% of maximum length (Lmax) under basal conditions, in the absence (1) or presence of: a PKG agonist (2) and a PKG inhibitor (3); under ischemic conditions in the absence (4) or presence of: a PKG agonist (5); a nitric oxide (NO) donor (6) and a phosphodiesterase 5 (PDE5) inhibitor (7). Results Under normoxia, the SFR was significantly attenuated by inhibition of PKG and remained unaltered with PKG activation. Ischemia induced a progressive decrease in myocardial contractility after stretch. Neither the PKG agonist nor the NO donor altered the myocardial response to stretch under ischemic conditions. However, the use of a PDE5 inhibitor in ischemia partially reversed the progressive deterioration in contractility. Conclusions PKG activity is essential for the SFR. During ischemia, a progressive decline in the force is observed in response to acute myocardial stretch. This dysfunctional response can be partially reversed by the use of PDE5 inhibitors.

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Castro-Ferreira, R., Neves, J. S., Ladeiras-Lopes, R., Leite-Moreira, A. M., Neiva-Sousa, M., Almeida-Coelho, J., … Leite-Moreira, A. F. (2014). Revisiting the slow force response: The role of the PKG signaling pathway in the normal and the ischemic heart. Revista Portuguesa de Cardiologia, 33(9), 493–499. https://doi.org/10.1016/j.repc.2014.03.006

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