Human RFamide-related peptide-1 diminishes cellular and integrated cardiac contractile performance

Peptides influence cardiac dysfunction however peptidergic modulation of contractile performance remains relatively uncharacterized We identified a novel human peptide that modulates mammalian contractile performance Members of the FMRFamide-related peptide (FaRP) family contain a C-terminal RFamide but structurally variant N-terminal extension We report human RFamide-related peptide-1 (hRFRP-1) and rat RFRP-1 rapidly and reversibly decreased shortening and relaxation in isolated mammalian cardiac myocytes in a dose dependent manner The mammalian FaRP 26RFa structurally related to RFRP-1 by only an RFamide did not influence myocyte contractile function The protein kinase C (PKC) inhibitor bisindolylmaleimide-1 blocked hRFRP-1 activity Pretreatment with pertussis toxin (PTX) did not diminish hRFRP-1 Influence on contractile function In addition intravenous injection of hRFRP-1 in mice decreased heart rate stroke volume ejection fraction and cardiac output Collectively these findings are consistent with the conclusion RFRP-1 is an endogenous signaling molecule that activates PKC and acts through a PTX-insensitive pathway to modulate cardiac contractile function Taken together these negative chronotropic inotropic and lusitropic effects of hRFRP-1 are significant they suggest direct acute cellular and organ-level responses in mammalian heart This is the first known study to identify a mammalian FaRP with cardio-depressant effects opening a new area of research on peptidergic modulation of contractile performance The high degree of RFRP structure conservation from amphibians to mammals and similarity to invertebrate cardioinhibitory peptides suggests RFRP-1 is involved in important physiological functions Elucidation of mechanisms involved in hRFRP-1 synthesis release and signaling may aid the development of strategies to prevent or attenuate cardiac dysfunction (C) 2010 Elsevier Inc All rights reserved