Abstract
It is well known that stretch increases the hearts contractility, although the cellular mechanisms that produce the stretch response are not fully understood. Recently, using a unique bioassay system, we showed unequivocally that stretching the left ventricle of isolated perfused rat hearts released paracrine/autocrine factors [[1]Ward M.-L. Shen X. Greenwood D.R. Use of liquid chromatography-mass spectrometry (LC-MS) to detect substances of nanomolar concentration in the coronary effluent of isolated perfused hearts.Prog Biophys Mol Biol. 2014 Jul 24; Google Scholar]. Preliminary analysis of our data using a metabolomics approach suggested these factors were prostanoids, constituting a set of signalling pathways not previously associated with regulation of the heart. Quantitative and statistical analyses using differential LCMS/MS of the coronary effluent collected from un-stretched and stretched hearts identified prostaglandins F2α and E2 as significantly different between stretched and un-stretched samples (P < 0.01). Exogenous PGF2α and PGE2 applied to isolated trabeculae from rat hearts elicited a positively inotropic response from PGF2α, but not PGE2. PGF2ɑ, over a concentration range of 1 nM - 1 μM, increased both the Ca2+ transients and isometric stress in trabeculae, reaching steady-state after 10 - 15 min, without altering the time course of Ca2+ transient decay. The positive inotropic effect of PGF2α was mediated through a protein kinase C (PKC) signalling pathway that involved activation of the sarcolemmal Na+/H+ exchanger. These data suggest PGF2α is important in maintaining homeostasis during volume loading in healthy hearts. However, under pathophysiological conditions, sustained release of PGF2α might be important in that activation of detrimental hypertrophic pathways.
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