Abstract 13039: Prostaglandin E1 Facilitates 5-HT4 Serotonergic and Beta-adrenergic Receptor Mediated Inotropic Effects in Failing Human Heart
Introduction and hypothesis: Prostaglandins have displayed both beneficial and detrimental effects in clinical studies in patients with severe heart failure. Prostaglandins are known to increase cardiac output, but the mechanism is not clarified. Here, we assessed the hypothesis that prostaglandins increase contractility in human heart by amplifying cAMP-dependent inotropic responses.
Methods: Contractility was measured ex vivo in isolated left ventricular strips from explanted human hearts. Phosphodiesterase (PDE) activity was measured through a two-step PDE activity assay on homogenates of the same failing human left ventricles.
Results: PGE1 (1 µM) alone did not modify contractility, but given prior, amplified maximal serotonin (5-HT)-evoked (10 µM) contractile responses several-fold (24±7 with PGE1, n=8 vs. 3±2, 5-HT alone, n=9, % above basal, p<0.05). The 5-HT-evoked inotropic response was amplified by the PDE3 inhibitor cilostamide and further amplified when PGE1 was given simultaneously with cilostamide (26±6, n=9, vs. 56±12, n=9, % above basal, p<0.05). The maximal β-adrenergic inotropic response was unaffected by PGE1 alone. However, in this sitiuation, the time to reach 90% of maximal isoprenaline-evoked inotropic response was significantly shortened compared to isoprenaline alone (299±33s, n=14 vs. 406±46s, n=14, p<0.05). PGE1 also facilitated the inotropic effect of isoprenaline above that with PDE3 inhibition alone (time to reach 90%: 111±39s, n=14 vs. 183±37s, n=14 respectively, p<0.05). PGE1 did not modify PDE activity in the homogenate, neither alone nor when given simultaneously with PDE3 and/or PDE4 inhibitors.
Conclusion: Our results show that PGE1 can enhance cAMP-mediated responses in failing human ventricle, possibly explaining some of the hemodynamic effects of prostaglandins. The mechanism seems to be independent of PDE inhibition. Possibly, PGE1 may facilitate 5-HT and β-adrenergic-mediated inotropic effects by synergistic effects upon adenylyl cyclase activation. Alternatively, PGE1 contributes to a re-organization of factors regulating compartmentation, allowing more efficient transduction of cAMP signaling to activate the contractile apparatus.
- © 2011 by American Heart Association, Inc.