The family of G-protein coupled receptors (GPCRs) are amongst the best-described regulators of cardiovascular pathophysiology. In rodents, intracerebroventricular administration of orexins increases mean arterial pressure and heart rate. However, important peripheral actions of orexins and their cognate receptors is now increasingly of interest.
In this study we demonstrated that both receptors are present across the rat heart, at mRNA and protein level. Moreover, we also demonstrate that the rat heart is a potential source of orexins, since the prepro-orexin gene appears to be present, as well as the cleaved functional orexins A (OR-A) and B (OR-B). Treatment of myocytes with OR-B resulted in a dose-dependent increase of myosin light chain (MLC20) and Troponin I phosphorylation. In isolated rat myocytes, acute application of OR-B but not OR-A (10 nM) caused an increase in contractile strength but has little effect on diastolic or systolic calcium levels. A specific OX2R agonist ([Ala11, D-Leu15]-Orexin B) at 10 nM had the same effect as OR-B, whereas blocking of OX1R using a specific antagonist (SB- 408124), did not alter the effect of OR-B.
Activation of ERK1/2 was required for the OR-B-induced activation of MLC20, since treatment of myocytes with the inhibitor of MEK1 (U0126) inhibited the OR-B-induced phosphorylation of MLC20. Collectively, these data point towards a novel role for OR-B in cardiac function.
Our novel observations provide a new insight into the regulation of cardiac contractions by orexins independent of CNS input, and suggest that these effects are mediated via a dedicated OR-B/OX2R pathway.
01 - 05 Apr 2006
European Society of Endocrinology