Endocrine Abstracts

Aims/hypothesis: Oxytocin (OT) and OT receptor (OTR) are expressed in the heart. During OT synthesis, its precursor, termed OT-Gly-Lys-Arg (OT-GKR), is abundantly accumulated in the developing rat heart. Because the OTR is primarily associated with Gq/11protein subunit that activates protein synthesis, we hypothesised that OT can cause cardiomyocyte hypertrophy. On the other hand, OTR signalling is associated with anti-hypertrophic atrial natriuretic peptide (ANP) release and nitric oxide (NO) activation in the heart. Consequently, we investigated whether OT treatment promotes or inhibits hypertrophy in cardiomyocytes.

Methods: The experiments were carried out in newborn and adult rat cardiomyocyte cultures. The enhanced protein synthesis and increased cardiomyocyte volume were stimulated by a 24 h treatment with endothelin-1 (ET-1) or angiotensin II (Ang II).

Results: Treatment with OT or OT-GKR did not increased [³⁵S]-methionine incorporation by cardiomyocytes and not changed cell volume during 24–72 h. The treatment of newborn rat cardiomyocytes with OT or its abundant cardiac precursor, OT-GKR, revealed ANP protein and increased intracellular cGMP accumulation. Consequently, the cardiomyocyte hypertrophy related to ET-1 and Ang II was abolished by the treatment of 10 nM OT or 10 nM OT-GKR. The ANP receptor blockade by anantin and NO synthases by L-NAME, inhibited cGMP enhancement in cardiomyocytes exposed to OT. In the presence of inhibitors STO-609 and compound C the anti-hypertrophic OT effects in cardiomyocytes was reduced which suggest that OT signalling includes activation of calcium–calmodulin kinase kinase and AMP-activated protein kinase pathways. Moreover, in ET-1 stimulated cells, OT treatment normalized reduced Akt phosphorylation, prevented abundant accumulation of ANP and blocked ET-1-mediated translocation of nuclear factor of activated T-cells (NFAT).

Conclusion: cGMP/protein kinase G mediates OT-induced anti-hypertrophic response with the contribution of ANP and NO. OT treatment represents a novel approach in attenuation of hypertrophy during development and cardiac pathology.