Endocrine Abstracts

We have uncovered the cardioprotective functional oxytocin (OT) system in the rat and human heart. In rat model of heart infarct, OT treatment significantly reduced infarct size, decreased cardiomyocytes (CM) diameter, increased expression of atrial natriuretic peptide (ANP) and improved parameters of heart function. Consequently, in this report we investigated hypothesis that OT-related mechanism of ANP synthesis or release, plays a role in the control of CM hypertrophy.

The experiments were carried out in culture of newborn and adult rat CM in which hypertrophy was stimulated by endothelin-1 (ET-1, 100 nM). After 24-h CM hypertrophy was assessed by increased protein synthesis (30% as determined by [³⁵S]-methionine incorporation) and increased cell surface area (increase by 70%). OT (100 nM) treatment completely abolished hypertrophic effect of ET-1 in CM and reduced hypertrophy induced by other GqPCR agonists, such as the angiotensin II and phenylephrine. OT dose-dependently increased ANP release from the CM, ANP accumulation in the cell perinuclear region and increased the intracellular cGMP concentrations in newborn rat CM. However, the ANP receptor blockade by anantin did not completely inhibited cGMP enhancement in CMs exposed to OT suggesting also contribution of NO. Indeed, OT-mediated cGMP production in CM were reduced by l-NAME, a non specific inhibitor of NO synthases, partially reduced by 1400 W, an inhibitor of inducible NOS, and ODQ, an inhibitor of NO-sensitive guanylyl cyclases. STO-609 and compound C inhibition of anti-hypertrophic OT effects in CM indicated also the contribution of calcium–calmodulin kinase kinase and AMP-activated protein kinase pathways. Western-blot demonstrated that OT stimulates phoshorylation of Akt/PI3K pathway. Moreover, OT treatment normalized Akt phosphorylation reduced by ET-1, prevented abundant accumulation of ANP in hypertrophic cells and blocked ET-1-mediated translocation of transcription factor, NFAT, into the cell nuclei.

In conclusion, anti-hypertrophic OT effect in CM involves Akt/PI3K and AMPK signaling cascades. cGMP/protein kinase G mediate OT-induced anti-hypertrophic response with contribution of ANP and NO.