Evaluation of oxytocin pharmacokinetic : pharmacodynamic profile and establishment of its cardiomyogenic potential in swine
Cell therapy has been suggested as a promising treatment for myocardial regeneration through cardiomyocyte replacement or by preventing apoptosis of surviving myocardium and/or improving neovascularisation. Bone marrow stem cells (BMSCs) express cardiac markers in vitro upon stimulation with different inducers. The BMSCs have been used as cell therapy after myocardial infarction (MI) in pre-clinical and clinical studies. Recent reports have uncovered the potential beneficial effects of oxytocin (OT) after MI. Particularly, OT is an inducer of cardiomyogenic differentiation of embryonic stem cells and this differentiation is mediated by the nitric oxide (NO)-soluble guanylyl cyclase pathway. However, some studies have shown that OT exhibits nonlinear pharmacokinetics and that this could explain the previously described controversial hemodynamic alterations.   Therefore the objectives of the present work were to:   1) Characterize the pharmacokinetic profile of different dosing regimens of OT in swine, by using a more suitable pharmacokinetic / pharmacodynamic modelization that could explain the time-course of cardiovascular and renal effects observed following OT administration.   2) To isolate, differentiate and find the optimum time of porcine BMSC (pBMSC) differentiation based on the expression of cardiac related transcription factors and structural proteins expressed at different passages.   3) To induce and quantify the OT-mediated cardiomyogenic differentiation of pBMSCs.   4) To document the role of the NO pathway in the OT-mediated cardiomyogenic differentiation of pBMSCs.   We found that OT pharmacokinetics are better explained by target-mediated drug disposition (TMDD) kinetics, because the time-course of plasma OT concentration depends on the binding capacity to its receptor, as well as OT elimination (metabolism).  Also, we found that OT-mediated cardiomyogenic differentiation of pBMSCs should be induced during the first passages, because passaging affects the phenotypic profile of pBMSCs, as well as the differentiation potential of pBMSCs.   We observed that OT induces cardiomyogenic differentiation of pBMSCs, because OT-induced cells expressed cardiac markers, and the expression of cardiac specific proteins was more abundant in OT-treated cells vs. 5-azacytidine-treated cells, which has been used widely as a cardiomyogenic differentiation inducer of adult stem cells. Moreover, OT improved proliferation of pBMSCs. Finally, we observed that the inhibition of the NO pathway significantly affects the expression of cardiac specific proteins.  To conclude, these studies demonstrate some interesting potential in cardiomyogenic differentiation of adult stem cells for OT, but its precise role in cell therapy will need prudence and further investigations.
Porc Pharmacokinetic Pharmacodynamic Oxytocin Adult stem cells Cardiomyogenic differentiation Nitric oxide Swine Pharmacokinetics Pharmacodynamics