Oxytocin (OT) and its receptor (OTR) are expressed in the heart and are involved in the physiological cardiovascular functional system. Although it is known that OT/OTR signaling is cardioprotective by reducing the inflammatory response and improving cardiovascular function, the role of OT in the cardiac electrical excitation modulation has not been clarified. This study investigates the molecular mechanism of the action of OT on cardiomyocyte membrane excitation focusing on the L-type Ca2+ channel. Our methodology uses molecular biological methods and a patch-clamp technique on rat cardiomyocytes with OT, combined with several signal inhibitors and/or activators. Our results show that long-term treatment of OT significantly decreases the expression of Cav1.2 mRNA, and reduces the L-type Ca2+ channel current (ICa.L) in cardiomyocytes. OT downregulates the phosphorylated component of a transcription factor adenosine-3′,5′-cyclic monophosphate (cAMP) response element binding protein (CREB), whose action is blocked by OTR antagonist and pertussis toxin, a specific inhibitor of the inhibitory GTP-binding regulators of adenylate cyclase, Gi. On the other hand, the upregulation of Cav1.2 mRNA expression by isoproterenol is halted by OT. Furthermore, inhibition of phospholipase C (PLC) was without effect on the OT action to downregulate Cav1.2 mRNA—which suggests a signal pathway of Gi/protein kinase A (PKA)/CREB mediated by OT/OTR. These findings indicate novel signaling pathways of OT contributing to a downregulation of the Cav1.2-L-type Ca2+ channel in cardiomyocytes.

Background: The neurohypophyseal hormones oxytocin (OT) and [Arg 8 ]-vasopressin (AVP) have recently been implicated in cardiac function. This study was designed to investigate actions of OT and AVP on regulation of the voltage-gated Ca 2þ channel in cardiomyocytes.Methods and Results: Cultured neonatal rat cardiomyocytes were stimulated with OT or AVP (10 À8 M to 10 À6 M) for 24-72 h, followed by real-time PCR and patch clamp studies. Although OT did not exert any modulatory effect on L-type Ca 2þ channel current, as a shortterm effect, stimulation of cardiomyocytes with OT but not AVP decreased the expression of Ca V 1.2 mRNA with a reduced L-type Ca 2þ channel current. A transcription factor CREB mRNA expression was down-regulated by OT treatment, although T-type Ca 2þ channels (Ca V 3.1, Ca V 3.2) were unaffected by OT or AVP.Conclusion: OT but not AVP down-regulates L-type Ca 2þ channel expression through the inhibition of CREB transcriptional, suggesting a novel mechanism of OT action in the cardiac electrophysiology. (J Arrhythmia 2010; 26: 111-118)

Background: The neurohypophyseal hormones oxytocin (OT) and [Arg8]‐vasopressin (AVP) have recently been implicated in cardiac function. This study was designed to investigate actions of OT and AVP on regulation of the voltage‐gated Ca2+ channel in cardiomyocytes.Methods and Results: Cultured neonatal rat cardiomyocytes were stimulated with OT or AVP (10‐8 M to 10‐6 M) for 24‐72 h, followed by real‐time PCR and patch clamp studies. Although OT did not exert any modulatory effect on L‐type Ca2+ channel current, as a shortterm effect, stimulation of cardiomyocytes with OT but not AVP decreased the expression of Cav1.2 mRNA with a reduced L‐type Ca2+ channel current. A transcription factor CREB mRNA expression was down‐regulated by OT treatment, although T‐type Ca2+ channels (Cav3.1, Cav3.2) were unaffected by OT or AVP.Conclusion: OT but not AVP down‐regulates L‐type Ca2+ channel expression through the inhibition of CREB transcriptional, suggesting a novel mechanism of OT action in the cardiac electrophysiology.