Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart

作者：Pakhomov Nikolai^*; Pustovit Ksenia; Potekhina Victoria; Filatova Tatiana; Kuzmin Vladislav; Abramochkin Denis

来源：European Journal of Pharmacology, 2018, 820: 97-105.

DOI：10.1016/j.ejphar.2017.12.024

• Heart
• Purine receptors
• Diadenosine polyphosphates
• Protein kinase C, phosphodiesterase, nitric oxide

Extracellular diadenosine polyphosphates (Ap(n)A) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular Ap(n)A cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie Ap(n)A action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap(4)A) effects in the rat heart has been investigated for the first time.
Extracellular Ap(4)A caused significant decreasing of the ventricular inotropy. Ap(4)A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca2+ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap(4)A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap(4)A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective.
In conclusion, our results allow suggesting that Ap(4)A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap4A-caused inhibition of the rat heart contractility.

• 出版日期2018-2-5