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J Cardiovasc Pharmacol. 2019 Jul 22. doi: 10.1097/FJC.0000000000000700. [Epub ahead of print]

The novel inodilator ORM-3819 relaxes isolated porcine coronary arteries: role of voltage-gated potassium channels activation.

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Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
Orion Pharma, Espoo, Finland.
MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary.


Relaxation and changes in the transmembrane potential of vascular smooth muscle induced by ORM-3819, a novel inodilating compound, were investigated in isolated porcine coronary arteries. Isometric tone was studied on arterial rings precontracted by KCl (30 mM) and resting membrane potential was investigated by a conventional microelectrode technique. ORM-3819 in the concentration range 0.38-230.6 µM evoked concentration-dependent relaxation with a maximum value of 58.1% and an effective concentration of the relaxing substance that caused 50% of maximum relaxation of 72.2 µM. The maximum hyperpolarization produced by ORM-3819 at a concentration of 120 µM (-2.6±0.81 mV, N=10) did not differ significantly from that induced by C-type natriuretic peptide (CNP), an endogenous hyperpolarizing mediator, at a concentration of 1.4 µM (-3.6±0.38 mV, N=17). The same effect elicited by the known inodilator levosimendan was less pronounced at a concentration of 3.7 µM: -1.82±0.44 mV, N=22 (P<0.05 vs CNP). The voltage-gated potassium channel inhibitor 4-aminopyridine, at a concentration of 5 mM, attenuated the relaxation induced by ORM-3819 at concentrations of 41.6 or 117.2 µM. These results suggest that ORM-3819 is a potent vasodilating agent able to relieve coronary artery vasospasm by causing hyperpolarization of vascular smooth muscle cells via processes involving activation of voltage-gated potassium channels.

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