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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.

Author information

1
Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
2
Orion Pharma, Espoo, Finland.
3
MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary.

Abstract

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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