Dataset Information

Levosimendan-induced venodilation is mediated by opening of potassium channels.

ABSTRACT: Unique vascular responses adhere to the cardiovascular efficacy of the inodilator levosimendan. In particular, selective venodilation appears to explain its clinical benefit during pulmonary hypertension complicated by heart failure with preserved ejection fraction. Vasodilators increase vessel diameter in various parts of the vascular system to different degrees and thereby influence blood pressure, its distribution, and organ perfusion depending on their mechanisms of action. Levosimendan and its long-lived active metabolite OR-1896 mobilize a set of vasodilatory mechanisms, that is, the opening of the ATP-sensitive K⁺ channels and other K⁺ channels on top of a highly selective inhibition of the phosphodiesterase III enzyme. A vessel-specific combination of the above vasodilator mechanisms-in concert with cardiac effects and cardiovascular reflex regulations-illustrates the pharmacological profile of levosimendan in various cardiovascular disorders. While levosimendan has been known to be an inotrope, its properties as an activator of ATP-sensitive K⁺ channels have gone largely ignored with respect to clinical applications. Here, we provide a summary of what is known about the ATP-sensitive K⁺ channel properties in preclinical studies and now for the first time, its ATP-sensitive K⁺ channel properties in a clinical trial.

SUBMITTER: Burkhoff D

PROVIDER: S-EPMC8712848 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Astrocytes form extensive intercellular networks through gap junctions to support both biochemical and electrical coupling between adjacent cells. ATP-sensitive K(+) (K(ATP)) channels couple cell metabolic state to membrane excitability and are enriched in glial cells. Activation of astrocytic mitochondrial K(ATP) (mitoK(ATP)) channel regulates certain astrocytic functions. However, less is known about its impact on electrical coupling between directly coupled astrocytes ex vivo. By using dual patch clamp recording, we found that activation of mitoK(ATP) channel increased the electrical coupling ratio in brain slices. The electrical coupling ratio started to increase 3 min after exposure to Diazoxide, a mitoK(ATP) channel activator, peaked at 5 min, and maintained its level with little adaptation until the end of the 10-min treatment. Blocking the mitoK(ATP) channel with 5-hydroxydecanoate, inhibited electrical coupling immediately, and by 10-min, the ratio dropped by 71% of the initial level. Activation of mitoK(ATP) channel also decreased the latency time of the transjunctional currents by 50%. The increase in the coupling ratio resulting from the activation of the mitoK(ATP) channel in a single astrocyte was further potentiated by the concurrent inhibiting of the channel on the recipient astrocyte. Furthermore, Meclofenamic acid, a gap-junction inhibitor which completely blocked the tracer coupling, hardly reversed the impact of mitoK(ATP) channel's activation on electrical coupling (by 7%). The level of mitochondrial Connexin43, a gap junctional subunit, significantly increased by 70% in astrocytes after 10-min Diazoxide treatment. Phospho-ERK signals were detected in Connexin43 immunoprecipitates in the Diazoxide-treated astrocytes, but not untreated control samples. Finally, inhibiting ERK could attenuate the effects of Diazoxide on electrical coupling by 61%. These findings demonstrate that activation of astrocytic mitoK(ATP) channel upregulates electrical coupling between hippocampal astrocytes ex vivo. In addition, this effect is mainly via up-regulation of the Connexin43-constituted gap junction coupling by an ERK-dependent mechanism in the mitochondria.

Dataset Information

Levosimendan-induced venodilation is mediated by opening of potassium channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets