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.

Trial registration: ClinicalTrials.gov NCT03541603.

Keywords: Heart failure with preserved ejection fraction; Levosimendan; Pharmacology; Pulmonary hypertension; Therapy; Venodilation.

Conflict of interest statement

S.R. is Chief Medical Officer at Tenax Therapeutics. P.P. is full time employee at Orion Pharma. Z.P. and D.B. have nothing to declare.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Schematic illustration of levosimendan‐induced putative vasodilating mechanisms. Levosimendan is capable to mobilize a set of vasodilatory mechanisms. Stimulatory and inhibitory effects are illustrated by green and red arrows, respectively. Effects of levosimendan are highlighted by dashed arrows. 5′AMP: 5′ adenosine monophosphate; AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cylic guanosine monophosphate; GTP, guanosine triphosphate; l‐Arg: l‐arginine; MLCK, myosin light chain kinase; NO, nitric oxide; NOS, nitric oxide synthase; PDE III, phosphodiesterase III; PDE IV, phosphodiesterase IV; PKA: protein kinase A; PKG, protein kinase G; sGC, soluble guanylate cyclase. See the text for further abbreviations and details.

Figure 2

Hypothetical explanation for increased tissue sensitivity of levosimendan‐evoked vasodilation with marked venodilation. An increased level of levosimendan‐induced vasodilation can relate to more than a single vasodilator effector mechanism.

Figure 3

Stressed and unstressed vascular volume. The volume inside a vessel at near zero transmural pressure is termed ‘unstressed volume’ (blue). It fills the system without exerting tension in the vessel wall. The blood volume that creates positive transmural pressure via the elastic recoil of the vessel wall is termed ‘stressed volume’ (red). Mean circulatory filling pressure (MCFP) is a function of stressed volume and vascular compliance; compliance is the slope of the pressure–volume curve above the unstressed volume. (A) Cross section of a blood vessel. (B) The relationship between blood volume and MCFP. (C) The venous system contains approximately 70% of the blood volume. The splanchnic vascular bed serves as a reservoir and will adjust the amount of venous return based on signalling from the autonomic nervous system. In chronic HF, the increased sympathetic tone associated with activation of the renin–angiotensin–aldosterone system will also activate the splanchnic circulation to increase venous return, referred to SBV. This will increase the CVP and the pulmonary capillary wedge pressure. Q, cardiac output; R, systemic vascular resistance; RA: right atrium. Panels (A) and (B) freely adapted from Grübler et al. Panel (C) is freely adapted from Noel‐Morgan and Muir.