Abstract
IntroductionLevosimendan is approved for left heart failure and is also used in right heart failure to reduce right ventricular afterload. Despite the fact that pulmonary arteries (PAs) and pulmonary veins (PVs) contribute to cardiac load, their responses to levosimendan are largely unknown.Materials and MethodsLevosimendan-induced vasorelaxation of PAs and PVs was studied in precision-cut lung slices from guinea pigs by videomicroscopy; baseline luminal area was defined as 100%. Intracellular cAMP- and cGMP-levels were measured by ELISA and NO end products were determined by the Griess reaction.ResultsLevosimendan relaxed control PVs (116%) and those pre-constricted with an endothelinA-receptor agonist (119%). PAs were only relaxed if pre-constricted (115%). Inhibition of KATP-channels (glibenclamide), adenyl cyclase (SQ 22536) and protein kinase G (KT 5823) largely attenuated the levosimendan-induced relaxation in control PVs, as well as in pre-constricted PAs and PVs. Inhibition of BKCa 2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine) only contributed to the relaxant effect of levosimendan in pre-constricted PAs. In both PAs and PVs, levosimendan increased intracellular cAMP- and cGMP-levels, whereas NO end products remained unchanged. Notably, basal NO-levels were higher in PVs. The KATP-channel activator levcromakalim relaxed PAs dependent on cAMP/PKA/PKG and increased cAMP-levels in PAs.DiscussionLevosimendan initiates complex and divergent signaling pathways in PAs and PVs. Levosimendan relaxes PAs and PVs primarily via KATP-channels and cAMP/cGMP; in PAs, BKCa 2+- and Kv-channels are also involved. Our findings with levcromakalim do further suggest that in PAs the activation of KATP-channels leads to the production of cAMP/PKA/PKG. In conclusion, these results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of PVs.
Highlights
Levosimendan is approved for left heart failure and is used in right heart failure to reduce right ventricular afterload
Our findings with levcromakalim do further suggest that in pulmonary arteries (PAs) the activation of KATP-channels leads to the production of cAMP/protein kinase A (PKA)/protein kinase G (PKG). These results suggest that levosimendan might reduce right ventricular afterload by relaxation of PAs as well as pulmonary hydrostatic pressure and pulmonary edema by relaxation of pulmonary veins (PVs)
We studied the relaxant effects of the inodilator levosimendan in control and pre-constricted pulmonary vessels and compared it to the b-receptor agonist isoproterenol
Summary
Levosimendan is approved for left heart failure and is used in right heart failure to reduce right ventricular afterload. Levosimendan is used to treat right heart failure and secondary pulmonary hypertension (PH) [2], since several studies suggested that it decreases right ventricular afterload and mean pulmonary arterial pressure (mPAP) [3,4]. Other studies failed to observe such effects [5,6] and in two patients with idiopathic PH levosimendan even elevated mPAP [7] These conflicting data raise the possibility that the effects of levosimendan on right ventricular afterload are explained by improved left ventricular contractility rather than by reduced pulmonary vascular resistance (PVR). Differences between PAs and PVs are highly relevant to left- and right-sided heart failure, it is completely unknown whether levosimendan acts differently in both vascular systems which are known for their remarkably distinct behaviour [16,17]. PVs contribute up to 40% to PVR [18] and their relaxation would be a useful intervention to reduce pulmonary edema, left ventricular volume-overload and secondary PH
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