PMID- 32421724 OWN - NLM STAT- MEDLINE DCOM- 20200803 LR - 20200803 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 15 IP - 5 DP - 2020 TI - Levosimendan reduces segmental pulmonary vascular resistance in isolated perfused rat lungs and relaxes human pulmonary vessels. PG - e0233176 LID - 10.1371/journal.pone.0233176 [doi] LID - e0233176 AB - INTRODUCTION: Levosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats' isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS). MATERIAL AND METHODS: In IPL, levosimendan (10 muM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naive and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA. RESULTS: Levosimendan did not relax untreated lungs or naive PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs. DISCUSSION: Levosimendan reduces rats' segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension. FAU - Rieg, Annette Dorothea AU - Rieg AD AUID- ORCID: 0000-0002-7043-5494 AD - Department of Anaesthesiology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Suleiman, Said AU - Suleiman S AD - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Bunting, Nina Andrea AU - Bunting NA AD - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Verjans, Eva AU - Verjans E AD - Department of Paediatrics, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Spillner, Jan AU - Spillner J AD - Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, Rhenish-Westphalian Technical University, Aachen, Germany. FAU - Schnoring, Heike AU - Schnoring H AD - Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, Rhenish-Westphalian Technical University, Aachen, Germany. FAU - Kalverkamp, Sebastian AU - Kalverkamp S AD - Department of Cardiac and Thoracic Surgery, Medical Faculty Aachen, Rhenish-Westphalian Technical University, Aachen, Germany. FAU - Schroder, Thomas AU - Schroder T AD - Department of Surgery, Luisenhospital Aachen, Aachen, Germany. FAU - von Stillfried, Saskia AU - von Stillfried S AD - Institute of Pathology, Medical Faculty Aachen, Rhenish-Westphalian Technical University, Aachen, Germany. FAU - Braunschweig, Till AU - Braunschweig T AD - Institute of Pathology, Medical Faculty Aachen, Rhenish-Westphalian Technical University, Aachen, Germany. FAU - Schalte, Gereon AU - Schalte G AD - Department of Anaesthesiology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Uhlig, Stefan AU - Uhlig S AD - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. FAU - Martin, Christian AU - Martin C AD - Institute of Pharmacology and Toxicology, Medical Faculty Aachen, Rhenish Westphalian Technical University, Aachen, Germany. LA - eng PT - Journal Article DEP - 20200518 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 349552KRHK (Simendan) SB - IM MH - Animals MH - Female MH - Humans MH - *Hypertension, Pulmonary/metabolism/physiopathology MH - *Lung/blood supply/metabolism/physiopathology MH - Male MH - Perfusion MH - *Pulmonary Artery/metabolism/physiopathology MH - *Pulmonary Veins/metabolism/physiopathology MH - Rats MH - Rats, Wistar MH - Simendan/*pharmacology MH - Vascular Resistance/*drug effects PMC - PMC7233573 COIS- The authors have declared that no competing interests exist. EDAT- 2020/05/19 06:00 MHDA- 2020/08/04 06:00 PMCR- 2020/05/18 CRDT- 2020/05/19 06:00 PHST- 2020/02/20 00:00 [received] PHST- 2020/04/29 00:00 [accepted] PHST- 2020/05/19 06:00 [entrez] PHST- 2020/05/19 06:00 [pubmed] PHST- 2020/08/04 06:00 [medline] PHST- 2020/05/18 00:00 [pmc-release] AID - PONE-D-20-04981 [pii] AID - 10.1371/journal.pone.0233176 [doi] PST - epublish SO - PLoS One. 2020 May 18;15(5):e0233176. doi: 10.1371/journal.pone.0233176. eCollection 2020.