https://doi.org/10.4081/cardio.2024.25
Preferential vasodilator effects of levosimendan in resistance pulmonary arteries in a rodent pulmonary embolism model
Published: March 28, 2024
Abstract Views: 373
PDF: 16
HTML: 0
HTML: 0
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Background: We compared the vasoactive effects of levosimendan on isolated conduit pulmonary arteries (CPA) and resistance pulmonary arteries (RPA) versus mesenteric arteries, and we assessed the pulmonary artery (PA) vascular function and the PA vasoactive effects of levosimendan in a rodent pulmonary embolism (PE) model.
Methods: One group of male Wistar rats (200-300 g) was killed by decapitation to obtain pulmonary and mesenteric rings. Another group was assigned to a massive PE or saline solution infusion. After euthanasia, mesenteric arteries and CPA (1-2 mm) and RPA (≤0.5 mm) were dissected and cut into 2-3 mm wide rings, recording contractile tension. We obtained the concentration-response curves of cumulative doses of levosimendan on pre-contracted arterial rings from decapitated and sham/embolized animals. A set of RPA rings was exposed to acute hypoxia. The effect of PE on the pulmonary vasoactive function was assessed by dose-response curves of acetylcholine (ACh) and endothelin-1 (ET-1) of PA rings from sham/embolized animals.
Results: Levosimendan relaxant potency of RPA was similar to that of mesenteric arteries and higher than CPA, while mesenteric rings showed the maximal relaxant effect, followed by RPA and CPA, respectively. PE did not affect the vasoactive response of PA rings either to ACh or to ET-1, and the relaxant effects of CPA and RPA to levosimendan were also preserved. Acute hypoxia reduced (p<0.05) but did not avoid the RPA relaxant effect of levosimendan.
Conclusions: Levosimendan is a more specific vasodilator of RPA with a similar relaxant potency as mesenteric arteries, which is preserved after PE but significantly reduced during hypoxia.
Archer SL, Huang JM, Reeve HL, et al. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia, Circ Res 1996;78:431-42.
DOI: https://doi.org/10.1161/01.RES.78.3.431
Archer SL, Wu XC, Thebaud B, et al. Preferential expression and function of voltage-gated, O2-sensitive k+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: Ionic diversity in smooth muscle cells. Circ Res 2004;95:308-18.
DOI: https://doi.org/10.1161/01.RES.0000137173.42723.fb
Farmakis D, Alvarez J, Gal TB, et al. Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper. Int J Cardiol 2016;222:303-12.
DOI: https://doi.org/10.1016/j.ijcard.2016.07.202
Yokoshiki H, Sperelakis N. Vasodilating mechanisms of levosimendan. Cardiovasc Drugs Ther 2003;17:111-3.
DOI: https://doi.org/10.1023/A:1025379400395
De Witt BJ, Ibrahim IN, Bayer E, et al. An analysis of responses to levosimendan in the pulmonary vascular bed of the cat. Anesth Analg 2002;94:1427-33.
DOI: https://doi.org/10.1213/00000539-200206000-00009
Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M. Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 2001;29:2185-93.
DOI: https://doi.org/10.1097/00003246-200111000-00022
Kerbaul F, Gariboldi V, Giorgi R, et al. Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure. Crit Care Med 2007;35:1948-54.
DOI: https://doi.org/10.1097/01.CCM.0000275266.33910.8D
Malacrida L, Taranto E, Angulo M, Alvez Cruz I, GJC. Levosimendan improves right ventricular function and energy metabolism in a sheep model of submasive pulmonary embolism, Eur Heart J Acute Cardiovasc Care 2012;1:10.
Wiklund A, Kylhammar D, Radegran G. Levosimendan attenuates hypoxia-induced pulmonary hypertension in a porcine model, J Cardiovasc Pharmacol 2012;59:441-9.
DOI: https://doi.org/10.1097/FJC.0b013e31824938f0
Kleber FX, Bollmann T, Borst MM, et al. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study, J Clin Pharmacol 2009;49:109-15.
DOI: https://doi.org/10.1177/0091270008325150
Morelli A, Teboul JL, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 2006;34:2287-93.
DOI: https://doi.org/10.1097/01.CCM.0000230244.17174.4F
Stratmann G, Gregory GA. Neurogenic and humoral vasoconstriction in acute pulmonary thromboembolism. Anesth Analg 2003;97:341-54.
DOI: https://doi.org/10.1213/01.ANE.0000068983.18131.F0
Smulders YM. Contribution of pulmonary vasoconstriction to haemodynamic instability after acute pulmonary embolism. Implications for treatment? Neth J Med 2001;58:241-7.
DOI: https://doi.org/10.1016/S0300-2977(01)00117-6
Devera L, Malacrida L, Taranto E, Angulo M, Alvez I, GJC. Efectos del levosimendan sobre la función arterial y la poscarga dinámica pulmonares durante el tromboembolismo submasivo. Rev Esp Cardiol 2008;61:140.
Perez-Vizcaino F, Villamor E, Moro M, Tamargo J. Pulmonary versus systemic effects of vasodilator drugs: an in vitro study in isolated intrapulmonary and mesenteric arteries of neonatal piglets. Eur J Pharmacol 1996;314:91-8.
DOI: https://doi.org/10.1016/S0014-2999(96)00548-1
Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 1977;41:19-26.
DOI: https://doi.org/10.1161/01.RES.41.1.19
Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121:877-905.
DOI: https://doi.org/10.1378/chest.121.3.877
Cogolludo A, Moreno L. Frazziano G, et al. Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovasc Res 2009;82:296-302.
DOI: https://doi.org/10.1093/cvr/cvn349
Yildiz O, Nacitarhan C, Seyrek M. Potassium channels in the vasodilating action of levosimendan on the human umbilical artery. J Soc Gynecol Investig 2006;13:312-5.
DOI: https://doi.org/10.1016/j.jsgi.2006.02.005
Yildiz O, Seyrek M, Yildirim V, Demirkilic U, Nacitarhan C. Potassium channel-related relaxation by levosimendan in the human internal mammary artery. Ann Thorac Surg 2006;81:1715-9.
DOI: https://doi.org/10.1016/j.athoracsur.2005.12.057
Dias-Junior CA, Souza-Costa DC, Zerbini T, da Rocha JB, Gerlach RF, Tanus-Santos JE. The effect of sildenafil on pulmonary embolism-induced oxidative stress and pulmonary hypertension. Anesth Analg 2005;101:115-20.
DOI: https://doi.org/10.1213/01.ANE.0000153499.10558.F3
Tan W, Madhavan K, Hunter KS, Park D, Stenmark KR. Vascular stiffening in pulmonary hypertension: cause or consequence? Pulm Circ 2014;4:560-80.
DOI: https://doi.org/10.1086/677370
Santana DB, Barra JG, Grignola JC, Gines FF, Armentano RL. Pulmonary artery smooth muscle activation attenuates arterial dysfunction during acute pulmonary hypertension. J Appl Physiol (1985) 2005;98:605-13.
DOI: https://doi.org/10.1152/japplphysiol.00361.2004
Reho JJ, Zheng X, Fisher SA. Smooth muscle contractile diversity in the control of regional circulations. Am J Physiol Heart Circ Physiol 2014;306:H163-72.
DOI: https://doi.org/10.1152/ajpheart.00493.2013
Souza-Costa DC, Zerbini T, Palei AC, Gerlach RF, Tanus-Santos JE. L-arginine attenuates acute pulmonary embolism-induced increases in lung matrix metalloproteinase-2 and matrix metalloproteinase-9. Chest 2005;128:3705-10.
DOI: https://doi.org/10.1378/chest.128.5.3705
Kao SJ, Chen HI. Nitric oxide mediates acute lung injury caused by fat embolism in isolated rat's lungs. J Trauma 2008;64:462-9.
DOI: https://doi.org/10.1097/TA.0b013e318058aa2e
Tanus-Santos JE, Gordo WM, Cittadino M, Moreno H, Jr. Plasma cGMP levels in air embolism-induced acute lung injury. J Crit Care 2000;15:137-41.
DOI: https://doi.org/10.1053/jcrc.2000.19229
Toba M, Nagaoka T, Morio Y, et al. Involvement of rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats, Am J Physiol Lung Cell Mol Physiol 2010;298:L297-303.
DOI: https://doi.org/10.1152/ajplung.90237.2008
Dias-Junior CA, Tanus-Santos JE. Hemodynamic effects of sildenafil interaction with a nitric oxide donor compound in a dog model of acute pulmonary embolism. Life Sci 2006;79:469-74.
DOI: https://doi.org/10.1016/j.lfs.2006.01.034
Papp Z, Edes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;159:82-7.
DOI: https://doi.org/10.1016/j.ijcard.2011.07.022
Parissis JT, Andreadou I, Bistola V, et al. Novel biologic mechanisms of levosimendan and its effect on the failing heart. Expert Opin Investig Drugs 20081;7:1143-50.
DOI: https://doi.org/10.1517/13543784.17.8.1143
Nieminen MS, Buerke M, Cohen-Solal A, et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: a review and expert consensus opinion. Int J Cardiol 2016;218;150-7.
DOI: https://doi.org/10.1016/j.ijcard.2016.05.009
How to Cite
Bedo, C., & Grignola, J. C. (2024). Preferential vasodilator effects of levosimendan in resistance pulmonary arteries in a rodent pulmonary embolism model. Global Cardiology, 2(1). https://doi.org/10.4081/cardio.2024.25
Copyright (c) 2024 the Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
