Preferential Vasodilator Effects of Levosimendan in Resistance Pulmonary Arteries in a Rodent Pulmonary Embolism Model

Camila Bedo, Juan C Grignola

Abstract


Background: We compared the vasoactive effects of levosimendan on isolated conduit (CPA) and resistance (RPA) pulmonary arteries versus mesenteric arteries and we assessed the PA vascular function and the PA vasoactive effects of levosimendan in a rodent 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 (i.d. 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 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.


Keywords


levosimendan; pulmonary embolism; pulmonary arteries; vasodilatation; hypoxia

Full Text:

433

References


Archer SL, Huang JM, Reeve HL, Hampl V, Tolarova S, Michelakis E, Weir EK. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res. 1996; 78:431-442. http://www.ncbi.nlm.nih.gov/pubmed/8593702

Archer SL, Wu XC, Thebaud B, Nsair A, Bonnet S, Tyrrell B, McMurtry MS, Hashimoto K, Harry G, Michelakis ED. 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; 95:308-318. 10.1161/01.RES.0000137173.42723.fb

Farmakis D, Alvarez J, Gal TB, Brito D, Fedele F, Fonseca C, Gordon AC, Gotsman I, Grossini E, Guarracino F, Harjola VP, Hellman Y, Heunks L, Ivancan V, Karavidas A, Kivikko M, Lomivorotov V, Longrois D, Masip J, Metra M, Morelli A, Nikolaou M, Papp Z, Parkhomenko A, Poelzl G, Pollesello P, Ravn HB, Rex S, Riha H, Ricksten SE, Schwinger RH, Vrtovec B, Yilmaz MB, Zielinska M, Parissis J. 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; 222:303-312. 10.1016/j.ijcard.2016.07.202

Yokoshiki H, Sperelakis N. Vasodilating mechanisms of levosimendan. Cardiovasc Drugs Ther. 2003; 17:111-113. http://www.ncbi.nlm.nih.gov/pubmed/14562823

De Witt BJ, Ibrahim IN, Bayer E, Fields AM, Richards TA, Banister RE, Kaye AD. An analysis of responses to levosimendan in the pulmonary vascular bed of the cat. Anesth Analg. 2002; 94:1427-1433. http://www.ncbi.nlm.nih.gov/pubmed/12032000

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; 29:2185-2193. http://www.ncbi.nlm.nih.gov/pubmed/11700420

Kerbaul F, Gariboldi V, Giorgi R, Mekkaoui C, Guieu R, Fesler P, Gouin F, Brimioulle S, Collart F. Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure. Crit Care Med. 2007; 35:1948-1954. 10.1097/01.CCM.0000275266.33910.8D

Malacrida L, Taranto E, Angulo M, Alvez Cruz I, JC G. 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; 59:441-449. 10.1097/FJC.0b013e31824938f0

Kleber FX, Bollmann T, Borst MM, Costard-Jackle A, Ewert R, Kivikko M, Petterson T, Pohjanjousi P, Sonntag S, Wikstrom G. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: Results of a pilot study. J Clin Pharmacol. 2009; 49:109-115. 10.1177/0091270008325150

Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, De Gaetano A, Picchini U, Orecchioni A, Carbone I, Tritapepe L, Pietropaoli P, Westphal M. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: A pilot study. Crit Care Med. 2006; 34:2287-2293. 10.1097/01.CCM.0000230244.17174.4F

Stratmann G, Gregory GA. Neurogenic and humoral vasoconstriction in acute pulmonary thromboembolism. Anesth Analg. 2003; 97:341-354. http://www.ncbi.nlm.nih.gov/pubmed/12873915

Smulders YM. Contribution of pulmonary vasoconstriction to haemodynamic instability after acute pulmonary embolism. Implications for treatment? Neth J Med. 2001; 58:241-247. http://www.ncbi.nlm.nih.gov/pubmed/11395221

Devera L, Malacrida L, Taranto E, Angulo M, Alvez I, JC G. [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; 314:91-98. http://www.ncbi.nlm.nih.gov/pubmed/8957223

Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977; 41:19-26. http://www.ncbi.nlm.nih.gov/pubmed/862138

Wood KE. Major pulmonary embolism: Review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002; 121:877-905. http://www.ncbi.nlm.nih.gov/pubmed/11888976

Cogolludo A, Moreno L, Frazziano G, Moral-Sanz J, Menendez C, Castaneda J, Gonzalez C, Villamor E, Perez-Vizcaino F. Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovasc Res. 2009; 82:296-302. 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; 13:312-315. 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; 81:1715-1719. 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; 101:115-120. 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? (2013 grover conference series). Pulm Circ. 2014; 4:560-580. 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; 98:605-613. 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:H163-172. 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; 128:3705-3710. 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; 64:462-469. 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; 15:137-141. 10.1053/jcrc.2000.19229

Toba M, Nagaoka T, Morio Y, Sato K, Uchida K, Homma N, Takahashi K. 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. 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; 79:469-474. 10.1016/j.lfs.2006.01.034

Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, Mebazaa A, Landoni G, Grossini E, Caimmi P, Morelli A, Guarracino F, Schwinger RH, Meyer S, Algotsson L, Wikstrom BG, Jorgensen K, Filippatos G, Parissis JT, Gonzalez MJ, Parkhomenko A, Yilmaz MB, Kivikko M, Pollesello P, Follath F. Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012; 159:82-87. 10.1016/j.ijcard.2011.07.022

Parissis JT, Andreadou I, Bistola V, Paraskevaidis I, Filippatos G, Kremastinos DT. Novel biologic mechanisms of levosimendan and its effect on the failing heart. Expert Opin Investig Drugs. 2008; 17:1143-1150. 10.1517/13543784.17.8.1143

Nieminen MS, Buerke M, Cohen-Solal A, Costa S, Edes I, Erlikh A, Franco F, Gibson C, Gorjup V, Guarracino F, Gustafsson F, Harjola VP, Husebye T, Karason K, Katsytadze I, Kaul S, Kivikko M, Marenzi G, Masip J, Matskeplishvili S, Mebazaa A, Moller JE, Nessler J, Nessler B, Ntalianis A, Oliva F, Pichler-Cetin E, Poder P, Recio-Mayoral A, Rex S, Rokyta R, Strasser RH, Zima E, Pollesello P. The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion. Int J Cardiol. 2016; 218:150-157. 10.1016/j.ijcard.2016.05.009

Shewan LG, Coats AJS, Henein M. Requirements for ethical publishing in biomedical journals. . International Cardiovascular Forum Journal. 2015;2. 10.17987/icfj.v2i1.4




DOI: https://doi.org/10.17987/icfj.v11i0.433


Copyright (c) 2017 The Authors

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.