{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T02:24:07Z","timestamp":1773714247130,"version":"3.50.1"},"reference-count":105,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,11]],"date-time":"2019-03-11T00:00:00Z","timestamp":1552262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO\/cGMP and H2S\/KATP signaling pathways and blockade of \u03b11-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases.<\/jats:p>","DOI":"10.3390\/molecules24050987","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T03:49:31Z","timestamp":1552362571000},"page":"987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO\/cGMP and H2S\/KATP Pathways and Blockade of \u03b11-Adrenoceptors and Calcium Channels"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2439-6973","authenticated-orcid":false,"given":"Daniella","family":"Medina-Ruiz","sequence":"first","affiliation":[{"name":"Posgrado en Ciencias Qu\u00edmico Biol\u00f3gicas, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Cerro de las Campanas S\/N, Quer\u00e9taro C.P. 76010, Mexico"},{"name":"Laboratorio de Investigaci\u00f3n Qu\u00edmica y Farmacol\u00f3gica de Productos Naturales, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berenice","family":"Erreguin-Luna","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n Qu\u00edmica y Farmacol\u00f3gica de Productos Naturales, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-7068","authenticated-orcid":false,"given":"Francisco J.","family":"Luna-V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n Qu\u00edmica y Farmacol\u00f3gica de Productos Naturales, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2869-588X","authenticated-orcid":false,"given":"Antonio","family":"Romo-Mancillas","sequence":"additional","affiliation":[{"name":"Laboratorio de Dise\u00f1o Asistido por Computadora y S\u00edntesis de F\u00e1rmacos, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-9013","authenticated-orcid":false,"given":"Alejandra","family":"Rojas-Molina","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n Qu\u00edmica y Farmacol\u00f3gica de Productos Naturales, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3711-6491","authenticated-orcid":false,"given":"C\u00e9sar","family":"Ibarra-Alvarado","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n Qu\u00edmica y Farmacol\u00f3gica de Productos Naturales, Facultad de Qu\u00edmica, Universidad Aut\u00f3noma de Quer\u00e9taro, Centro Universitario, Quer\u00e9taro 76010, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/jch.12624","article-title":"Polypharmacy in older adults with hypertension: A comprehensive review","volume":"18","author":"Mukete","year":"2016","journal-title":"J. Clin. Hypertens."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1656938","DOI":"10.1155\/2016\/1656938","article-title":"Prevalence and associated factors of hypertension: A community-based cross-sectional study in municipalities of Kathmandu, Nepal","volume":"2016","author":"Dhungana","year":"2016","journal-title":"Int. J. Hypertens."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1001\/jama.2013.284427","article-title":"Evidence-based guideline for the management of high blood pressure in adults","volume":"311","author":"James","year":"2014","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/bjaceaccp\/mku061","article-title":"Antihypertensive drugs","volume":"15","author":"Jackson","year":"2015","journal-title":"BJA Educ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"j5542","DOI":"10.1136\/bmj.j5542","article-title":"Incremental effects of antihypertensive drugs: Instrumental variable analysis","volume":"359","author":"Markovitz","year":"2017","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/apha.12628","article-title":"Endothelium-dependent hyperpolarization: Age, gender and blood pressure, do they matter?","volume":"219","author":"Leung","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Goto, K., Ohtsubo, T., and Kitazono, T. (2018). Endothelium-dependent hyperpolarization (EDH) in hypertension: The role of endothelial ion channels. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010315"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1080\/19336950.2018.1454814","article-title":"Pharmacologic targeting of endothelial Ca2+ -activated K+ channels: A strategy to improve cardiovascular function","volume":"12","author":"John","year":"2018","journal-title":"Channels"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cjca.2015.02.008","article-title":"Oxidative stress and human hypertension: Vascular mechanisms, biomarkers, and novel therapies","volume":"31","author":"Montezano","year":"2015","journal-title":"Can. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/HJH.0000000000000833","article-title":"Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation","volume":"34","author":"Stead","year":"2016","journal-title":"J. Hypertens."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6904327","DOI":"10.1155\/2016\/6904327","article-title":"Interaction of hydrogen sulfide with nitric oxide in the cardiovascular system","volume":"2016","author":"Nagpure","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9049782","DOI":"10.1155\/2016\/9049782","article-title":"Physiological importance of hydrogen sulfide: Emerging potent neuroprotector and neuromodulator","volume":"2016","author":"Panthi","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40035-018-0108-x","article-title":"Hydrogen sulfide, nitric oxide, and neurodegenerative disorders","volume":"7","author":"Panthi","year":"2018","journal-title":"Transl. Neurodegener."},{"key":"ref_14","first-page":"S291","article-title":"Cardiovascular effects of gasotransmitter donors","volume":"65","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.bcp.2018.01.017","article-title":"Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension","volume":"149","author":"Gheibi","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1039\/c2cs15271a","article-title":"Nitric Oxide Release Part III. Measurement and Reporting","volume":"41","author":"Coneski","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1039\/C3MD00362K","article-title":"Hydrogen sulfide donors in research and drug development","volume":"5","author":"Song","year":"2014","journal-title":"Med. Chem. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Luna-V\u00e1zquez, F.J., Ibarra-Alvarado, C., Rojas-Molina, A., Romo-Mancillas, A., L\u00f3pez-Vallejo, F.H., Sol\u00eds-Guti\u00e9rrez, M., Rojas-Molina, J.I., and Rivero-Cruz, F. (2016). Role of nitric oxide and hydrogen sulfide in the vasodilator effect of ursolic acid and uvaol from black cherry prunus serotina fruits. Molecules, 21.","DOI":"10.3390\/molecules21010078"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.fitote.2012.05.014","article-title":"Vasorelaxant activity of some structurally related triterpenic acids from Phoradendron reichenbachianum (Viscaceae) mainly by NO production: Ex vivo and in silico studies","volume":"83","author":"Rios","year":"2012","journal-title":"Fitoterapia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"475","DOI":"10.2174\/138620711795767866","article-title":"Integrating virtual screening and combinatorial chemistry for accelerated drug discovery","volume":"14","author":"Caulfield","year":"2011","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13384","DOI":"10.3390\/molecules200713384","article-title":"Molecular docking and structure-based drug design strategies","volume":"20","author":"Ferreira","year":"2015","journal-title":"Molecules"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.compbiolchem.2018.03.026","article-title":"In-silico evidences for binding of Glucokinase activators to EGFR C797S to overcome EGFR resistance obstacle with mutant-selective allosteric inhibition","volume":"74","author":"Patel","year":"2018","journal-title":"Comput. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2174\/1386207043328706","article-title":"Virtual screening methods that complement HTS","volume":"7","author":"Stahura","year":"2004","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1021\/ci050550m","article-title":"2D structure depiction","volume":"46","author":"Clark","year":"2006","journal-title":"J. Chem. Inf. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A new approach fo rapid, accurate docking and scoring. II. Enrichment factors in database screening","volume":"2","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/6675","article-title":"Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation","volume":"6","author":"Fischmann","year":"1999","journal-title":"Nat. Struct. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1074\/jbc.M805459200","article-title":"Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H2S","volume":"284","author":"Sun","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1261\/rna.1563609","article-title":"DOCK 6: Combining techniques to model RNA\u2014Small molecule complexes","volume":"15","author":"Lang","year":"2009","journal-title":"RNA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1021\/ci300399w","article-title":"Consensus docking: Improving the reliability of docking in a virtual screening context","volume":"53","author":"Houston","year":"2013","journal-title":"J. Chem. Inf. Model."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1136\/hrt.2006.087999","article-title":"Carvedilol improves endothelium-dependent vasodilation in patients with dilated cardiomyopathy","volume":"93","author":"Nishioka","year":"2007","journal-title":"Heart"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1177\/1074248415626300","article-title":"Nebivolol acts as a S-nitrosoglutathione reductase inhibitor","volume":"21","author":"Jiang","year":"2016","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1111\/j.1440-1681.2006.04386.x","article-title":"Vasorelaxing effects of propranolol in rat aorta and mesenteric artery: A role for nitric oxide and calcium entry blockade","volume":"33","author":"Priviero","year":"2006","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"H134","DOI":"10.1152\/ajpheart.00023.2009","article-title":"NO production and eNOS phosphorylation induced by epinephrine through the activation of -adrenoceptors","volume":"297","author":"Figueroa","year":"2009","journal-title":"AJP Hear. Circ. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s00394-012-0320-x","article-title":"Endothelium\/nitric oxide mechanism mediates vasorelaxation and counteracts vasoconstriction induced by low concentration of flavanols","volume":"52","author":"Aggio","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_39","unstructured":"Alegr\u00eda-Gonz\u00e1lez, C.L. (2017). Estudios de Acoplamiento Molecular y Simulaciones de Din\u00e1mica Molecular de Triterpenos Selectos en las Enzimas \u00d3xido N\u00edtrico Sintasa Endotelial y Cistationina Gamma-Liasa, Universidad Aut\u00f3noma de Quer\u00e9taro."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.drudis.2014.07.012","article-title":"Recent computational advances in the identification of allosteric sites in proteins","volume":"19","author":"Lu","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1002\/cmdc.201700064","article-title":"Identifying protein allosteric transitions for drug discovery with 1D NMR","volume":"12","author":"Krimm","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_42","first-page":"455","article-title":"Pharmacokinetics of isoxsuprine hydrochloride administered orally and intramuscularly to female healthy volunteers","volume":"59","author":"Marzo","year":"2009","journal-title":"Arzneimittelforschung"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.bmc.2009.11.062","article-title":"Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists","volume":"18","author":"Jozwiak","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.vph.2012.12.004","article-title":"Propranolol-induced relaxation in the rat basilar artery","volume":"58","author":"Cekic","year":"2013","journal-title":"Vascul. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.coph.2012.12.002","article-title":"Beta blockers, nitric oxide, and cardiovascular disease","volume":"13","author":"Vanhoutte","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1111\/jcpt.12375","article-title":"Midodrine for the weaning of vasopressor infusions","volume":"41","author":"Poveromo","year":"2016","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.3892\/ijmm.2016.2578","article-title":"Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats with streptozotocin-induced diabetes by suppressing the nuclear factor-B\/IB system through the activation of AMP-activated protein kinase","volume":"37","author":"Tang","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/iub.1185","article-title":"(\u2013) -Epicatechin reduces blood pressure and improves vasorelaxation in spontaneously hypertensive rats by NO-mediated mechanism","volume":"65","author":"Galleano","year":"2013","journal-title":"IUBMB Life"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/BF02766088","article-title":"Nitric oxide synthase in bronchial epithelium and nitric oxide metabolites in the lungs of rats with bronchial asthma after fenoterol inhalation","volume":"130","author":"Eliseeva","year":"2000","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ejphar.2015.08.020","article-title":"\u03b22-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: Implication in delayed inotropic effect","volume":"765","author":"Odnoshivkina","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"96","DOI":"10.4103\/0250-474X.151604","article-title":"Protective effect of sitagliptin and rosuvastatin combination on vascular endothelial dysfunction in type-2 diabetes","volume":"77","author":"Nade","year":"2015","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1152\/ajpcell.00282.2016","article-title":"Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: Mechanisms and implications","volume":"312","author":"Szabo","year":"2017","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9161","DOI":"10.1073\/pnas.1202916109","article-title":"Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation","volume":"109","author":"Coletta","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"252","DOI":"10.3109\/10641963.2015.1081233","article-title":"Nebivolol ameliorates asymmetric dimethylarginine-induced vascular response in rat aorta via \u03b23 adrenoceptor-mediated mechanism","volume":"38","author":"Wang","year":"2016","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1161\/01.CIR.102.6.677","article-title":"Nebivolol: A third-generation beta-blocker that augments vascular nitric oxide release: Endothelial beta(2)-adrenergic receptor-mediated nitric oxide production","volume":"102","author":"Broeders","year":"2000","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1161\/CIRCULATIONAHA.104.532960","article-title":"Endothelial \u03b23-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation \u03b2-blocker nebivolol","volume":"112","author":"Dessy","year":"2005","journal-title":"Circulation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/j.1476-5381.2009.00074.x","article-title":"Investigation of the different adrenoceptor targets of nebivolol enantiomers in rat thoracic aorta","volume":"156","author":"Quang","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.3892\/mmr.2013.1329","article-title":"The effects of carvedilol on cardiac structural remodeling: The role of endogenous nitric oxide in the activity of carvedilol","volume":"7","author":"Chen","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.pharep.2015.03.008","article-title":"Anti-thrombotic effects of nebivolol and carvedilol: Involvement of \u03b22 receptors and COX-2\/PGI2 pathways","volume":"67","author":"Kozlovski","year":"2015","journal-title":"Pharmacol. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.bbrc.2016.01.089","article-title":"Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1\/TFAM pathway in human umbilical vein endothelial cells (HUVECs)","volume":"470","author":"Yao","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2174\/1570161053586903","article-title":"Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?","volume":"3","author":"Oliveira","year":"2005","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s11064-014-1367-2","article-title":"Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: Involvement of Akt and Nrf2\/ARE pathways","volume":"39","author":"Wang","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1111\/j.1476-5381.2010.01148.x","article-title":"EDHF: Spreading the influence of the endothelium","volume":"164","author":"Garland","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6008","DOI":"10.1093\/emboj\/20.21.6008","article-title":"The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener","volume":"20","author":"Zhao","year":"2001","journal-title":"EMBO J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1089\/ars.2011.4359","article-title":"Modulation of ion channels by hydrogen sulfide","volume":"17","author":"Peers","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.theriogenology.2015.11.010","article-title":"Doppler sonographic examination of uterine and placental perfusion in cows in the last month of gestation and effects of epidural anesthesia and isoxsuprine","volume":"85","author":"Bruckmaier","year":"2016","journal-title":"Theriogenology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2746\/042516400777591543","article-title":"Affinity of isoxsuprine for adrenoreceptors in equine digital artery and implications for vasodilatory action","volume":"32","author":"Belloli","year":"2000","journal-title":"Equine Vet. J."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Hill, J.W., Thompson, J.F., Carter, M.B., Edwards, B.S., Sklar, L.A., and Rosenberg, G.A. (2014). Identification of isoxsuprine hydrochloride as a neuroprotectant in ischemic stroke through cell-based high-throughput screening. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096761"},{"key":"ref_69","first-page":"243","article-title":"The effects of isoxsuprine hydrochloride on the cyclic nucleotide system in the rat uterus","volume":"190","author":"Amer","year":"1974","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1016\/0024-3205(78)90231-X","article-title":"Beta1 and beta2 receptor mechanisms in rat jugular veins: Differences between norepinephrine and isoproterenol-induced relaxation","volume":"23","author":"Cohen","year":"1978","journal-title":"Life Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1095\/biolreprod30.5.1117","article-title":"Mechanism of action of isoprenaline, isoxuprine, terbutaline and orciprenaline on gravid human isolated myometrium. Influence of the neuronal uptake process","volume":"30","author":"Calixto","year":"1984","journal-title":"Biol. Reprod."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1474-8673.1985.tb00122.x","article-title":"Effects of isoxuprine and nylidrin on adrenoreceptors in rat vas deferens","volume":"5","author":"Abel","year":"1985","journal-title":"J. Aut. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1111\/j.2042-3306.1995.tb04996.x","article-title":"Characterization of b-adrenoceptors in equine digital veins: Implications of the modes of vasodilatory action of isoxsuprine","volume":"27","author":"Elliott","year":"1995","journal-title":"Equine Vet. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1139\/y02-042","article-title":"Altered coronary and cardiac adrenergic response in the failing hamster heart: Role of cyclooxygenase derivatives","volume":"80","author":"Brousseau","year":"2002","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"H756","DOI":"10.1152\/ajpheart.00886.2015","article-title":"\u03b2-Adrenergic-mediated vasodilation in young men and women: Cyclooxygenase restrains nitric oxide synthase","volume":"310","author":"Limberg","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_76","first-page":"518","article-title":"Beta adrenoceptor subtype in isolated human, monkey and dog epicardial coronary arteries","volume":"253","author":"Toda","year":"1990","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_77","first-page":"85","article-title":"A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour","volume":"1","author":"Raymajhi","year":"2003","journal-title":"Kathmandu Univ. Med. J."},{"key":"ref_78","first-page":"483","article-title":"A clinical study of feto-maternal outcome of tocolytic agent nifedipine as compared to isoxsuprine hydrochloride in preterm labor","volume":"2","author":"Zahir","year":"2015","journal-title":"MedPulse-Int. Med. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/j.1751-7176.2011.00513.x","article-title":"Calcium channel blockers","volume":"13","author":"Elliott","year":"2011","journal-title":"J. Clin. Hypertens."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1177\/1074248414530508","article-title":"Calcium channel blockers in cardiovascular pharmacotherapy","volume":"19","author":"Godfraind","year":"2014","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/BF00168443","article-title":"Facilitation of the vasorelaxant action of calcium antagonists by basal nitric oxide in depolarized artery","volume":"354","author":"Salomone","year":"1996","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature19102","article-title":"Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs","volume":"537","author":"Tang","year":"2016","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1021\/acs.jcim.6b00505","article-title":"MayaChemTools: An Open Source Package for Computational Drug Discovery","volume":"56","author":"Sud","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.2147\/DDDT.S133944","article-title":"Modeling the human Nav1.5 sodium channel: Structural and mechanistic insights of ion permeation and drug blockade","volume":"11","author":"Ahmed","year":"2017","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1038\/nsb1203-980","article-title":"Announcing the worldwide Protein Data Bank","volume":"10","author":"Berman","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"D345","DOI":"10.1093\/nar\/gku1214","article-title":"The RCSB Protein Data Bank: Views of structural biology for basic and applied research and education","volume":"43","author":"Rose","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Aid Mol. Des."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2014Ligand discovery for everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1021\/ci3001277","article-title":"ZINC: A free tool to discover chemistry for biology","volume":"52","author":"Irwin","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC\u2014A free database of commercially available compounds for virtual screening","volume":"45","author":"Irwin","year":"2005","journal-title":"J. Chem. Inf. Model."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.cbpc.2007.06.002","article-title":"Biochemical and pharmacological characterization of toxins obtained from the fire coral Millepora complanata","volume":"146","author":"Aguilar","year":"2007","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Castro-Ruiz, J.E., Rojas-Molina, A., Luna-V\u00e1zquez, F.J., Rivero-Cruz, F., Garc\u00eda-Gasca, T., and Ibarra-Alvarado, C. (2017). Affinin (Spilanthol), isolated from heliopsis longipes, induces vasodilation via activation of gasotransmitters and prostacyclin signaling pathways. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010218"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jep.2015.07.048","article-title":"Vasorelaxant effects of Shunaoxin pill are mediated by NO\/cGMP pathway, HO\/CO pathway and calcium channel blockade in isolated rat thoracic aorta","volume":"173","author":"Huo","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1042\/bj2060267","article-title":"Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat","volume":"206","author":"Stipanuk","year":"1982","journal-title":"Biochem. J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1021\/ci200097m","article-title":"Pharmer: Efficient and exact pharmacophore search","volume":"51","author":"Koes","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s10852-005-9022-1","article-title":"Clustering rules: A comparison of partitioning and hierarchical clustering algorithms","volume":"5","author":"Reynolds","year":"2006","journal-title":"J. Math. Model. Algorithms"},{"key":"ref_98","unstructured":"Maechler, M., Rousseeuw, P., Struyf, A., Hubert, M., and Hornik, K. (2019, March 10). Cluster: Cluster Analysis Basics and Extensions. Available online: https:\/\/cran.r-project.org\/package=cluster."},{"key":"ref_99","unstructured":"(2019, March 10). R-Core-Team R: A Language and Environment for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ct700301q","article-title":"GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jmgm.2005.12.005","article-title":"Automatic atom type and bond type perception in molecular mechanical calculations","volume":"25","author":"Wang","year":"2006","journal-title":"J. Mol. Graph. Model."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Sousa Da Silva, A.W., and Vranken, W.F. (2012). ACPYPE\u2014AnteChamber PYthon Parser interfacE. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-367"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/protein\/7.3.385","article-title":"A new method for predicting binding affinity in computer-aided drug design","volume":"7","author":"Aqvist","year":"1994","journal-title":"Protein Eng."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/5\/987\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:37:56Z","timestamp":1760186276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/5\/987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,11]]},"references-count":105,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["molecules24050987"],"URL":"https:\/\/doi.org\/10.3390\/molecules24050987","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,11]]}}}