Melatonin as a novel cardioprotective therapy in pulmonary hypertension

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dc.contributor.advisorLecour, Sandrineen_ZA
dc.contributor.advisorSliwa-Hahnle, Karenen_ZA
dc.contributor.authorMaarman, Gerald Jeromeen_ZA
dc.date.accessioned2015-05-26T14:15:48Z
dc.date.available2015-05-26T14:15:48Z
dc.date.issued2014en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractPulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure which leads to right ventricular hypertrophy and failure. The mechanism involved in the pathophysiology of the disease remains unclear but it is suggested that oxidative stress may trigger cardiovascular dysfunction associated with the disease. To date, there is no efficient therapy against PH and novel therapies are urgently needed. Melatonin is a powerful antioxidant that can confer benefit against ischemia-reperfusion injury and hypertension. We therefore hypothesised that melatonin may confer cardiovascular benefits against PH. Methods: Oxidative stress (plasma lipid peroxidation, antioxidant capacity and antioxidant enzyme activity) was assessed in healthy (n=10), in patients with PH (n=10), in Long Evans rats (n≥6) or in a rat model of PH induced 28 days after the injection of monocrotaline (MCT, 80mg/kg, subcutaneous) (n≥6). Melatonin (75ng/L, nutritional concentration), 4mg/kg or 6mg/kg (therapeutic dose) was given daily in the drinking water of rats, with the treatment started 5 days before the injection of MCT, on the day of the injection or 14 days after the injection of MCT. The development of PH was measured by assessing right ventricular hypertrophy, cardiac fibrosis, oxidative stress and cardiac function (via echocardiography and the isolated heart Langendorff perfusion model). Results: Plasma oxidative stress was increased in both patients and rats with PH compared with their respective controls. A chronic treatment with melatonin (75ng/L, 4mg/kg or 6mg/kg) starting on the day of the injection with MCT in rats with PH reduced right ventricular hypertrophy, cardiac dysfunction and plasma oxidative stress compared with control rats. Furthermore, the beneficial effect of melatonin (6mg/kg) could be observed when given as a preventive (5 days prior to the injection of MCT) or as a curative therapy (14 days after the injection of MCT). Conclusions: Our data demonstrate that chronic treatment of melatonin confers cardioprotection in a rat model of PH. As melatonin is inexpensive, safe (no reported side effects) and already available over the counter in many countries, we propose that melatonin should be considered as a novel preventive/curative therapy to limit cardiac dysfunction in patients with PH.en_ZA
dc.identifier.apacitationMaarman, G. J. (2014). <i>Melatonin as a novel cardioprotective therapy in pulmonary hypertension</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/12872en_ZA
dc.identifier.chicagocitationMaarman, Gerald Jerome. <i>"Melatonin as a novel cardioprotective therapy in pulmonary hypertension."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2014. http://hdl.handle.net/11427/12872en_ZA
dc.identifier.citationMaarman, G. 2014. Melatonin as a novel cardioprotective therapy in pulmonary hypertension. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Maarman, Gerald Jerome AB - Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure which leads to right ventricular hypertrophy and failure. The mechanism involved in the pathophysiology of the disease remains unclear but it is suggested that oxidative stress may trigger cardiovascular dysfunction associated with the disease. To date, there is no efficient therapy against PH and novel therapies are urgently needed. Melatonin is a powerful antioxidant that can confer benefit against ischemia-reperfusion injury and hypertension. We therefore hypothesised that melatonin may confer cardiovascular benefits against PH. Methods: Oxidative stress (plasma lipid peroxidation, antioxidant capacity and antioxidant enzyme activity) was assessed in healthy (n=10), in patients with PH (n=10), in Long Evans rats (n&#8805;6) or in a rat model of PH induced 28 days after the injection of monocrotaline (MCT, 80mg/kg, subcutaneous) (n&#8805;6). Melatonin (75ng/L, nutritional concentration), 4mg/kg or 6mg/kg (therapeutic dose) was given daily in the drinking water of rats, with the treatment started 5 days before the injection of MCT, on the day of the injection or 14 days after the injection of MCT. The development of PH was measured by assessing right ventricular hypertrophy, cardiac fibrosis, oxidative stress and cardiac function (via echocardiography and the isolated heart Langendorff perfusion model). Results: Plasma oxidative stress was increased in both patients and rats with PH compared with their respective controls. A chronic treatment with melatonin (75ng/L, 4mg/kg or 6mg/kg) starting on the day of the injection with MCT in rats with PH reduced right ventricular hypertrophy, cardiac dysfunction and plasma oxidative stress compared with control rats. Furthermore, the beneficial effect of melatonin (6mg/kg) could be observed when given as a preventive (5 days prior to the injection of MCT) or as a curative therapy (14 days after the injection of MCT). Conclusions: Our data demonstrate that chronic treatment of melatonin confers cardioprotection in a rat model of PH. As melatonin is inexpensive, safe (no reported side effects) and already available over the counter in many countries, we propose that melatonin should be considered as a novel preventive/curative therapy to limit cardiac dysfunction in patients with PH. DA - 2014 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Melatonin as a novel cardioprotective therapy in pulmonary hypertension TI - Melatonin as a novel cardioprotective therapy in pulmonary hypertension UR - http://hdl.handle.net/11427/12872 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/12872
dc.identifier.vancouvercitationMaarman GJ. Melatonin as a novel cardioprotective therapy in pulmonary hypertension. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2014 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/12872en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherMedicineen_ZA
dc.titleMelatonin as a novel cardioprotective therapy in pulmonary hypertensionen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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