Idiopathic Pulmonary Arterial Hypertension (IPAH) is a rare progressive disease characterized by sustained elevation in pulmonary blood pressure and vascular resistances that progresses to the right ventricular failure and has a high mortality. Among the proximate causes it has been proposed the endothelial dysfunction that increases the synthesis of endothelin-1 (ET-1). ET-1 is responsible for a significant vasoconstriction, resulting in vascular remodeling of the small and medium-sized pulmonary arteries. Current pharmacological treatment of patients with primary pulmonary arterial hypertension includes principally endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors, prostanoids, soluble guanylate cyclase stimulants, and less frequently, calcium channel blockers. Among endothelin receptor antagonists, bosentan is a non-selective ETA and ETB receptors antagonist, that has shown to delay clinical worsening and to improve hemodynamic parameters of patients with pulmonary arterial hypertension. Macitentan is a new highly potent, ETA and ETB receptors antagonist. Indeed, bosentan and macitentan do not differ much in the mechanism of action, but in their pharmacokinetic and pharmacodynamic characteristics. In the literature, there are few studies comparing the effects of the two drugs in a model of PAH induced by monocrotaline (MCT) in rats. The purpose of this study was to investigate the effects of these two molecules in the above model, on hemodynamic variables (blood and pulmonary arterial pressure), right ventricular structure and function, and circulating biochemical markers (endothelin and cardiac troponin). In this study, male Wistar rats (n=67) received 60 mg/Kg monocrotaline or vehicle subcutaneously. 48 hours after monocrotaline injection rats began treatment by gavage, with either bosentan (300 mg/kg/die) or macitentan (10mg/Kg/die) or vehicle, for 21 days. After 14 days of treatment, blood pressure was measured in conscious animals. On day 21, animals were anesthetized and echocardiography and right ventricle catheterization were performed. Blood was then withdrawn and animals were sacrificed. After sacrifice heart and lungs were removed and fixed by immersion in formalin and then embedded in paraffin. Systemic and pulmonary arterial pressure decreased in both treated groups compared to those that received vehicle. By echocardiography, more variables showed an improvement in right ventricle structure and function in rats treated with macitentan compare to those treated with bosentan. A better survival was also observed in the macitentan group in which 9/10 (90%) rats survived compared to bosentan in which 11/15 (73%) rats were alive at the end of the experiment. Another significant founding was 77% reduction in circulating high sensitivity troponin plasma level in macitentan treated animals, but not in bosentan treated, when compared to vehicle rats.
L’ ipertensione polmonare arteriosa idiopatica (IPAH) è una malattia rara, progressiva caratterizzata da un aumento sostenuto della pressione arteriosa e delle resistenze vascolari polmonari che evolve verso l’ insufficienza ventricolare destra e presenta un’ elevata mortalità. Sono state identificate diverse cause tra cui la disfunzione endoteliale che aumenta la sintesi di endotelina-1 (ET-1) responsabile di una consistente vasocostrizione con un conseguente rimodellamento vascolare delle piccole e medie arteriole polmonari. L’ attuale trattamento farmacologico dei pazienti con ipertensione polmonare arteriosa primaria comprende gli antagonisti dei recettori dell’ endotelina, gli inibitori delle fosfodiesterasi 5, i prostanoidi, gli stimolanti della guanilato ciclasi solubile e, meno frequentemente, i calcio-antagonisti. Tra gli antagonisti dei recettori dell’ endotelina, il bosentan è un antagonista dei recettori ETA ed ETB, non selettivo che ha dimostrato ritardare il peggioramento clinico e migliorare i parametri emodinamici dei pazienti affetti da ipertensione polmonare arteriosa; il macitentan è un farmaco nuovo, molto potente, anch’ esso un doppio antagonista dei recettori dell’ endotelina. Bosentan e macitentan infatti non differiscono tanto per il meccanismo d’ azione, quanto per le loro caratteristiche farmacocinetiche e farmacodinamiche. Tuttavia, in letteratura, si trovano pochi studi di confronto degli effetti dei due farmaci nella IPAH indotta da monocrotalina nel ratto. Lo scopo dello studio è stato quello di approfondire gli effetti di queste due molecole, nel modello sopra citato, valutando le variabili emodinamiche (pressione arteriosa e polmonare), la struttura e la funzione del ventricolo destro e marcatori biochimici circolanti (endotelina e troponina cardiaca). In questo studio ratti Wistar maschi (n=67) hanno ricevuto 60 mg/Kg di monocrotalina o veicolo sottocute. 48 ore dopo sono iniziati i trattamenti giornalieri, per gavage, di bosentan (300 mg/Kg) o macitentan (10mg/Kg) oppure veicolo ai ratti che hanno ricevuto l’ iniezione di monocrotalina. Dopo due settimane dall’ iniezione di monocrotalina è stata misurata la pressione arteriosa negli animali non anestetizzati. Il 21° giorno sono stati effettuati, in anestesia, l’ esame ecocardiografico, il cateterismo in ventricolo destro, il prelievo di plasma; cuore e polmoni sono stati prelevati al sacrificio. I risultati mostrano pressioni, sia sistemica arteriosa che polmonare, diminuite nei due gruppi di ratti trattati con i farmaci in studio. All’ ecocardiografia più variabili, di struttura e di funzione del ventricolo destro, si riducono negli animali che trattati con macitentan, a differenza di quelli trattati con bosentan. I dati nel loro insieme suggeriscono un maggior effetto del nuovo farmaco macitentan rispetto al bosentan, oltre che una maggior sopravvivenza dei ratti col primo farmaco citato (9/10 ratti trattati con macitentan vs. 11/15 ratti trattati con bosentan). Un altro dato metodologico importante si è ottenuto dall’ analisi del biomarcatore circolante troponina cardiaca. In riferimento a quest’ ultima, si ha una riduzione del 77% con macitentan e nulla con bosentan.
IPERTENSIONE ARTERIOSA POLMONARE INDOTTA DA MONOCROTALINA NEL RATTO: EFFETTI DI DUE ANTAGONISTI RECETTORIALI DELL’ ENDOTELINA, BOSENTAN E MACITENTAN
SECOMANDI, ALESSANDRA
2013/2014
Abstract
Idiopathic Pulmonary Arterial Hypertension (IPAH) is a rare progressive disease characterized by sustained elevation in pulmonary blood pressure and vascular resistances that progresses to the right ventricular failure and has a high mortality. Among the proximate causes it has been proposed the endothelial dysfunction that increases the synthesis of endothelin-1 (ET-1). ET-1 is responsible for a significant vasoconstriction, resulting in vascular remodeling of the small and medium-sized pulmonary arteries. Current pharmacological treatment of patients with primary pulmonary arterial hypertension includes principally endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors, prostanoids, soluble guanylate cyclase stimulants, and less frequently, calcium channel blockers. Among endothelin receptor antagonists, bosentan is a non-selective ETA and ETB receptors antagonist, that has shown to delay clinical worsening and to improve hemodynamic parameters of patients with pulmonary arterial hypertension. Macitentan is a new highly potent, ETA and ETB receptors antagonist. Indeed, bosentan and macitentan do not differ much in the mechanism of action, but in their pharmacokinetic and pharmacodynamic characteristics. In the literature, there are few studies comparing the effects of the two drugs in a model of PAH induced by monocrotaline (MCT) in rats. The purpose of this study was to investigate the effects of these two molecules in the above model, on hemodynamic variables (blood and pulmonary arterial pressure), right ventricular structure and function, and circulating biochemical markers (endothelin and cardiac troponin). In this study, male Wistar rats (n=67) received 60 mg/Kg monocrotaline or vehicle subcutaneously. 48 hours after monocrotaline injection rats began treatment by gavage, with either bosentan (300 mg/kg/die) or macitentan (10mg/Kg/die) or vehicle, for 21 days. After 14 days of treatment, blood pressure was measured in conscious animals. On day 21, animals were anesthetized and echocardiography and right ventricle catheterization were performed. Blood was then withdrawn and animals were sacrificed. After sacrifice heart and lungs were removed and fixed by immersion in formalin and then embedded in paraffin. Systemic and pulmonary arterial pressure decreased in both treated groups compared to those that received vehicle. By echocardiography, more variables showed an improvement in right ventricle structure and function in rats treated with macitentan compare to those treated with bosentan. A better survival was also observed in the macitentan group in which 9/10 (90%) rats survived compared to bosentan in which 11/15 (73%) rats were alive at the end of the experiment. Another significant founding was 77% reduction in circulating high sensitivity troponin plasma level in macitentan treated animals, but not in bosentan treated, when compared to vehicle rats.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/24402