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Interacciones de la ranolazina con agentes vasoactivos endógenos y exógenos

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Interacciones de la ranolazina con agentes vasoactivos endógenos y exógenos

dc.contributor.advisor	Vila Salinas, José María
dc.contributor.advisor	Mauricio Aviñó, María Dolores
dc.contributor.advisor	Martínez León, Juan Bautista
dc.contributor.author	Campos Carot, Elena
dc.contributor.other	Departament de Fisiologia	es_ES
dc.date.accessioned	2022-12-16T09:45:42Z
dc.date.available	2022-12-17T05:45:06Z
dc.date.issued	2022	es_ES
dc.date.submitted	19-12-2022	es_ES
dc.identifier.uri	https://hdl.handle.net/10550/84793
dc.description.abstract	La ranolazina se utiliza como terapia complementaria en pacientes con cardiopatía isquémica estable que sean intolerantes o no hayan respondido a los antianginosos clásicos. En los últimos años sus indicaciones han aumentado especialmente en el tratamiento de las arritmias y de la insuficiencia cardíaca. Ha demostrado tener un efecto beneficioso en la disfunción diastólica inducida por estrés oxidativo cardíaco, en la angina microvascular y en la diabetes. También ha demostrado ser efectiva en patologías neurológicas como la epilepsia o el dolor crónico, y se le han atribuido propiedades antinflamatorias. Actúa inhibiendo la INaL en los miocitos y ejerce un efecto cardioprotector al evitar la sobrecarga de calcio del miocardio mitigando la distensión diastólica, estabilizando la actividad eléctrica y mejorando el flujo sanguíneo coronario. La evidencia sobre su acción relajante en los vasos coronarios ha despertado el interés por estudiar sus efectos vasculares a nivel periférico. Se ha evidenciado que induce vasodilatación en diferentes lechos vasculares. No obstante, sus efectos vasculares en la vena safena humana han sido poco estudiados a pesar de la importancia de este injerto vascular en la cirugía coronaria. El objetivo de este estudio fue estudiar los efectos vasculares de la ranolazina en la vena safena humana. Se obtuvieron muestras de 53 pacientes intervenidos de bypass aorto-coronario que se montaron en un sistema de baño de órganos para el registro de la tensión isométrica. Además, se determinó la expresión proteica mediante Western Blot de los receptores de la eNOS, los receptores adrenérgicos α1 y de los canales KCa de alta conductancia. La ranolazina produjo relajación sólo en anillos precontraídos con fenilefrina (10-7-10-6 M) y no con otros agonistas contráctiles. El efecto se mantuvo tanto en anillos con endotelio como en anillos sin endotelio si bien la eliminación mecánica de dicha capa celular disminuyó la respuesta relajante. La incubación con indometacina (10 5 M) no afectó la respuesta a la ranolazina mientras que la presencia de L-NAME (10 4 M) redujo parcialmente la relajación sugiriendo la participación del NO en su mecanismo de acción. La relajación remanente a la ranolazina se redujo aún más con TEA (10 3 M) y caribdotoxina (10 7 M) posiblemente porque los canales de KCa de alta conductancia contribuyen en su efecto relajante. En presencia de verapamilo (10 6 M), la curva de relajación de la ranolazina se desplazó hacia la derecha evidenciando una participación activa de los canales ICaL en la vasodilatación inducida por el fármaco. Además, la ranolazina (10-6-10-5 M) redujo tanto la contracción neurógena inducida por el estímulo eléctrico como la inducida por fenilefrina. En presencia de inhibidores, únicamente la caribdotoxina (10 7 M) disminuyó sus efectos produciendo un aumento de la respuesta contráctil al estímulo eléctrico. La ranolazina aumentó la expresión de la proteína del canal de KCa de alta conductancia, disminuyó significativamente la expresión del receptor adrenérgico α1 y no modificó la expresión de la eNOS. En conjunto, nuestros resultados indican que: 1) La relajación inducida por la ranolazina en la vena safena depende parcialmente del NO endotelial. 2) Los canales ICaL y KCa de alta conductancia contribuyen significativamente a la relajación inducida por la ranolazina. 3) La ranolazina reduce la respuesta adrenérgica contráctil actuando como un antagonista de los adrenorreceptores α1.	es_ES
dc.description.abstract	Ranolazine is a piperazine derivative ([+]-N-[2,6- dimethylphenyl]-4[2hydroxy- 3-(2-methoxyphenoxy)-propyl]-1-piperazine acetamide)(Tamargo et al., 2010), which since its approval by the FDA in 2006, has been used as an add-on therapy for the management of patients with chronic stable ischemic heart disease who are intolerant or not adequately controlled by first-line drugs (beta-blockers, calcium antagonists and nitrates). In recent years its clinical indications have increased, especially in the management of arrhythmias (Rosa et al., 2015) and heart failure (Sossalla and Maier, 2012). Its beneficial effect has recently been proved in diastolic dysfunction induced by cardiac oxidative stress (Lovelock et al., 2012) as well as in microvascular angina (Villano et al., 2013) and even in type II diabetic patients in which seems to improve glycemic control by lowering blood glucose and glycosylated hemoglobin levels and facilitating the effects of insulin (Fu et al., 2013). Ranolazine has also been proven to be effective in neurological pathologies such as epilepsy (Kahlig et al., 2010) or chronic pain (Gould et al., 2014) and anti-inflammatory properties has also been attributed to it (Deshmukh et al., 2009). Its relaxing action on coronary vessels has sparked interest in studying its peripheral vascular effects. Accordingly, several animal studies have shown that it induces vasodilation in different vascular beds such as pig coronary and femoral (Nieminen et al. 2011) or the human brachial arteries (Lamendola et al., 2013). In some of the studies, vasodilation appears to depend on endothelial factors such as NO (Deshmukh et al. 2009) or EDHF (Deng et al., 2012), while in others its vasodilator effect appears to be independent of the functionality of said cell layer. Ranolazine acts selectively by inhibiting INaL in myocytes and, thereby, exerts a cardioprotective effect by preventing calcium overload in myocardial cells, relieving diastolic distension of the left ventricle, stabilizing myocardial electrical activity and improving coronary blood flow (Banerjee et al., 2017; Belardinelli, 2006). However, its vascular effects in vitro in the human saphenous vein have been poorly studied. Given the importance of this vessel in coronary bypass surgery, the purpose of this study was to evaluate the vascular effects of ranolazine in the human saphenous vein, especially the mechanisms at the endothelial level. Venous segments of the internal saphenous vein were obtained from 53 patients undergoing coronary artery bypass grafting. Once prepared, each sample was placed in an organ bath system for isometric tension recording. To evaluate the relaxant response induced by ranolazine and characterize the different endothelial factors that could mediate its vascular effects, concentration-response curves to ranolazine were performed in the presence of different mediators. Frequency-response curves were also performed to evaluate its action on the adrenergic vasoconstrictor response. In addition, protein expression of eNOS receptors, α1 adrenergic receptors and large conductance KCa channels located in vascular tissue was determined by Western Blot. Ranolazine induced a concentration-dependent relaxation only in rings pre-contracted with phenylephrine (10-7-10-6 M) but not with other contractil agonists. Furthermore, in these venous segments, denudation of endothelium significantly reduced its relaxant effects. In the presence of inhibitors, indomethacin (10-5 M) did not affect ranolazine-induced relaxation while L-NAME (10-4 M) reduced drug-induced relaxation in rings with endothelium, suggesting the involvement of NO in its mechanism of action. Endothelium-dependent relaxation was further reduced with TEA (10-3 M) and charybdotoxin (10-7 M) while with TRAM-34 (10-6 M) and apamin (10-6 M) no significant changes were observed, indicating that large conductance KCa channels contribute significantly to the relaxant response to ranolazine. In another set of experiments performed with verapamil (10-6 M), the relaxation curve of ranolazine (10-9-10-4 M) shifted to the right showing that the relaxation induced by ranolazine is partially due to the involvement of ICaL channels. Ranolazine (10-5-10-4 M) decreased phenylephrine-induced contractions in venous segments in a concentration-dependent manner. The relaxant effect was maintained after adding indomethacin (10-5 M), L-NAME (10-4 M), apamin (10-6 M) and TRAM-34 (10-6 M), again suggesting the participation of large conductance KCa channels. Endogenous adrenergic contractions induced by electric field stimulation were reduced by ranolazine (10-6-10-5 M) in a concentration-dependent manner. In the presence of inhibitors, only charybdotoxin (10-7 M) decreased its effects, producing an increase in the contractile response to electrical stimulation. Finally, ranolazine increased large conductance KCa channel protein expression, significantly decreased α1 adrenergic receptor expression, and did not modify eNOS expression. In view of the results obtained, it can be concluded that: 1) Relaxation induced by ranolazine in the saphenous vein partly depends on endothelial NO. 2) ICaL and large conductance KCa channels significantly contribute to ranolazine-induced relaxation. 3) Ranolazine decreases the contractile adrenergic response acting as an antagonist of α1 adrenergic receptors.	en_US
dc.format.extent	156 p.	es_ES
dc.language.iso	es	es_ES
dc.subject	ranolazina	es_ES
dc.subject	vena safena humana	es_ES
dc.subject	tono vascular	es_ES
dc.subject	bypass coronario	es_ES
dc.title	Interacciones de la ranolazina con agentes vasoactivos endógenos y exógenos	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::CIENCIAS DE LA VIDA	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS	es_ES
dc.embargo.terms	0 days	es_ES