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1.
Eur J Pharmacol ; 789: 431-438, 2016 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-27492365

RESUMEN

We tested the hypothesis that ranolazine (Ran) is cardioprotective in a model of ischemia /reperfusion and we elucidated the intracellular mechanism. Anesthetized rabbits were subjected to is chemia and reperfusion and were divided into 5 groups: 1) Control, 2) Preconditioning (PreC), 3) Postconditioning (PostC), 4) RanA and 5) RanB, respectively treated with intravenous ranolazine, either 10min before or during index ischemia. Ranolazine was initially given over 60s and then from the beginning and throughout the whole reperfusion period. The infarcted to the risk ratio was calculated (%I/R). In a second series consisting of respective to the first series groups, the animals were subjected to the same interventions up to the 10th min of reperfusion where tissue samples were taken for immunoblotting of Akt, eNOS, ERK½ and GSK3ß (RISK pathway). In a third series, RanA+Wort, RanB+Wort and Wort groups were treated with ranolazine as RanA and RanB groups but with the addition of the PI3 inhibitor Wortmaninn (Wort) and %I/R calculated. Ranolazine reduced the % I/R in RanA and RanB compared to the Control (23.1±1.7%, 17.6±2.0% vs 47.6±1.0%, P<0.05). %I/R reduction achieved in the RanA and RanB groups was comparable to that observed in PreC and PostC (16.3±2.1%, 26.2±2.1%, respectively P<0.05 vs Control). Phosphorylation of Akt, ERK½, eNOS and GSK3ß were higher in PreC, PostC and in both ranolazine treated groups. Wortmannin abrogated ranolazine's %I/R reduction (RanA+Wort 31.4±1.7%, RanB+Wort 32.4±2.4%). Ranolazine reduces %I/R and triggers cardioprotection with a similar to conditioning mechanism which upregulates the RISK pathway.


Asunto(s)
Cardiotónicos/farmacología , Poscondicionamiento Isquémico/métodos , Precondicionamiento Isquémico Miocárdico/métodos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Daño por Reperfusión Miocárdica/patología , Ranolazina/farmacología , Anestesia , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hemodinámica/efectos de los fármacos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Conejos
2.
J Pharm Pharmacol ; 66(8): 1140-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24766266

RESUMEN

OBJECTIVES: We investigated the effects of novel selective and non-selective adenosine receptor agonists (ARs) on cardioprotection. METHODS: Male rabbits divided into six groups were subjected to 30-min heart ischaemia and 3-h reperfusion: (1) control group, (2) postconditioning (PostC) group, (3) group A: treated with the non-selective agonist (S)-PHPNECA, (4) group B: treated with the A1 agonist CCPA, (5) group C: treated with the A2A agonist VT 7 and (6) group D: treated with the A3 agonist AR 170. The infarcted (I) and the areas at risk (R) were estimated as %I/R. In additional rabbits of all groups, heart samples were taken for determination of Akt, eNOS and STAT 3 at the 10th reperfusion minute. KEY FINDINGS: (S)-PHPNECA and CCPA reduced the infarct size (17.2 ± 2.9% and 17.9 ± 2.0% vs 46.8 ± 1.9% in control, P < 0.05), conferring a benefit similar to PostC (26.4 ± 0.3%). Selective A2A and A3 receptor agonists did not reduce the infarct size (39.5 ± 0.8% and 38.7 ± 3.5%, P = NS vs control). Akt, eNOS and STAT 3 were significantly activated after non-selective A1 ARs and PostC. CONCLUSIONS: Non-selective and A1 but not A2A and A3 ARs agonists are essential for triggering cardioprotection. The molecular mechanism involves both RISK and the JAK/STAT pathways.


Asunto(s)
Corazón/efectos de los fármacos , Agonistas del Receptor Purinérgico P1/farmacología , Receptores Purinérgicos/metabolismo , Animales , Cardiotónicos/farmacología , Masculino , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Conejos
3.
Bioorg Med Chem ; 20(19): 5948-56, 2012 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-22925446

RESUMEN

Novel purine analogues bearing nitrate esters were designed and synthesized in an effort to develop compounds triggering endogenous cardioprotective mechanisms such as ischemic preconditioning (IPC) or postconditioning (PostC). The majority of the compounds reduced infarct size compared to the control group in anesthetized rabbits, whereas administration of the most active analogue 16 at a dose of 3.8 µmol/kg resulted on a significant reduction of infarct size, compared to PostC group (13.4 ± 1.9% vs 26.4 ± 2.3%). These findings introduce a novel class of promising pharmacological compounds that could be used as mimics or enhancers of PostC.


Asunto(s)
Cardiotónicos/química , Cardiotónicos/uso terapéutico , Poscondicionamiento Isquémico/métodos , Infarto del Miocardio/tratamiento farmacológico , Purinas/química , Purinas/uso terapéutico , Animales , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Infarto del Miocardio/patología , Miocardio/patología , Nitratos/química , Nitratos/uso terapéutico , Conejos
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