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La upregulación de la expresión de la fosfodiesterasa 1A1 se asocia con el desarrollo de la tolerancia a los nitratos
1Department of Medicine, University of Rochester, Rochester, NY, USA.
Circulation
|November 7, 2001
Resumen
La tolerancia al nitrato puede deberse al aumento de la actividad de la fosfodiesterasa 1A1 (PDE1A1), que degrada el monofosfato cíclico de guanosina (cGMP). La inhibición de PDE1A1 podría ser una nueva estrategia para superar esta tolerancia.
Área de la Ciencia:
- Farmacología Farmacología.
- Biología Cardiovascular Biología Cardiovascular
- Biología Molecular Biología Molecular
Sus antecedentes:
- La eficacia de la nitroglicerina (NTG) está limitada por el rápido desarrollo de tolerancia.
- NTG genera óxido nítrico (NO), aumentando el monofosfato cíclico de guanosina (cGMP) para la vasodilatación.
- El aumento de la actividad de la fosfodiesterasa (PDE) que reduce el cGMP es una causa potencial de tolerancia a los nitratos.
Objetivo del estudio:
- Para investigar el papel de la actividad de la PDE en la tolerancia NTG.
- Para determinar si la expresión o actividad de PDE1A1 aumenta con la tolerancia a NTG.
Principales métodos:
- Las ratas recibieron una infusión continua de NTG para inducir la tolerancia.
- La actividad de la PDE y la expresión de la PDE1A1 (Western blot, qRT-PCR) se analizaron en aortas de rata.
- La vinpocetina, un inhibidor de la PDE1, se utilizó para evaluar la recuperación funcional.
Principales resultados:
- La tolerancia a la NTG se asoció con un aumento de la actividad de la PDE (PDE1A1) estimulada por Ca2+/calmodulina.
- La expresión de PDE1A1 aumentó 2,3 veces en aortas de rata tolerantes debido a la regulación al alza del ARNm.
- La vinpocetina restauró parcialmente la sensibilidad vascular al NTG y bloqueó la reducción de la GMPc inducida por la angiotensina II.
Conclusiones:
- La upregulación de la PDE1A1 contribuye al deterioro de la vasodilatación NO/cGMP en la tolerancia a los nitratos.
- Este mecanismo también puede aumentar la vasoconstricción mediada por Ca2+.
- Dirigirse a PDE1A1 ofrece una estrategia terapéutica potencial para prevenir o revertir la tolerancia a los nitratos.
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