J. Pharm. Pharmacogn. Res., vol. 14, no. 1, Article ID 2507, Jan-Feb 2026.
DOI: https://doi.org/10.56499/jppres_14.1.2507Original Article
Sildenafil and metformin combination attenuates monocrotaline-induced pulmonary hypertension via TNF-α and ERK1/2 modulation
[Combinación de sildenafil y metformina atenúa la hipertensión pulmonar inducida por monocrotalina mediante la modulación de TNF-α y ERK1/2]
Agus Cahyono1,2, Irwanto3*, Mahrus Abdur Rahman3, Widjiati Widjiati4
1Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
2Department of Clinical Medicine, Faculty of Medicine, Universitas Surabaya, Surabaya, Indonesia.
3Department of Child Health, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
4Department of Veterinary Science, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia.
*E-mail: irwanto@fk.unair.ac.id
Abstract
Context: Pediatric pulmonary hypertension (PH) is associated with poor outcomes and limited US-approved pharmacotherapies.
Aims: To evaluate the effects of sildenafil, metformin, and their combination on hemodynamics, inflammatory mediators, and vascular remodeling in monocrotaline (MCT)-induced PH.
Methods: Male Wistar rats received MCT (60 mg/kg, s.c.). Beginning 24 h later, animals were assigned to MCT-control, sildenafil (5 mg/kg), metformin (100 mg/kg), or combined therapy for 21 days. On day 22, right-heart catheterization was performed. Serum TNF-α and ERK1/2 were measured by ELISA, and pulmonary arterial remodeling was assessed by HE and α-SMA staining with intima-media thickness measurements.
Results: Relative to MCT-control, all treatments lowered mPAP; the combination group exhibited the most considerable reductions in TNF-α and ERK1/2, and a partial reduction in intima-media thickness.
Conclusions: Sildenafil and metformin, particularly in combination, improved pulmonary hemodynamics and attenuated inflammation in MCT-PH. Confirmation in lung tissue (e.g., p-ERK1/2) and cell-specific analyses is warranted.
Keywords: extracellular signal-regulated kinase; metformin; monocrotaline; pulmonary hypertension; sildenafil; tumor necrosis factor-α.
Resumen
Contexto: La hipertensión pulmonar (HP) pediátrica se asocia con malos resultados y farmacoterapias limitadas aprobadas en EE. UU.
Objetivos: Evaluar los efectos del sildenafilo, la metformina y su combinación sobre la hemodinámica, los mediadores inflamatorios y la remodelación vascular en la HP inducida por monocrotalina (MCT).
Métodos: Ratas Wistar machos recibieron MCT (60 mg/kg, s.c.). Veinticuatro horas después, los animales fueron asignados a un grupo control con MCT, a un grupo con sildenafilo (5 mg/kg), a un grupo con metformina (100 mg/kg) o a un grupo con terapia combinada durante 21 días. El día 22, se realizó un cateterismo cardíaco derecho. Se midieron los niveles séricos de TNF-α y ERK1/2 mediante ELISA, y la remodelación arterial pulmonar se evaluó mediante tinción de HE y α-SMA con mediciones del espesor de la íntima-media.
Resultados: En comparación con el grupo control con MCT, todos los tratamientos redujeron la PAPm; El grupo de combinación mostró las reducciones más considerables de TNF-α y ERK1/2, así como una reducción parcial del grosor íntima-media.
Conclusiones: El sildenafil y la metformina, especialmente en combinación, mejoraron la hemodinámica pulmonar y atenuaron la inflamación en pacientes con HP-MCT. Se justifica la confirmación en tejido pulmonar (p. ej., p-ERK1/2) y en análisis celulares específicos.
Palabras Clave: factor de necrosis tumoral-α; hipertensión pulmonar; metformina; monocrotalina; quinasa regulada por señales extracelulares; sildenafil.
Citation Format: Cahyono A, Irwanto, Rahman MA, Widjiati W (2026) Sildenafil and metformin combination attenuates monocrotaline-induced pulmonary hypertension via TNF-α and ERK1/2 modulation. J Pharm Pharmacogn Res 14(1): 2507. https://doi.org/10.56499/jppres_14.1.2507
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