Sildenafil and metformin combination attenuates monocrotaline-induced pulmonary hypertension via TNF-α and ERK1/2 modulation
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.
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