Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.
This study provides evidence for extensive pulmonary vascular remodeling, despite the absence of RV hypertrophy, in a mouse model of schistosomiasis, including the formation of plexiform-like lesions. Inflammatory cytokines and lung egg burden may contribute to vascular lesion formation.
Background
The pathogenic mechanisms underlying pulmonary arterial hypertension (PAH) due to schistosomiasis, one of the most common causes of pulmonary hypertension (PH) worldwide, remains unknown. We hypothesized that TGF-β signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.
Methods and Results
Mice sensitized and subsequently challenged with S. mansoni eggs developed PH associated with an increase in right ventricular systolic pressure (RVSP), thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase dependent vasoconstriction accounted for about 60% of the increase in RVSP. The pulmonary vascular remodeling and PH were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced PH. Blockade of TGF-β signaling also led to a decrease in IL4 and IL13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated PAH have evidence of TGF-β signaling in their remodeled pulmonary arteries.
Conclusions
Experimental S. mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
Background-Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra™) in pre-and postoperative children with increased PVR because of CHD. Methods and Results-12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3Ϯ1.0 Wood Units*m 2 ) were studied during cardiac catheterization ("cath laboratory"), or within 2 hours after return from cardiac surgery ("post op"), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (F i O 2 ϭ0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil ("cath laboratory", 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the "cath laboratory" patient group, PϽ0.05, and 25.8% versus 14.6% in the post op patient group, Pϭ0.09. The increase in cGMP in response to NO was potentiated (2-to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Q s / Q t ϭ16.5Ϯ4.7% to 25.5Ϯ18.2% Pϭ0.04). Conclusions-Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.
Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.
Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.
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