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Right ventricular (RV) remodeling coupled with extensive apoptosis in response to unrestrained biomechanical stress may lead to RV failure (RVF), which is the immediate cause of death in the majority of patients with pulmonary arterial hypertension (PAH). Overexpression of β2-adrenergic receptor (β2-AR) signaling has been reported to induce myocardiotoxicity in patients with left heart failure. However, the role of β2-AR signaling in the pathophysiology of PAH development has remained elusive. To address this issue, the present study investigated the changes in cardiopulmonary function and structure, as well as the expression of regulators of fibrosis and apoptosis in RVF following monocrotaline (MCT; 60 mg/kg, i.p.)-induced PAH in rats. Cardiopulmonary function and structure, remodeling and apoptosis, as well as G protein-coupled receptor (GPCR) and β2-AR signaling, were documented over a period of 6 weeks. In the early stages, elevated pulmonary arterial pressure, pulmonary lesions, RV hypertrophy, evidence of left ventricular (LV) hyperfunction and accelerated heart rate were observed in animals with MCT-induced PAH. The levels of angiotensin II receptor type 1b (Agtr1b), Agtr2 and Agt were markedly upregulated and the expression of β2-AR phospho-Ser(355,356) steadily decreased in the right heart. As the disease progressed, LV dysfunction was observed, as evidenced by decreased LV systolic pressure and increased LV end-diastolic pressure, which was accompanied by a sustained increase in circulating brain natriuretic peptide levels. Of note, increased levels of cardiomyocyte apoptosis and concomitant RV remodeling, including hypertrophy, dilatation, inflammation and fibrosis, were observed, despite the enhanced RV contractility. Furthermore, alterations in GPCR signaling and activation in β2-AR-Gs-protein kinase A/Ca2+/calmodulin-dependent kinase II signaling were observed in the late stages of PAH. These results suggested that treatment with MCT results in adaptive and maladaptive RV remodeling and apoptosis during the progression of PAH, which is accompanied by distinct changes in the β2-AR signaling. Therefore, these results enable researchers to better understand of pathophysiology of MCT-induced PAH, as well as to determine the effects of novel therapies.

An ultra-high-performance liquid chromatography mass spectrometry method was established to detect and identify the chemical constituents of Zi Shen Formula (ZSF) and its metabolites in serum, urine and feces, after oral administration to rats. A total of 68 compounds were characterized in ZSF extracts. In vivo, 38 prototype components and 32 metabolites of ZSF were tentatively identified in rat serum, urine and feces. Seven metabolic pathways including demethylation, hydroxylation, oxidation, sulfation, glucuronidation, methylation and de-caffeoyl were proposed to be involved in the generation of these metabolites. It was found that glucuronidation, methylation and demethylation were the major metabolic processes of alkaloids, while demethylation, methylation, sulfation and de-caffeoyl were the major metabolic pathways of phenylethanoid glycosides. The main metabolic pathways of steroidal saponins were oxidation and isotype reactions. These findings are significant for our understanding of the metabolism of ZSF. The proposed metabolic pathways of bioactive components might be crucial for further studies of the mechanisms of action and pharmacokinetic evaluations of ZSF.

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