C1q/TNF-related protein-9 ameliorates hypoxia-induced pulmonary hypertension by regulating secretion of endothelin-1 and nitric oxide mediated by AMPK in rats

Injury/dysfunction of the endothelium of pulmonary arteries contributes to hypoxia-induced pulmonary hypertension (HPH). We investigated whether C1q/tumor necrosis factor-related protein-9 (CTRP9), a newly identified cardiovascular agent, has protective roles in the development of HPH. HPH was induced in adult male rats by chronic hypobaric hypoxia. CTRP9 overexpression by adeno-associated virus (AAV)-CTRP9 transfection attenuated the increases in right ventricular systolic pressure, right ventricular hypertrophy index, and pulmonary arterial remodeling of rats under hypoxia. Importantly, CTRP9 overexpression improved endothelium-dependent vasodilation in pulmonary arterioles in HPH rats. CTRP9 overexpression enhanced expression of phosphorylated 5′-adenosine monophosphate-activated protein kinase (p-AMPK) and phosphorylated endothelial nitric oxide synthase (p-eNOS), and reduced phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) expression in pulmonary microvascular endothelial cells (PMVECs) of HPH rats. In cultured PMVECs, CTRP9 not only preserved the decrease of AMPK and eNOS phosphorylation level and nitric oxide (NO) production induced by hypoxia, but also blocked the increase in hypoxia-induced ERK1/2 phosphorylation level and endothelin (ET)-1 production. Furthermore, the effects of CTRP9 were interrupted by inhibitors or knockdown of AMPK. CTRP9 enhances NO production and reduces ET-1 production by regulating AMPK activation. CTRP9 could be a target for HPH.

Cardiovascular Pharmacological Support Among Preterm Infants in Chinese Referral Center Neonatal Intensive Care Units

Objective: To describe cardiovascular pharmacological support in infants born at <34 weeks' gestation within the first postnatal week in Chinese neonatal intensive care units (NICUs).Design: A secondary analysis of data from a multicenter randomized controlled study (REIN-EPIQ). A questionnaire regarding cardiovascular support practices was also completed by all participating NICUs.Setting: Twenty-five tertiary hospitals from 19 provinces in China.Patients: All infants born at <34 weeks' gestation and admitted to participating NICUs within the first postnatal week from May 2015 to April 2018 were included. Infants who were discharged against medical advice were excluded.Measures and Main Results: Among the 26,212 preterm infants <34 weeks, 16.1% received cardiovascular pharmacological support. The use rates increased with decreasing gestational age and birth weight, with 32.5% among infants <28 weeks and 35.9% among infants <1,000 g. Cardiovascular pharmacological support was independently associated with higher risks of death (aOR 2.8; 95% CI 2.4–3.3), severe intraventricular hemorrhage (IVH) (aOR 2.1; 95% CI 1.8–2.5) and bronchopulmonary dysplasia (BPD) (aOR 2.2; 95% CI 2.0–2.5). Overall 63.1% courses of cardiovascular pharmacological support were >3 days. Prolonged cardiovascular pharmacological support (>3 days) was independently associated with lower rates of survival without morbidity in very-low-birth-weight infants, compared with infants with shorter durations. Dopamine was the most commonly used cardiovascular agent. The cardiovascular pharmacological support rates varied from 1.9 to 65.8% among the participating NICUs.Conclusions: The rate of cardiovascular pharmacological support within the first postnatal week was high with prolonged durations in Chinese NICUs. Marked variation in cardiovascular support existed among participating NICUs. Cardiovascular pharmacological support during the early postnatal period, especially prolonged, may be associated with adverse neonatal outcomes.Clinical Trial Registration: The original trial was registered as “Reduction of Infection in Neonatal Intensive Care Units using the Evidence-based Practice for Improving Quality” (ID: NCT02600195) on clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02600195?term=NCT02600195&draw=2&rank=1.

Synthesis, Characterization and Solubility Determination of 6-Phenyl-pyridazin-3(2H)-one in Different Pharmaceutical Solvents

The current research work proposed the solubility data and solution thermodynamic properties of the cardiovascular agent 6-phenylpyridazin-3(2H)-one [PPD] in twelve pharmaceutical solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa”. The measured solubilities of PPD were regressed well with “van’t Hoff and Apelblat models”. The solid phases of pure and equilibrated PPD were characterized using differential scanning calorimetry and powder X-ray differactometry, and the results suggested no transformation of PPD into solvates/hydrates/polymorphs after equilibrium. The solubilities of PPD in a mole fraction at “T = 318.2 K” were noted at a maximum in dimethyl sulfoxide (DMSO, 4.73 × 10−1), followed by polyethylene glycol-400 (PEG-400, 4.12 × 10−1), Transcutol® (3.46 × 10−1), ethyl acetate (EA, 81 × 10−2), 2-butanol (2.18 × 10−2), 1-butanol (2.11 × 10−2), propylene glycol (PG, 1.50 × 10−2), isopropyl alcohol (IPA, 1.44 × 10−2), ethylene glycol (EG, 1.27 × 10−2), ethanol (8.22 × 10−3), methanol (5.18 × 10−3) and water (1.26 × 10−5). Similar tendencies were also noted at other studied temperatures. The results of the “apparent thermodynamic analysis” showed an endothermic and entropy-driven dissolution of PPD in all pharmaceutical solvents. The results of the activity coefficients suggested a maximum interaction at the molecular level in PPD-DMSO, PPD-PEG-400 and PPD-Transcutol, compared with other combination of the solute and solvents.

Ranolazine: A true pluripotent cardiovascular drug or jack of all trades, master of none?

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Although the majority of patients with CVD are treated with interventional procedures, a substantial number require medical therapy in terms of both prognosis and symptomatic relief. However, commonly used agents such as β-blockers and calcium channel blockers reduce blood pressure in patients whose resting pressures are often already low. Ranolazine is a promising agent that does not have significant effects on blood pressure or heart rate. Use of this drug has been documented in various cardiovascular conditions, including ischaemic heart disease, heart failure and arrhythmias. This review article aimed to examine current evidence on the use of ranolazine in various cardiovascular conditions in order to determine whether it is a true pluripotent cardiovascular agent or, on the other hand, a “jack of all trades, master of none.”

The Effects and Mechanism of Saponins of Panax notoginseng on Glucose Metabolism in 3T3-L1 Cells

This study was carried out to determine the effect of saponins of Panax notoginseng (SPN), a naturally occurring cardiovascular agent, on: (1) glucose uptake, (2) GLUT4 translocation and (3) glycogen synthesis in 3T3-L1 adipocytes. Electrospray ionization-Mass spectrometry (ESI-MS) was used to determine the structural characterization of the major active components of SPN. 3T3-L1 adipocytes were cultured and treated with 100 nM insulin alone or with 10, 50 and 100 μg/ml of SPN. [3H]2-deoxyglucose glucose uptake, GLUT4 immunofluorescence imaging and glycogen synthesis assay were carried out to determine the effects of SPN on glucose metabolism. Under insulin stimulation, SPN significantly increased glucose uptake in a dose-dependent manner; 50 μg/ml of SPN increased glucose uptake by 64% (p < 0.001). Immunofluorescence imaging and analysis have revealed that 50 and 100 μg/ml of SPN increased GLUT4 in the plasma membrane by 3-fold and 6-fold respectively (p < 0.001). Furthermore, the incorporation of D-[U-14C] glucose into glycogen was enhanced by 53% in 3T3-L1 cells treated with 100 μg/ml of SPN (p < 0.01 vs. insulin stimulation alone). SPN, a naturally occurring agent used to treat ischemic cardio-cerebral vascular disease in China, enhanced insulin-stimulated glucose uptake and glycogen synthesis in adipocytes. The results of this study indicate that SPN may have a therapeutic potential for hyperglycaemia in type 2 diabetes.