5S management improves the service quality in the outpatient-emergency pharmacy: from management process optimisation to staff capacity enhancement.

OBJECTIVE: As a high-efficiency demanding department in a hospital, the outpatient pharmacy has a great need for quality improvement to provide superior medical service for patients. Little is known about the application of 5S management in a hospital pharmacy department. The aim of this study was to evaluate the impacts of 5S management on pharmaceutical service quality and staff capacity in the outpatient-emergency pharmacy. METHODS: We carried out a 5S project in the outpatient-emergency pharmacy at a local hospital that involved processes including waste elimination, workplace standardisation, and optimisation of workflow and staff quality, and then evaluated the effects of the project. RESULTS: The equipment and items in the outpatient-emergency pharmacy were sorted. All the drugs were categorised and put in order. The redesigned workspace and standardised workflow during the project improved the accuracy and efficiency of drug dispensing. The satisfaction rate of patients regarding the pharmaceutical service quality in the outpatient-emergency pharmacy was elevated, as well as the satisfaction rate of pharmacists about their work experiences. The optimisation of objective conditions also stimulated a positive working attitude and professional ability promotion of pharmacists in the outpatient-emergency pharmacy. CONCLUSIONS: In this study, the 5S management method has proven useful for quality and efficiency improvement in the outpatient-emergency pharmacy, and could be generalised to other departments in a hospital, which provides further evidence of the advantages of the Lean tool in healthcare system management.

Predicting drug-drug interactions with physiologically based pharmacokinetic/pharmacodynamic modelling and optimal dosing of apixaban and rivaroxaban with dronedarone co-administration.

BACKGROUND: The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis. METHODS: Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature. RESULTS: The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14-1.50) to 1.31 (90 % CI: 1.12-1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15-1.68) to 1.46 (90 % CI: 1.24-1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function. CONCLUSIONS: Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF.

Rhizosphere and Straw Return Interactively Shape Rhizosphere Bacterial Community Composition and Nitrogen Cycling in Paddy Soil.

Currently, how rice roots interact with straw return in structuring rhizosphere communities and nitrogen (N) cycling functions is relatively unexplored. In this study, paddy soil was amended with wheat straw at 1 and 2% w/w and used for rice growth. The effects of the rhizosphere, straw, and their interaction on soil bacterial community composition and N-cycling gene abundances were assessed at the rice maturity stage. For the soil without straw addition, rice growth, i.e., the rhizosphere effect, significantly altered the bacterial community composition and abundances of N-cycling genes, such as archaeal and bacterial amoA (AOA and AOB), nirK, and nosZ. The comparison of bulk soils between control and straw treatments showed a shift in bacterial community composition and decreased abundance of AOA, AOB, nirS, and nosZ, which were attributed to sole straw effects. The comparison of rhizosphere soils between control and straw treatments showed an increase in the nifH gene and a decrease in the nirK gene, which were attributed to the interaction of straw and the rhizosphere. The number of differentially abundant genera in bulk soils between control and straw treatments was 13-23, similar to the number of 16-22 genera in rhizosphere soil between control and straw treatment. However, the number of genera affected by the rhizosphere effect was much lower in soil amended with straw (3-4) than in soil without straw addition (9). Results suggest possibly more pronounced impacts of straw amendments in shaping soil bacterial community composition.

Case Report: Miles Surgery Ameliorates High Blood Pressure in a Rectal Carcinoma Patient With Essential Hypertension.

Hypertension is one of the major causes of public health problems. Multiple factors affecting gastrointestinal tract function are involved in hypertension. Emerging studies have manifested that gut intervention may play significant roles in regulating blood pressure but the underlying mechanisms are complex and not fully clear. Here, we report a case of 66 years old male who had a long history of hypertension and received Miles surgery for rectal carcinoma. The blood pressure of this patient was returned to normal levels after the operation. The possible reasons could be the modulation of sympathetic tone and the gut microbiota-brain axis. This report provides evidence about the relevance between hypertension and gut intervention particularly in the colorectal sites and gives hints for investigating the possible mechanisms of hypertension and the novel strategy for blood pressure control.

Sinomenine in Cardio-Cerebrovascular Diseases: Potential Therapeutic Effects and Pharmacological Evidences.

Cardio-cerebrovascular diseases, as a major cause of health loss all over the world, contribute to an important part of the global burden of disease. A large number of traditional Chinese medicines have been proved effective both clinically and in pharmacological investigations, with the acceleration of the modernization of Chinese medicine. Sinomenine is the main active constituent of sinomenium acutum and has been generally used in therapies of rheumatoid arthritis and neuralgia. Varieties of pharmacological effects of sinomenine in cardio-cerebrovascular system have been discovered recently, suggesting an inspiring application prospect of sinomenine in cardio-cerebrovascular diseases. Sinomenine may retard the progression of atherosclerosis by attenuating endothelial inflammation, regulating immune cells function, and inhibiting the proliferation of vascular smooth muscle cells. Sinomenine also alleviates chronic cardiac allograft rejection relying on its anti-inflammatory and anti-hyperplastic activities and suppresses autoimmune myocarditis by immunosuppression. Prevention of myocardial or cerebral ischemia-reperfusion injury by sinomenine is associated with its modulation of cardiomyocyte death, inflammation, calcium overload, and oxidative stress. The regulatory effects on vasodilation and electrophysiology make sinomenine a promising drug to treat hypertension and arrhythmia. Here, in this review, we will illustrate the pharmacological activities of sinomenine in cardio-cerebrovascular system and elaborate the underlying mechanisms, as well as give an overview of the potential therapeutic roles of sinomenine in cardio-cerebrovascular diseases, trying to provide clues and bases for its clinical usage.

Straw decreased N2O emissions from flooded paddy soils via altering denitrifying bacterial community compositions and soil organic carbon fractions.

Straw return is widely applied to increase soil fertility and soil organic carbon storage. However, its effect on N2O emissions from paddy soil and the associated microbial mechanisms are still unclear. In this study, wheat straw was amended to two paddy soils (2% w/w) from Taizhou (TZ) and Yixing (YX), China, which were flooded and incubated for 30 d. Real-time PCR and Illumina sequencing were used to characterize changes in denitrifying functional gene abundance and denitrifying bacterial communities. Compared to unamended controls, straw addition significantly decreased accumulated N2O emissions in both TZ (5071 to 96 mg kg-1) and YX (1501 to 112 mg kg-1). This was mainly due to reduced N2O production with decreased abundance of major genera of nirK and nirS-bacterial communities and reduced nirK and nirS gene abundances. Further analyses showed that nirK-, nirS- and nosZ-bacterial community composition shifted mainly along the easily oxidizable carbon (EOC) arrows following straw amendment among four different soil organic carbon fractions, suggesting that increased EOC was the main driver of alerted denitrifying bacterial community composition. This study revealed straw return suppressed N2O emission via altering denitrifying bacterial community compositions and highlighted the importance of EOC in controlling denitrifying bacterial communities.

MiR-223-3p in Cardiovascular Diseases: A Biomarker and Potential Therapeutic Target.

Cardiovascular diseases, involving vasculopathy, cardiac dysfunction, or circulatory disturbance, have become the major cause of death globally and brought heavy social burdens. The complexity and diversity of the pathogenic factors add difficulties to diagnosis and treatment, as well as lead to poor prognosis of these diseases. MicroRNAs are short non-coding RNAs to modulate gene expression through directly binding to the 3'-untranslated regions of mRNAs of target genes and thereby to downregulate the protein levels post-transcriptionally. The multiple regulatory effects of microRNAs have been investigated extensively in cardiovascular diseases. MiR-223-3p, expressed in multiple cells such as macrophages, platelets, hepatocytes, and cardiomyocytes to modulate their cellular activities through targeting a variety of genes, is involved in the pathological progression of many cardiovascular diseases. It participates in regulation of several crucial signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B, insulin-like growth factor 1, nuclear factor kappa B, mitogen-activated protein kinase, NOD-like receptor family pyrin domain containing 3 inflammasome, and ribosomal protein S6 kinase B1/hypoxia inducible factor 1 α pathways to affect cell proliferation, migration, apoptosis, hypertrophy, and polarization, as well as electrophysiology, resulting in dysfunction of cardiovascular system. Here, in this review, we will discuss the role of miR-223-3p in cardiovascular diseases, involving its verified targets, influenced signaling pathways, and regulation of cell function. In addition, the potential of miR-223-3p as therapeutic target and biomarker for diagnosis and prediction of cardiovascular diseases will be further discussed, providing clues for clinicians.

Anisodamine Ameliorates Hyperkalemia during Crush Syndrome through Estradiol-Induced Enhancement of Insulin Sensitivity.

Hyperkalemia is a major cause of on-site death in crush syndrome (CS), which is more severe and common in male victims. Anisodamine is a belladonna alkaloid and widely used in China for treatment of shock through activation of α7 nicotinic acetylcholine receptor (α7nAChR). The present work was designed to study the protective effect of anisodamine in CS and the possible role of estradiol involved. Male and ovariectomized female CS mice exhibited lower serum estradiol and insulin sensitivity, and higher potassium compared to the relative female controls at 6 h after decompression. There was no gender difference in on-site mortality in CS mice within 24 h after decompression. Serum estradiol increased with similar values in CS mice of both gender compared to that in normal mice. Anisodamine decreased serum potassium and increased serum estradiol and insulin sensitivity in CS mice, and methyllycaconitine, selective antagonist of α7nAChR, counteracted such effects of anisodamine. Treatment with anisodamine or estradiol increased serum estradiol and insulin sensitivity, decreased serum potassium and on-site mortality, and eliminated the difference in these parameters between CS mice received ovariectomy or its sham operation. Anisodamine could also increase blood pressure in CS rats within 3.5 h after decompression, which could also be attenuated by methyllycaconitine, without influences on heart rate. These results suggest that activation of α7nAChR with anisodamine could decrease serum potassium and on-site mortality in CS through estradiol-induced enhancement of insulin sensitivity.

Estrogen weakens muscle endurance via estrogen receptor-p38 MAPK-mediated orosomucoid (ORM) suppression.

Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females.

Protective cerebrovascular effects of hydroxysafflor yellow A (HSYA) on ischemic stroke.

The purpose of the present work was designed to explore protective cerebrovascular effects of hydroxysafflor yellow A (HSYA), and provide preclinical efficacy and mechanism data for its possible application in patients with cerebral ischemia. The protective effect of HSYA on ischemic stroke was evaluated by infarct sizes and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Cerebrovascular permeability was detected by Evans blue dye leakage in MCAO rats. Cerebral blood flow, as well as blood pressure and heart rate were monitored using flow probes in Beagle dogs. Basilar artery tension isolated from Beagle dogs was evaluated with an MPA 2000 data-acquisition system. Coagulation-related function was also judged, including rabbit platelet aggregation by adenosine diphosphate (ADP) and platelet-aggregating factor (PAF), rabbit blood viscosity by a blood viscometer, and thrombus formation by rat arterial-venous shunts. Results showed that HSYA treatment significantly decreased the infarct sizes, neurological scores and cerebrovascular permeability in rats with MCAO. However, cerebral blood flow, blood pressure and heart rate were not affected by HSYA. In vitro, HSYA had a strong effect on cerebrovascular vasodilatation, and significantly decreased platelet aggregation, blood viscosity, and thrombogenesis. Besides well-known anti-coagulation effects, HSYA protects against ischemic stroke by dilating cerebral vessels and improving cerebrovascular permeability.

Biochar decreases nitrogen oxide and enhances methane emissions via altering microbial community composition of anaerobic paddy soil.

Biochar application to agricultural soil is an appealing approach to mitigate nitrous oxide (N2O) and methane (CH4) emissions. However, the underlying microbial mechanisms are unclear. In this study, a paddy soil slurry was incubated anaerobically for 14d with biochar amendments produced from rice straw at 300, 500, or 700°C (B300, B500, and B700) to study their influences on greenhouse gas emissions. Illumina sequencing was used to characterize shift of soil bacterial and archaeal community composition. After peaking at day 1, N2O emission then sharply decreased to low levels while CH4 started to emit at day 3 then continually increased with incubation. Compared to control soil (57.9mgkg-1 soil), B300, B500, and B700 amendments decreased N2O peak emission to 17.9, 1.28, and 0.59mgkg-1, mainly due to increased soil pH. In contrast, the amendments enhanced CH4 production from 58.2 to 93.4, 62.6, and 63.4mgkg-1 at day 14 due to increased soil dissolved organic carbon. Abundance of denitrifying bacteria (e.g., Bacilli, 7.07-13.6 vs. 16.9%) was reduced with biochar amendments, especially with B500 and B700, contributing to the decreased N2O emissions. However, larger pore size of B500 and B700 (surface area of 68.1 and 161m2g-1) than B300 (4.40m2g-1) favored electron transfer between bacteria and iron minerals, leading to increased abundance of iron-reducing bacteria, (e.g., Clostridia, 48.2-50.6 vs. 33.3%), which competed with methanogens to produce CH4, thereby leading to lower increase in CH4 emission. Biochar amendments with high pH and surface area might be effective to mitigate emission of both N2O and CH4 from paddy soil.

Diurnal Variation of the Peripheral Cholinergic Antiinflammatory Function in Mice.

AIMS: Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock. METHODS: Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine. RESULTS: Both levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA. CONCLUSION: Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

Sodium Sulfide, a Hydrogen Sulfide-Releasing Molecule, Attenuates Acute Cerebral Ischemia in Rats.

AIMS: Acute cerebral ischemia may lead to ischemic stroke, which is a major cause of death and disability worldwide. Hydrogen sulfide (H2 S) functions importantly in mammalian systems. The present work was designed to study the effect of sodium sulfide, a donor of H2 S, on acute cerebral ischemia. METHODS: Acute cerebral focal ischemia was produced by middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. Bilateral vertebral arteries and common carotid arteries were blocked to establish cerebral global ischemia in SD rats. Acute cerebral anoxia was produced by hypobaric anoxia in C57BL/6 mice and hypoxic anoxia in SD rats. Nimodipine and aspirin were set as positive control separately. RESULTS: Infarct size after MCAO was decreased by sodium sulfide. Sodium sulfide improved cerebral energy metabolism after cerebral global ischemia and prolonged survival time of animals with acute cerebral anoxia. In addition, increased cerebral blood flow and decreased cerebrovascular resistance, blood viscosity, and thrombogenesis were observed in animals treated with sodium sulfide. In cultured neurons, sodium sulfide increased cell viability and decreased cell apoptosis induced by oxygen-glucose deprivation. CONCLUSION: Sodium sulfide, a H2 S donor, presents protective effect on acute cerebral ischemia, and might be a promising therapeutic drug.

MicroRNA-124 negatively regulates LPS-induced TNF-α production in mouse macrophages by decreasing protein stability.

AIM: MicroRNAs play pivotal roles in regulation of both innate and adaptive immune responses. In the present study, we investigated the effects of microRNA-124 (miR-124) on production of the pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-treated mouse macrophages. METHODS: Mouse macrophage cell line RAW264.7 was stimulated with LPS (100 ng/mL). The levels of miR-124 and TNF-α mRNA were evaluated using q-PCR. ELISA and Western blotting were used to detect TNF-α protein level in cell supernatants and cells, respectively. 3'-UTR luciferase reporter assays were used to analyze the targets of miR-124. For in vivo experiments, mice were injected with LPS (30 mg/kg, ip). RESULTS: LPS stimulation significantly increased the mRNA level of miR-124 in RAW264.7 macrophages in vitro and mice in vivo. In RAW264.7 macrophages, knockdown of miR-124 with miR-124 inhibitor dose-dependently increased LPS-stimulated production of TNF-α protein and prolonged the half-life of TNF-α protein, but did not change TNF-α mRNA levels, whereas overexpression of miR-124 with miR-124 mimic produced the opposite effects. Furthermore, miR-124 was found to directly target two components of deubiquitinating enzymes: ubiquitin-specific proteases (USP) 2 and 14. Knockdown of USP2 or USP14 accelerated protein degradation of TNF-α, and abolished the effect of miR-124 on TNF-α protein stability. CONCLUSION: miR-124, targeting USP2 and USP14, negatively regulates LPS-induced TNF-α production in mouse macrophages, suggesting miR-124 as a new therapeutic target in inflammation-related diseases.

Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway.

On-site mortality in crush syndrome remains high due to lack of effective drugs based on definite diagnosis. Anisodamine (Ani) is widely used in China for treatment of shock, and activation of α7 nicotinic acetylcholine receptor (α7nAChR) mediates such antishock effect. The present work was designed to test whether activation of α7nAChR with Ani decreased mortality in crush syndrome shortly after decompression. Sprague-Dawley rats and C57BL/6 mice with crush syndrome were injected with Ani (20 mg/kg and 28 mg/kg respectively, i.p.) 30 min before decompression. Survival time, serum potassium, insulin, and glucose levels were observed shortly after decompression. Involvement of α7nAChR was verified with methyllycaconitine (selective α7nAChR antagonist) and PNU282987 (selective α7nAChR agonist), or in α7nAChR knockout mice. Effect of Ani was also appraised in C2C12 myotubes. Ani reduced mortality and serum potassium and enhanced insulin sensitivity shortly after decompression in animals with crush syndrome, and PNU282987 exerted similar effects. Such effects were counteracted by methyllycaconitine or in α7nAChR knockout mice. Mortality and serum potassium in rats with hyperkalemia were also reduced by Ani. Phosphorylation of Na/K-ATPase was enhanced by Ani in C2C12 myotubes. Inhibition of tyrosine kinase on insulin receptor, phosphoinositide 3-kinase, mammalian target of rapamycin, signal transducer and activator of transcription 3, and Na/K-ATPase counteracted the effect of Ani on extracellular potassium. These findings demonstrated that activation of α7nAChR could decrease on-site mortality in crush syndrome, at least in part based on the decline of serum potassium through insulin signaling-Na/K-ATPase pathway.

[Effects of nitrogen application rates on apparent soil nitrogen surplus of late sowing wheat with straw returning in rice-wheat rotation].

Field experiments were conducted to study the effects of varying rates of nitrogen application on soil mineral nitrogen content, amount of nitrogen released from the straw, and grain yield of late sowing wheat with straw returning. The result showed that a high nitrogen fertilizer application rate enhanced the mineral nitrogen content in the soil layer of 0 to 50 cm, and also in the lower soil layers when using N at 270 and 360 kg · hm(-2) with the advance of growth stages. The amount of nitrogen released form the straw increased as the nitrogen application rate increased; the lowest appeared from overwintering to jointing, and the highest from jointing to maturity. During the whole growing season, apparent nitrogen surplus occurred when the nitrogen application rate was higher than 180 kg · hm(-2). The N surplus before jointing was significantly higher than that from jointing to maturity. Grain yield reached the highest at a nitrogen application rate of 270 kg · hm(-2), and a higher application rate obviously decreased the nitrogen use efficiency. It could be concluded that applying nitrogen at 270 kg · him(-2) could improve the grain yield of late sowing wheat with straw returning with the optimal ecological benefit.

Ketanserin improves cardiac performance after myocardial infarction in spontaneously hypertensive rats partially through restoration of baroreflex function.

AIM: Baroreflex dysfunction is associated with a higher rate of sudden death after myocardial infarction (MI). Ketanserin enhances baroreflex function in rats. The present work was designed to examine whether ketanserin improves the post-MI cardiac function and to explore the possible mechanism involved. METHODS: Spontaneously hypertensive rats (SHR) were treated with ketanserin (0.3 mg·kg(-1)·d(-1)). Two weeks later, blood pressure and baroreflex function were measured, followed by a ligation of the left coronary artery. The expressions of vesicular acetylcholine transporter (VAChT) and α7 nicotinic acetylcholine receptor (α7-nAChR) in ischemic myocardium, angiogenesis, cardiac function, and left ventricular (LV) remodeling were evaluated subsequently. RESULTS: Ketanserin significantly improved baroreflex sensitivity (0.62±0.21 vs 0.34±0.12 ms/mmHg, P<0.01) and vagal tonic activity (heart rate changes in response to atropine, 54.8±16.2 vs 37.6±13.4 bpm, P<0.01) without affecting the blood pressure or basic heart rate in SHR. Treatment of SHR with ketanserin prominently improved cardiac function and alleviated LV remodeling, as reflected by increases in the ejection fraction, fractional shortening, and LV systolic pressure as well as decreases in LV internal diameter and LV relative weight. The capillary density, vascular endothelial growth factor expression, and blood flow in the ischemic myocardium were significantly higher in the ketanserin-treated group. In addition, ketanserin markedly increased the expression of VAChT and α7-nAChR in ischemic myocardium. CONCLUSION: Ketanserin improved post-MI cardiac function and angiogenesis in ischemic myocardium. The findings provide a mechanistic basis for restoring baroreflex function using ketanserin in the treatment of MI.

Baroreflex deficiency hampers angiogenesis after myocardial infarction via acetylcholine-α7-nicotinic ACh receptor in rats.

AIMS: Angiogenesis is critical for re-establishing blood supply to ischaemic myocardium after myocardial infarction (MI). Human studies have associated arterial baroreflex (ABR) deficiency with higher rate of sudden death after MI. The present work was designed to examine whether ABR deficiency affects angiogenesis in MI rats. METHODS AND RESULTS: Baroreflex sensitivity (BRS) was determined in conscious rats at 1 month after occlusion of the left anterior descending coronary artery. The survival time was significantly shorter in Sprague-Dawley rats with BRS <0.60 ms/mmHg vs. those with BRS ≥0.60 ms/mmHg. Sinoaortic denervation destroyed ABR, and decreased capillary density, regional blood flow and vascular endothelial growth factor (VEGF) concentration after MI. Ketanserin (0.6 mg/kg/day) enhanced BRS, and increased capillary density, regional blood flow, and VEGF. Sinoaortic denervation also reduced the expression of vesicular acetylcholine (ACh) transporter and α7-nicotinic ACh receptor (α7-nAChR). Angiogenesis after MI was significantly attenuated in α7-nAChR knockout mice. In contrast, increase in endogenous ACh with cholinesterase inhibitor pyridostigmine (30 mg/kg/day) increased angiogenesis after MI. In cultured cardiac microvascular endothelial cells, ACh stimulated the expression of VEGF, phosphorylation of VEGF receptor 2, and tube formation in a manner dependent upon α7-nAChR. CONCLUSION: Our results demonstrated that ABR deficiency could attenuate angiogenesis in ischaemic myocardium. These findings provide further mechanistic basis for enhancing baroreflex function in the treatment of MI.