Background We recently showed that intravenous sodium nitroprusside treatment (SNP) could relieve the pulmonary vasospasm of pulmonary embolism (PE) and non-pulmonary embolism (non-PE) regions in a rabbit massive pulmonary embolism (MPE) model associated with shock. The present study explored the potential role of cardiopulmonary sympathetic activity on the pathogenesis and the impact of vasodilators on cardiopulmonary sympathetic activity in this model. Methods Rabbits were randomly divided into sham operation group (S group, n = 8), model group (M, equal volume of saline intravenously, n = 11), SNP group (3.5 μg/kg/min intravenously, n = 10) and diltiazem group (DLZ, 6.0 μg/kg/min intravenously, n = 10). Results MPE resulted in reduced mean arterial pressure and increased mean pulmonary arterial pressure as well as reduced PaO 2 in the M, SNP and DLZ groups. Tyrosine hydroxylase (TH), neuropeptide Y (NPY) and endothelin-1 (ET-1) expression levels were significantly increased, while nitric oxide (NO) levels were reduced in both PE and non-PE regions in the M group. Both SNP and DLZ decreased mean pulmonary arterial pressure, reversed shock status, downregulated the expression of TH, NPY and ET-1, and increased NO levels in PE and non-PE regions. Conclusion Present results indicate that upregulation of the sympathetic medium transmitters TH and NPY in whole lung tissues serves one of the pathological features of MPE. The vasodilators SNP and DLZ could relieve pulmonary vasospasm in both embolization and non-embolization regions and reverse circulatory shock, thereby indirectly downregulating the sympathetic activation of the whole lung tissues and breaking a vicious cycle related to sympathetic activation in this model.

We established a rabbit model of acute massive pulmonary embolism (PE) with associated circulatory shock using autologous blood clots. Rabbits were randomly assigned to a sham operation group (S group), model group (M group; equal volume of saline intravenously after shock), and sodium nitroprusside group (SNP group; sodium nitroprusside intravenously after shock). SNP treatment significantly decreased mean pulmonary arterial pressure and increased mean arterial pressure and arterial partial pressure of oxygen and resulted in a partial reversal of the acute circulatory failure. The shock-reversal rate was 0% in the M group and 80% in the SNP group. Moreover, pulmonary artery angiography and echocardiography examinations evidenced alleviated PE-induced changes after SNP therapy. 5-Hydroxytryptamine was significantly reduced in both PE and non-PE tissues, thromboxane A level was significantly reduced in PE and tended to be lower in non-PE tissues, neutrophil accumulation was significantly reduced in both PE and non-PE tissues after SNP therapy. Our study demonstrated that pulmonary vasospasm in the nonembolic region might be a major pathologic factor leading to reduced left ventricular filling and circulatory shock after massive PE. Reduction of pulmonary vasospasm in the nonembolic area after SNP might serve as a major therapeutic mechanism involved in the observed beneficial effects of SNP in this model.

Background Annexin A1 (ANXA1) exerts anti-nociceptive effect through ANXA1 receptor formyl peptide receptor 2 (FPR2/ALX (receptor for lipoxin A4), FPR2) at the dorsal root ganglia (DRG) level. However, the mechanisms remain elucidated. By using radiant heat, hot/cold plate, tail flick, von Frey, and Randall-Selitto tests to detect nociception in intact and chemical (capsaicin, menthol, mustard oil, formalin or CFA) injected AnxA1 conditional knockout (AnxA1−/−) mice, applying calcium imaging and patch clamp recordings in cultured DRG neurons to measure neuronal excitability, conducting immunofluorescence and western blotting to detect the protein levels of TRPV1, FPR2 and its downstream molecules, and performing double immunofluorescence and co-immunoprecipitation to investigate the interaction between Calmodulin (CaM) and TRPV1; we aim to uncover the molecular and cellular mechanisms of ANXA1’s role in antinociception. Results AnxA1−/− mice exhibited significant sensitivity to noxious heat (mean ± SD, 6.2 ± 1.0 s vs. 9.9 ± 1.6 s in Hargreaves test; 13.6 ± 1.5 s vs. 19.0 ± 1.9 s in hot plate test; n = 8; P < 0.001), capsaicin (101.0 ± 15.3 vs. 76.2 ± 10.9; n = 8; P < 0.01), formalin (early phase: 169.5 ± 32.8 s vs. 76.0 ± 21.9 s; n = 8; P < 0.05; late phase: 444.6 ± 40.1 s vs. 320.4 ± 33.6 s; n = 8; P < 0.01) and CFA (3.5 ± 0.8 s vs. 5.9 ± 1.4 s; n = 8; P < 0.01). In addition, we found significantly increased capsaicin induced Ca2+ response, TRPV1 currents and neuronal firing in AnxA1 deficient DRG neurons. Furthermore, ANXA1 mimic peptide Ac2-26 robustly increased intracellular Ca2+, inhibited TRPV1 current, activated PLCβ and promoted CaM-TRPV1 interaction. And these effects of Ac2-26 could be attenuated by FPR2 antagonist Boc2. Conclusions Selective deletion of AnxA1 in DRG neurons enhances TRPV1 sensitivity and deteriorates noxious heat or capsaicin induced nociception, while ANXA1 mimic peptide Ac2-26 desensitizes TRPV1 via FPR2 and the downstream PLCβ-Ca2+-CaM signal. This study may provide possible target for developing new analgesic drugs in inflammatory pain.

Objective. Pathomechanism of coronary slow flow phenomenon remains largely unclear now. Present study observed the pathological and angiographic evolution in a pig model of coronary slow flow. Methods. Coronary slow flow was induced by repeat coronary injection of small doses of 40 µm microspheres in 18 male domestic pigs and angiographic and pathological changes were determined at 3 hours, 7 days, and 28 days after microspheres injection. Results. Compared to control group treated with coronary saline injection (n = 6) and baseline level, coronary flow was significantly reduced at 3 hours and 7 days but completely recovered at 28 days after coronary microsphere injection in slow flow group. Despite normal coronary flow at 28 days after microsphere injection, enhanced myocardial cytokine expression, left ventricular dysfunction, adverse remodelling, and ischemia/microembolism related pathological changes still persisted or even progressed from 3 hours to 28 days after coronary microsphere injection. Conclusions. Our results show that this large animal slow flow model could partly reflect the chronic angiographic, hemodynamic, and pathological changes of coronary slow flow and could be used to test new therapy strategies against the slow flow phenomenon.

No-reflow or slow-flow post revascularization remains a challenge in interventional cardiology. The "no-reflow" phenomenon is largely induced by microemboli of atherosclerotic debris, spasm, microvascular damage, and thrombi generated by percutaneous coronary intervention (PCI) procedure [1]. Clinical studies revealed that patients exhibiting no-reflow following reperfusion therapy for acute myocardial infarction (AMI) were associated with worse prognosis compared to patients without no-flow [1,2]. Currently, the mechanism of no-reflow has been exclusively studied in animal models of coronary artery ligation/ reperfusion [5] and coronary microembolization (CME) [3][4][5] in canine or pig models, as well as in the rat coronary autologous coronary thrombotic microembolism model [6]. However, ischemia/reperfusion model in pig and canine only partly reflects pathological changes of no-reflow, since clinical "no-reflow" phenomenon is largely induced by microemboli [1] but not induced by coronary artery occlusion. Recently, Ma et al. reported that continuous injection of 120,000 42 μm microspheres into the left anterior descending (LAD) did not induce changes on coronary thrombolysis in myocardial infarction (TIMI) grade and TIMI 3 coronary flow was maintained immediately after microembolization and hemodynamic parameters remained stable before and after CME [7]. Till now, there is no large animal model presenting angiographic evidence of slow flow.In this study, we established an angiographic coronary slow flow model in pig by repeated coronary injection of small doses of 40 μm microspheres. Eight male domestic pigs (3 to 4 months old, 25 ± 2 kg) were used in this study. Aspirin (2-3 mg/kg/d) was mixed in the food 3 days prior to experimental studies. All animals received humane care and that study protocols comply with the institution's guidelines.Pigs were anesthetized by an intramuscular injection of ketamine (15 mg/kg) combining with atropine (1 mg) and then fixed in a supine position on the workstation, 3-5 ml 3% pentobarbital sodium solution was injected via ear marginal vein on demand to maintain the anesthesia state. Oxygen saturation (SO 2 ) was measured with pulse oximeter. Anticoagulation was induced with 200 IU/kg heparin sodium. The right femoral artery was dissected and a 6 F vascular sheath was placed for arterial access. After initial coronary angiography (CAG) using 6 F JR3.5 guiding catheter (Medtronic, Inc.), ventriculography and LV pressure measurements with 5 F Pigtail catheter (Cordis Inc.), a 2.6 F infusion microtubule catheter (Terumo Corporation) was then placed at the middle part of the LAD artery for microsphere injection, and 0.1 ml stock solution with 12,000 microspheres was diluted in 5 ml saline and injected for 20 s through the 2.6 F infusion microtubule catheter; this procedure was repeated, followed by 2 × 0.2 ml stock solution diluted into 5 ml saline with 24,000 microsphere injection, then 0.3 ml stock solution diluted into 5 ml saline with 36,000 microsphere injection (interval bet...

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Background The pro-inflammatory cytokines were detected in pulmonary embolism (PE) and non-pulmonary embolism (non-PE) tissues to explore the role of inflammation responses and their relationship with the pulmonary blood flow in a rabbit model of acute pulmonary embolism combined with shock. Methods and Results Nineteen rabbits were randomly divided into sham operation group (S group, n = 8) and massive PE (MPE group, n = 11). The MPE model was established by injecting the autologous blood clots into the main pulmonary artery of rabbit. Pulmonary angiography showed that the pulmonary circulation time was significantly prolonged in the MPE group, and pulmonary blood flow was attenuated at 120 min post PE. Hematoxylin–eosin (HE) staining revealed enhanced inflammatory cell infiltration around the pulmonary vessels in PE and non-PE tissues, and obvious edema on the perivascular region. Meanwhile, the expressions of inducible nitric oxide synthase (iNOS) and arginase 1 (Arg-1) in pulmonary vascular and alveolar tissues were significantly upregulated and the iNOS/Arg-1 ratio was significantly higher in the MPE group than in the S group. Moreover, the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were also significantly increased in PE and non-PE tissues, and interleukin-6 (IL-6) level was significantly increased in non-PE tissues in the MPE group as compared to the S group. Thromboxane A2 (TXA 2 ) and alpha smooth muscle actin (α-SMA) levels were significantly higher in both PE and non-PE tissues in the MPE group than in the S group. Conclusion Activation of inflammation mediators in PE and non-PE tissues might be one of the crucial factors responsible for pulmonary vasculature constriction and pulmonary blood flow attenuation in this MPE model.