Effects and related mechanism of alpha-adrenergic receptor inhibitor phentolamine in a rabbit model of acute pulmonary embolism combined with shock.

BACKGROUND: To observe the effect and mechanism of alpha-adrenergic receptor inhibitor phentolamine (PTL) in a rabbit model of acute pulmonary embolism (APE) combined with shock. METHODS: Twenty-four New Zealand rabbits were randomly divided into sham operation group (S group, n = 8), model group (M group, n = 8) and PTL group (n = 8), the model of APE combined with shock was established. Mean pulmonary arterial pressure (MPAP), peripheral mean arterial pressure (MAP) and pulmonary circulation time were evaluated. The expression levels of α1 receptor, α2 receptor and their downstream molecules in pulmonary embolism (PE) and non-pulmonary embolism (non-PE) regions lung tissues were detected and compared, respectively. RESULTS: In M group, α receptor-related signaling pathways were significantly activated in both PE and non-PE areas as expressed by up-regulated α1, α2 receptor and phospholipase C (PLC); the expression level of phosphorylated protein kinase A (p-PKA) was significantly down-regulated; myosin light chain kinase (MLCK) and α-smooth muscle actin (α-SMA) levels were up-regulated. PTL treatment significantly improved pulmonary as well as systemic circulation failure: decreased MPAP, restored blood flow in non-PE area, shortened pulmonary circulation time, increased MAP, and restored the circulation failure. PTL induced significantly down-regulated expression of α1 receptor and its downstream molecule PLC in both PE and non-PE area, the expression level of α2 receptor was also down-regulated, the expression level of p-PKA was significantly up-regulated. PTL treatment can inhibit both α1 and α2 receptor-related signaling pathways in whole lung tissues, and inhibit Ca2+ signaling pathways. The expression level of MLCK and α-SMA were significantly down-regulated. Compared with PE area, the changes of expression levels of α receptor and its downstream molecules were more significant in the non-PE region. CONCLUSION: In this model of APE combined with shock, the sympathetic nerve activity was enhanced in the whole lung, α1 and α2 receptor and their downstream signaling activation might mediate blood flow failure in the whole lung. PTL treatment can effectively restore pulmonary blood flow in non-PE area and improve pulmonary as well as systemic circulation failure possibly through down-regulating α1 and α2 receptor and their downstream signaling pathways.

Association Between Inflammatory Mediators and Pulmonary Blood Flow in a Rabbit Model of Acute Pulmonary Embolism Combined With Shock.

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-1ß) 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 (TXA2) 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.

Potential role of sympathetic activity on the pathogenesis of massive pulmonary embolism with circulatory shock in rabbits.

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 PaO2 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.

Acute Beneficial Effects of Sodium Nitroprusside in a Rabbit Model of Massive Pulmonary Embolism Associated with Circulatory Shock.

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 A2 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.

A simple method of placing a coronary sinus catheter through the femoral vein in miniature swine.

The aim of the present study was to evaluate the feasibility of placing a coronary sinus (CS) catheter through the femoral veins of miniature swine. A total of 16 male domestic pigs (3-4 months old, 25±2 kg) were used. Firstly, the anatomic structure of the CS ostium of swine heart was observed at different angles under X-ray. The guide wire and Cobara catheter were subsequently advanced into the right atrium through the femoral vein. Subsequently, the guide wire was retracted behind the fix curve of the Cobara catheter and the catheter bent spontaneously in the absence of supporting guide wire following retraction. The catheter was then gently rotated clockwise to direct the catheter tip to the left allowing the catheter to easily be placed in the CS ostium. This method was associated with a short procedure time: The time on separation of the blood vessels was 15.5±5.8 min and the time of radiation exposure was 112±20 sec. The success rate of placing the catheter to CS ostium was 100%. Only one pig experienced a hematoma after the sheath was pulled out. All swine recovered without serious complications, such as perforation of coronary vein and pericardial tamponade. Therefore, this method of placing CS catheter is simple, safe and reliable, which may offer help for related research.

Evolution of Coronary Flow in an Experimental Slow Flow Model in Swines: Angiographic and Pathological Insights.

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.