OBJECTIVETo assess the effect of tetrandrine (Tet) pulmonary targeting microspheres on hypoxic pulmonary hypertension and evaluate its selective action on pulmonary circulation.

METHODSTwenty rats were exposed to hypoxic conditions for 3 weeks. Ten rats were used as normoxic controls. We administered Tet pulmonary targeting microspheres to 10 hypoxic rats and Tet aqueous solution to 10 hypoxic rats and the 10 control rats. Mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization, and mean systemic blood pressure (mSBP) was measured by left femoral catheterization.

RESULTSRats exposed to hypoxia developed pulmonary hypertension. The decrease in mPAP in rats treated with Tet pulmonary targeting microspheres was significantly greater than that in rats receiving Tet aqueous solution (P < 0.05), and the effects were longer with Tet pulmonary targeting microspheres. Moreover, Tet pulmonary targeting microspheres, unlike Tet aqueous solution, did not decrease mSBP.

CONCLUSIONTet pulmonary targeting microspheres were more effective than Tet aqueous solution treating hypoxic pulmonary hypertension and acted selectively on the pulmonary circulation.

Alkaloids ; administration & dosage ; Animals ; Benzylisoquinolines ; Blood Pressure ; drug effects ; Hypertension, Pulmonary ; drug therapy ; Hypoxia ; physiopathology ; Lung ; drug effects ; Male ; Microspheres ; Pulmonary Artery ; drug effects ; physiology ; Rats ; Rats, Wistar

OBJECTIVETo study the effect of taurine on apoptosis in PASMCs, and whether the death-receptor pathway act in the mechanism.

METHODCulture the PASMCs, and divided the cells into control, SD. Acridine orange(AO) assay and western-blot analysis on the expression of Bax, Bcl-2, Procaspase-3 and Fas were used to study the mechanism.

RESULTA major finding of this study is that the Tau effects many apoptosis index, such as increasing the expression of Bax and Fas, decreasing the expression of Procaspase-3, and Bcl-2, accrescencing the mitochondrial depolarization, causing the nuclear shrinkage, all these datas demonstrated that Tau induced the apoptosis in pulmonary artery smooth muscle cells through mitochondrial-dependent pathway.

CONCLUSIONTau induces the apoptosis in pulmonary artery smooth muscle cells through death-receptor.

Animals ; Apoptosis ; drug effects ; Male ; Muscle, Smooth, Vascular ; cytology ; drug effects ; Myocytes, Smooth Muscle ; drug effects ; Pulmonary Artery ; cytology ; drug effects ; Rats ; Rats, Wistar ; Taurine ; pharmacology

OBJECTIVETo investigate the effect of dexmedetomidine on 5-HT-induced constrictions of isolated human intrapulmonary arteries and explore the mechanisms.

METHODSLung tissue was obtained from patients undergoing surgery for lung carcinoma. Intrapulmonary arteries were dissected and cut into rings, which were mounted in a Multi Myograph system to determine the effect of dexmedetomidine (0.3-3 nmol/L) on 5-HT-induced vasoconstrictions. The influences of the endothelium removal and various drugs including L-NAME, yohimbine and indomethacin were tested on the effects of dexmedetomidine.

RESULTSDexmedetomidine (0.1-100 nmol/L) did not obviously affect the resting tension of endothelium-intact human intrapulmonary arteries. 5-HT induced concentration-dependent contraction in endothelium-intact intrapulmonary arteries [pD2: 6.11∓0.05, Emax: (102.10∓1.96)%]. In the rings with intact endothelium, dexmedetomidine (0.3-3 nmol/L) significantly attenuated the Emax and pD2 of 5-HT-induced vasoconstriction [pD2: 5.94∓0.03, Emax: (79.96∓1.31)%]. 5-HT also induced concentration-dependent contraction in endothelium-denuded intrapulmonary arteries [pD2: 6.10∓0.07, Emax: (107.40∓3.20)%]. Dexmedetomidine produced no significant effects on the rings with denuded endothelium. The effects of dexmedetomidine on 5-HT-induced vasoconstriction was suppressed by L-NAME and yohimbine, but not by indomethacin.

CONCLUSIONDexmedetomidine can inhibit 5-HT-induced vasoconstriction of isolated human intrapulmonary arteries probably through α2-adrenergic acceptor and NO released from the endothelium.

Adult ; Aged ; Dexmedetomidine ; pharmacology ; Female ; Humans ; In Vitro Techniques ; Male ; Middle Aged ; Pulmonary Artery ; drug effects ; Serotonin ; pharmacology ; Vasoconstriction ; drug effects

OBJECTIVETo study the effects of puerarin on pulmonary Vascular remodeling in rats with pulmonary hypertension induced by chronic hypoxia and hypercapnia.

METHODForty male rats (180-220) g of grade two were randomly divided into five groups: normal control group (NC), hypoxia-hypercapnia 1, 2, 3 week groups (LH1, LH2, LH3) and hypoxia-hypercapnia 3-week + puerarin group (LHP3 group, puerarin intraperitoneal injection, 20 mg x kg(-1) x d(-1)). Collagen I, III and their mRNA were observed in pulmonary arterioles by the technique of immunohistochemistry and in situ hybridization.

RESULTLight microscopy showed media thickness of pulmonary arterioles was much higher in LH3 group than that of NC group, and, vessel cavity turned more straiter in LH3 group than that of NC group. Howerer, the damage of pulmonary arterioles in LHP3 group was much slighter than that of LH3 group. The levels of plasma ET-1 and lung homogenates Hyr and MDA were much higher in rats of LH3 group than those of NC group (P < 0.01), and lower in LHP3 group than LH3 groups (P < 0.01). The activities of SOD in lung homogenates were significantly lowered in hypoxic and hypercapnic groups compared with control group (P < 0.01), but higher in LHP3 group than that of LH3 group. Plasma NO content of group LH was lower than that of group NC (P < 0.01), it was highter in group LHP3 than that of group LH3 (P < 0.01). Expression of collagen I and collagen I mRNA in pulmonary arterioles were significantly higher in rats of LH groups than those of NC group (P < 0.01), and they were lower in rats of LHP3 group than those of LH3 group (P < 0. 01). Expression of collagen III and collagen III mRNA were not significant difference among three groups.

CONCLUSIONPuerarin could improve pulmonary vascular remodeling in rats with pulmonary hypertension by inhibiting the deposition of collagen.

Animals ; Hypercapnia ; complications ; Hypertension, Pulmonary ; drug therapy ; Hypoxia ; complications ; Isoflavones ; pharmacology ; Male ; Oxidative Stress ; drug effects ; Pulmonary Artery ; drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley

This study was designed to observe the differences between main pulmonary arteries and the third-order branches of pulmonary arteries in the contractile response to phenylephrine (Phen), endothelin-1 (ET-1) and potassium chloride (KCl). The vascular tension changes of main and the third-order branches of pulmonary arteries induced by KCl, ET-1 and Phen were recorded by traditional vascular tone detection methods and microvascular ring technique, respectively. The results showed that Phen could cause a significant contraction in main pulmonary arteries, but did not induce apparent contraction in the third-order branches of pulmonary arteries. Compared with main pulmonary arteries, ET-1 contracted the third-order branches of pulmonary arteries with reduced maximal response value and PDvalue. In comparison with the main pulmonary arteries, contraction caused by KCl was enhanced in the third-order branches of pulmonary arteries. The results suggest that the vascular reactivity of main and the third-order branches of pulmonary arteries is different and it is important to study the vascular function of small branches of pulmonary arteries. This study could provide an important experimental basis for the further study on vascular function of small branches of pulmonary arteries and the functional changes in pulmonary hypertension.
Animals ; Endothelin-1 ; pharmacology ; Male ; Phenylephrine ; pharmacology ; Potassium Chloride ; pharmacology ; Pulmonary Artery ; drug effects ; Rats ; Vasoconstriction

OBJECTIVEPulmonary hypertension (PH) is a common complication of congenital heart defects with a left-to-right shunt characterized by high pulmonary blood flow. Pulmonary vascular structural remodeling (PVSR) is the pathological basis of PH. However, the pathophysiologic features and mechanisms responsible for PH and PVSR induced by increased pulmonary blood flow have not been fully understood. The present study was designed to explore the possible effect and mechanism of hydrogen sulfide (H(2)S) on the regulation of PVSR induced by high pulmonary flow in rats.

METHODSThirty-two male SD rats, weighing 120 - 140 g, were randomly divided into shunt group (n = 8), shunt + NaHS group (n = 8), control group (n = 8) and control + NaHS group (n = 8). Rats in shunt group and shunt + NaHS group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. Rats in the control and control + NaHS groups underwent the same experimental protocol as mentioned above except for the shunt procedure. Rats in the shunt + NaHS and control + NaHS groups were intraperitoneally injected with NaHS at 56 micromol/(kgxd), and rats in the shunt and control groups were injected with the same volume of physiological saline. After 11 weeks of experiment, rats were sacrificed and lung tissues were obtained. The percentage of muscularized artery (MA) was calculated. The changes in relative medial thickness (RMT) in small pulmonary arteries and median pulmonary arteries were examined. Proliferative cell nuclear antigen (PCNA), extracellular signal-regulated kinase (ERK1) and phosphorylation extracellular signal-regulated kinase (P-ERK1) protein expression were examined by Western blot, and at the same time, PCNA protein expression by pulmonary artery smooth muscle cells was observed by immunohistochemistry.

RESULTSAfter 11 weeks of shunt, compared with control group, the percentage of MA increased significantly (25.12 +/- 2.26 vs 14.42 +/- 3.41, P < 0.05), and RMT in small pulmonary arteries and median pulmonary arteries increased significantly in rats of shunt group (23.6 +/- 3.5 vs 12.6 +/- 2.1, 24.8 +/- 1.9 vs 13.5 +/- 2.2, P < 0.05 for all). PCNA protein expression in small and median pulmonary arteries increased significantly (0.49 +/- 0.04 vs 0.39 +/- 0.07, 0.46 +/- 0.08 vs 0.36 +/- 0.05, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries increased significantly (P < 0.01) in rats of shunt group compared with those of control group. After the administration of exogenous H(2)S donor, NaHS, for 11 weeks, in contrast to rats in shunt group, the percentage of MA decreased significantly (21.5 +/- 2.0 vs 25.1 +/- 2.3, P < 0.05), and RMT in small and median pulmonary arteries decreased significantly (20.2 +/- 2.8 vs 23.6 +/- 3.5, 20.8 +/- 3.1 vs 20.8 +/- 3.1, P < 0.05 for all) in rats of shunt + NaHS group. PCNA protein expression in small and median pulmonary artery smooth muscle cells decreased significantly (0.32 +/- 0.06 vs 0.49 +/- 0.04, 0.29 +/- 0.07 vs 0.46 +/- 0.08, P < 0.01 for all), and the ratio of PERK/ERK1 protein expression of pulmonary arteries decreased significantly (P < 0.01) in rats of shunt + NaHS group compared with that of shunt group.

CONCLUSIONH(2)S may play a regulatory role in pulmonary vascular structural remodeling induced by high pulmonary blood flow via mitogen-activated protein kinase (MAPK)/ERK signal transduction pathway.

Animals ; Hydrogen Sulfide ; pharmacology ; Hypertension, Pulmonary ; pathology ; physiopathology ; Lung ; pathology ; Male ; Pulmonary Artery ; drug effects ; physiopathology ; Rats ; Rats, Sprague-Dawley

Pulmonary arterial hypertension (PAH) secondary to chronic obstructive pulmonary disease (COPD) is incurable and it has an unpredictable survival rate. Two men who suffered from COPD presented with progressive dyspnea and edema, respectively. PAH, as estimated by the peak velocity of tricuspidal regurgitation, and the depressed myocardial performance index (MPI) of the right ventricle (RV) were noted on echocardiography. In addition to the baseline therapy for their depressed ventilatory function, we prescribed tadalafil 10 mg orally every other day for 2 weeks and then we doubled the dosage. They well tolerated the medication without any notable side effects. After 4 weeks of tadalafil treatment, the patients' pulmonary arterial pressure was decreased and the MPI of the RV was improved in both. The exercise capacity, as measured by the respiratory oxygen uptake, also improved from 10.9 mL/kg/min to 13.8 mL/kg/min in one patient. We report here on 2 patients with PAH secondary to COPD, and they showed notable improvement of their pulmonary hemodynamics and exercise capacity with the administration of tadalafil.
Pulmonary Disease, Chronic Obstructive/*complications ; Pulmonary Artery/drug effects/*pathology ; Phosphodiesterase Inhibitors/*therapeutic use ; Oxygen Consumption/drug effects ; Middle Aged ; Male ; Hypertension, Pulmonary/*drug therapy/etiology ; Humans ; Exercise Tolerance/drug effects ; Carbolines/*therapeutic use

OBJECTIVETo study the selective dilatation effects of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener, on pulmonary arterioles in hypoxic pulmonary hypertensive rat.

METHODSSD male rats were divided into 3 groups, control group, the rest were fed in hypoxic and normobaric environment (O2 10% +/- 0.5%, 8 h/d and 6 d/week) and divided into hypoxia group and hypoxia plus acetazolamide (Acz) group (hypoxic rats were treated with ig acetazolamide (Acz) 80 mg x kg(-1) d(-1)) . After 12 weeks, pulmonary arteriole rings about (197 +/- 4) microm were isolated and the tension of hypoxic pulmonary arterioles pre-contracted by 6 nmol/L endothelin-1 (FT-1) was observed with wire myograph system model (DMT 610 m). The relaxing response of hypoxic pulmonary arterioles induced by different concentration of Ipt were detected and endothelial activity was also tested by acetylcholine.

RESULTS10(-5) mol/L acetylcholine (ACh)-mediated vasodilatation was greatly reduced in the hypoxic group than those in control group (P < 0.01) and there was no significant difference between Acz treatment group and control group (P > 0.05). Ipt at the concentration ranging from 10(-11) mol/L to 10(-4) mol/L, caused dose dependent vasodilation on both hypoxic pulmonary arterioles and Acz treatment group (P > 0.05), but not on normal group.

CONCLUSIONThe endothelial function of pulmonary arterioles was damaged under hypoxic pulmonary hypertensive state, and Ipt showed selective dilatation effects on hypoxic pulmonary arterioles. Acz could improve the dysfunction of endothelial cells induced by hypoxic pulmonary hypertensive state, which didn't affect the selective dilatation effects of Ipt on hypoxic pulmonary arterioles.

Acetazolamide ; Animals ; Arterioles ; drug effects ; physiopathology ; Hypertension, Pulmonary ; physiopathology ; Hypoxia ; physiopathology ; Male ; Propylamines ; pharmacology ; Pulmonary Artery ; drug effects ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Vasodilator Agents ; pharmacology

Intravenous and intratracheal implantation of mesenchymal stem cells (MSCs) may offer ameliorating effects on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. The aim of this study was to examine the anti-remodeling effect of intravenous MSCs (VMSCs) and intratracheal MSCs (TMSCs) in rats with PH, and the underlying mechanisms. MSCs were isolated from rat bone marrow and cultured. PH was induced in rats by intraperitoneal injection of MCT. One week after MCT administration, the rats were divided into 3 groups in terms of different treatments: VMSCs group (intravenous injection of MSCs), TMSCs group (intratracheal injection of MSCs), PH group (no treatment given). Those receiving saline instead of MCT served as negative control (control group). Pulmonary arterial structure was pathologically observed, pulmonary arterial dynamics measured, and remodeling-associated cytokines Smad2 and Smad3 detected in the lungs, three weeks after MCT injection. The results showed that PH group versus control group had higher pulmonary arterial pressure (PAP) and wall thickness index (WTI) 21 days after MCT treatment. The expression of phosphorylated (p)-Smad2 and the ratio of p-Smad2/Smad2 were much higher in PH group than in control group. Fluorescence-labeled MSCs were extensively distributed in rats' lungs in VMSCs and TMSCs groups 3 and 14 days after transplantation, but not found in the media of the pulmonary artery. WTI and PAP were significantly lower in both VMSCs and TMSCs groups than in PH group three weeks after MCT injection. The p-Smad2 expression and the ratio of p-Smad2/Smad2 were obviously reduced in VMSCs and TMSCs groups as compared with those in PH group. In conclusion, both intravenous and intratracheal transplantation of MSCs can attenuate PAP and pulmonary artery remodeling in MCT-induced PH rats, which may be associated with the early suppression of Smad2 phosphorylation via paracrine pathways.
Animals ; Atrial Remodeling ; drug effects ; physiology ; Hypertension, Pulmonary ; chemically induced ; physiopathology ; Male ; Mesenchymal Stromal Cells ; pathology ; Monocrotaline ; pharmacology ; Pulmonary Artery ; drug effects ; physiopathology ; Rats ; Rats, Sprague-Dawley

For investigation of the regulatory mechanism of cholecystokinin-octapeptide (CCK-8) on pulmonary circulation in rabbits with endotoxic shock (ES) induced by lipopolysaccharides (LPS), mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) were evaluated for 5 h in five groups of rabbits: group of LPS (8 mg/kg, i.v.)-induced ES, group of CCK-8 pretreatment (15 microg/kg, i.v.) 15 min before LPS administration (8 mg/kg, i.v.), group of proglumide pretreatment (1 mg/kg, i.v.) 15 min before LPS administration (8 mg/kg, i.v.), group of CCK (15 microg/kg, i.v.) only, and normal saline (control) group. The pulmonary arterial tension was measured with isolated vascular ring technique. The results showed that LPS-induced pulmonary arterial hypertension was abolished by CCK-8. In contrast, proglumide, a nonspecific antagonist of CCK-8 receptor, potentiated the deleterious effect of LPS. The contractile response of isolated pulmonary artery to alpha-adrenoceptor agonist phenylephrine (PE) was enhanced and the relaxation response to acetylcholine (ACh) was depressed significantly after LPS was injected, but the effect could be reversed by CCK-8. These results suggest that pulmonary circulation is improved by CCK-8 in ES, and the regulatory effects of CCK-8 may be brought about by modulating the pulmonary arterial tension.
Animals ; Hypertension, Pulmonary ; etiology ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; physiology ; Rabbits ; Shock, Septic ; complications ; physiopathology ; Sincalide ; pharmacology ; Vasodilation ; drug effects