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

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

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

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

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

OBJECTIVETo investigate the effect of chloride channel blocker--niflumic acid (NFA) on the pathological process of hypoxia hypercapnia-induced pulmonary vasoconstriction in rats.

METHODSWe used the model of hypoxia hypercapnia-induced pulmonary vasoconstriction rats, and divided the second, third branch pulmonary artery rings randomly into four groups (n = 8): control group (N group), hypoxia hypercapnia group (H group), DMSO incubation group (HD group), niflumic acid group (NFA group). Under acute hypoxia hypercapnia conditions, we observed the effects of the three stages of hypoxia hypercapnia-induced pulmonary vasoconstriction (HHPV) incubated by NFA in the second, third brach pulmonary artery rings. At the same time, the values of rings' tension changings were recorded via the method of hypoxia hypercapnia conditions reactivity. And investigated the effect of NFA to HHPV.

RESULTS(1) Under the hypoxia hypercapnia condition, we observed a biphasic pulmonary artery contractile (the phase I rapid contraction and vasodilation; the phase II sustained contraction) response in both the second and the third branch pulmonary artery rings compared with the control group (P < 0.05 , P < 0.01); (2) The second and third pulmonary artery rings incubated by NFA which phase II persistent vasoconstriction were significantly attenuated compared with the H group (P < 0.05 , P < 0.01).

CONCLUSIONThe blocker of the chloride channels attenuates the second and third branch pulmonary artery rings constriction in rat, especially the phase II persistent vasoconstriction, so then have an antagonistic effect on HHPV.

Animals ; Chloride Channels ; antagonists & inhibitors ; Hypercapnia ; physiopathology ; Hypoxia ; physiopathology ; Niflumic Acid ; pharmacology ; Pulmonary Artery ; physiopathology ; Pulmonary Circulation ; Rats ; Vasoconstriction ; drug effects

OBJECTIVEHypoxic pulmonary hypertension is an important pathophysiologic process of various cardiovascular diseases. Sulfur dioxide (SO2) was considered as a kind of toxic gas previously, but recent studies suggested that SO2 could act as a key bioactive molecule in the pathogenesis of cardiovascular diseases. Therefore, this study was designed to examine the effect of sulfur dioxide on pulmonary vascular structure of hypoxic pulmonary hypertensive rats treated with SO2 donor substances.

METHODSThe rats were randomly divided into 3 groups: control group(n = 8), hypoxic group(n = 8) and hypoxic + SO2 group (n = 10, treated with SO2 donor Na2SO3/NaHSO3). The rats of hypoxic group and hypoxic + SO2 group were under a hypoxic condition for 21 days, while the rats of control group were exposed to room air. The mean pulmonary artery pressure was tested by means of right cardiac catheterization and the content of SO2 in plasma was investigated by high performance liquid chromatography (HPLC). The change in relative medial thickness (RMT) of pulmonary arteries was examined under optical microscope. The ultra-structural changes were observed under a transmission electron microscope. The data were analyzed through one-way analysis of variance (ANOVA) by SPSS 13.0 software.

RESULTSCompared with control group [(2.25 +/- 0.50) kPa], the mean pulmonary artery pressure of hypoxic group [(5.12 +/- 0.51) kPa] raised significantly (t = 5.091, P < 0.01) and RMT of hypoxic group (9.66 +/- 1.27) compared with control group (6.83 +/- 1.57) significantly raised (t = 3.392, P < 0.01). Ultrastructural observation showed the proliferation and degeneration of endothelial cells in small pulmonary arteries in rats with pulmonary hypertension. The internal elastic lamina was irregular. The proliferation of medial smooth muscle cells of arteries was shown at the level of respiratory bronchioles. The collagens also increased. Meanwhile, compared with control group [(33.36 +/- 5.62) micromol/L], the content of SO2 in plasma of hypoxic group [(27.01 +/- 4.17) micromol/L] declined (t = 2.067, P < 0.05). Whereas compared with that of hypoxic group [(5.12 +/- 0.51) kPa], the mean pulmonary artery pressure of hypoxic + SO2 group [(3.94 +/- 0.33) kPa] declined (t = 2.712, P < 0.01) and RMT of hypoxic + SO2 group (6.97 +/- 1.83) decreased compared with hypoxic group (9.66 +/- 1.27) (t = 3.009, P < 0.01). Compared with those of hypoxic group, the pulmonary artery ultrastructural changes in hypoxic group ameliorated obviously after using exogenous sulfur dioxide donor. The endothelial cells became flat and the smooth muscle cells of arteries slightly enlarged and arranged regularly. At the same time, compared with hypoxic group [(27.01 +/- 4.17) micromol/L], the content of SO2 in plasma of hypoxic + SO2 group [(29.89 +/- 4.52) micromol/L] raised (t = 1.263, P > 0.05).

CONCLUSIONSulfur dioxide plays an important role in the regulation of small pulmonary artery structural changes in hypoxic pulmonary hypertensive rats. The hypoxic pulmonary hypertensive damages can be ameliorated significantly after using exogenous SO2 donor.

Animals ; Hypertension, Pulmonary ; blood ; pathology ; physiopathology ; Hypoxia ; blood ; pathology ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; pathology ; Rats ; Rats, Wistar ; Sulfur Dioxide ; adverse effects ; blood

To explore the underlying mechanism(s) of pulmonary arterial hypertension in endotoxic shock, the roles of N-acetylcysteine (NAC), nitric oxide (NO) and carbon monoxide (CO) were investigated. Pulmonary arterial rings (3-mm width) were prepared from 24 rabbits. Lipopolysaccharide (LPS), after 7-hour incubation, decreased the endothelium-dependent relaxation response of the arterial ring (pre-contracted with phenylephrine) to acetylcholine (1 mumol/L), but did not affect the endothelium-independent relaxation response to sodium nitroprusside. The LPS effects were reduced by a concomitant incubation with the free radical scavenger (NAC), NO donor (L-arginine), and CO donor (hemin), respectively. On the other hand, the LPS effects were enhanced by applying heme oxygenase-1 (HO-1) inhibitor (zinc protoporphyrin) to block CO production. The response to acetylcholine changed from relaxation to contraction, however, the contractile response to phenylephrine increased significantly after pre-incubation with nitric oxide synthase (NOS) inhibitor (L-NAME) to block NO production, confirming the importance of CO and NO. These results show that LPS impairs endothelium-dependent relaxation of the pulmonary artery, which can be greatly reduced by the antioxidant, or by supplying with NO and CO. Thus, multiple factors are involved in this model of endotoxin-induced pulmonary hypertension.
Acetylcysteine ; metabolism ; Animals ; Carbon Monoxide ; metabolism ; Hypertension, Pulmonary ; etiology ; physiopathology ; Lipopolysaccharides ; toxicity ; Male ; Nitric Oxide ; metabolism ; Pulmonary Artery ; drug effects ; physiopathology ; Rabbits ; Shock, Septic ; complications

AIMTo study the effect of curcumin on pulmonary arterial pressure and type I collagen of pulmonary arterioles in pulmonary hypertensive rats induced by chronic hypoxia and hypercapnia.

METHODSThirty six rats were randomly divided into three groups: normal control group (NC), hypoxic hypercapnic group (HH) and hypoxic hypercapnia + curcumin group (HC). Collagen I in pulmonary arterioles was observed by the technique of immunohistochemistry.

RESULTS(1) The findings from hemodynamics showed that the mPAP in group HH was significantly higher than that in group NC and HC. Differences of mCAP among groups were not significant (P > 0.05). (2) Light microscopy showed the value of WA/TA (vessel wall area/total area), SMC (the density of medial smooth muscle cells) and thickness of pulmonary arterial media smooth cell layer(PAMT) were significantly higher in group HH than group NC (P < 0.01) and group HC (P < 0.01). (3) Electron microscopy showed that structure of the endothelial cells in pulmonary arterioles in group HC was near to normal, and the proliferation of medial smooth muscle cells and collagen fibers in adventitia was much lighter than those of group HH. (4) Expression of collagen I in pulmonary arterioles was significantly higher in group HH than group NC (P < 0.01) and group HC (P < 0.01).

CONCLUSIONCurcumin can decrease pulmonary arterial pressure, improve pulmonary vessel remodeling and inhibit the deposition of collagen I in pulmonary arterioles.

Animals ; Arterioles ; drug effects ; metabolism ; Collagen Type I ; metabolism ; Curcumin ; pharmacology ; Extracellular Matrix ; metabolism ; Hypercapnia ; metabolism ; physiopathology ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Hypoxia ; metabolism ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the role of apelin in the prevention of pulmonary hypertension induced by hypoxia in rats.

METHODSThe animal model of hypoxic pulmonary hypertension was established by exposing the rats to isobaric hypoxic chamber for 4 weeks (8 h/d, 6 d/ w). Forty male Sprague-Dawley rats were randomly divided into control group (NC), hypoxic group(HH), hypoxic with low-dose apelin (5 nmol/(kg x d) group(LA) and high-dose apelin (10 nmol/(kg x d) (HA). [pGlu]apelin-13 was administered into the rats of apelin groups by mini-osmotic pump subcutaneously. The mean pulmonary arterial pressure(mPAP) and the mean carotid arterial pressure (mCAP) were measured by either right or left cardiac catheterization, and the weight ratio of right ventricule/left ventricule plus septum (RV/(LV + S)) were calculated. The Masson's trichrome stained lung specimens were examined by light microscope to examine the vessel wall area/total area (WA/TA), vessel cavity area/total area (CA/TA) and media thickness of pulmonary arterioles (PAMT). Meanwhile, the lung homogenates were assayed for the activity of supeeroxide dismutase (SOD) and the content of malondialdehyde (MDA).

RESULTS(1) mPAP and RV/(LV + S) of HH group were significantly higher than those of NC group. mPAP of LA and HA groups were lower than those of HH group. The RV/(LV + S) of HA group was significantly lower than that of HH group, but there was no significant difference between HH group and LA group. (2) Masson's trichrome staining revealed that WA/TA and PAMT of HH group were higher than those of NC group. Administration of apelin significantly eliminated WA/TA and PAMT in LA and HA groups. (3) CA/TA of HH group was lower than that of NC group. Administration of apelin significantly elevated CA/TA in LA and HA groups. (4) The activity of SOD and content of MDA in HH group was, respectively, lower and higher than those in NC group. Apelin treatment increased the activity of SOD in LA and HA groups while decreased the content of MDA.

CONCLUSIONSApelin could play an important role in treatment of hypoxic pulmonary hypertension of rats and the mechanisms of protection were associated with vasodilation of pulmonary artery and inhibition of oxidative stress.

Animals ; Cardiotonic Agents ; pharmacology ; therapeutic use ; Hypertension, Pulmonary ; etiology ; physiopathology ; prevention & control ; Hypoxia ; complications ; physiopathology ; Intercellular Signaling Peptides and Proteins ; pharmacology ; therapeutic use ; Male ; Oxidative Stress ; drug effects ; Pulmonary Artery ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Vasodilation ; drug effects