Although hypoxic pulmonary vasoconstriction (HPV) has been recognized by many researchers, the precise mechanism remains unknown. As isolated pulmonary arteries will constrict in vitro in the response to hypoxia, the oxygen sensor/transduction mechanism must reside in the pulmonary arterial smooth muscle or in the endothelium, or in both. Unfortunately, much of the current evidence is conflicting, especially as to the dependency of HPV on the endothelium and the role of a K+ channel. Therefore, this experiment was attempted to clarify the dependency of HPV on the endothelium and the role of a K+ channel on HPV in rat pulmonary artery. The effects of hypoxia were investigated in isolated main pulmonary arteries precontracted with norepinephrine. Vascular rings were suspended for isometric tension recording in an organ chamber filled with a Krebs-Henseleit solution. Hypoxia was induced by gassing the chamber with 95% N2 + 5% CO2 and this was maintained for 20 min. Hypoxia elicited a vasoconstriction in arteries with endothelium. Mechanical disruption of the endothelium abolished HPV. There was no difference between the amplitude of the HPV induced by two consecutive hypoxic challenges and the effect of normoxic and hyperoxic control Krebs-Henseleit solution on a subsequent response to hypoxia. Inhibition of NO synthesis by treatment with N(omega)-nitro-L-arginine reduced HPV, but inhibition of a cyclooxygenase pathway by treatment with indomethacin had no effect on HPV. Blockades of a tetraetylammonium chloride-sensitive K+ channel abolished HPV. Verapamil, a Ca2+ entry blocker reduced HPV. In conclusion, these results suggest that HPV was dependent on the endothelium and that HPV can be considered to be induced by inhibition of the mechanisms of NO-dependent vasodilation such as the opening of a K+ channels.
Animal ; Anoxia/physiopathology* ; Blood Vessels/physiopathology ; Calcium Channel Blockers/pharmacology ; Cyclooxygenase Inhibitors/pharmacology ; Enzyme Inhibitors/pharmacology ; Indomethacin/pharmacology ; Nitroarginine/pharmacology ; Pulmonary Circulation/physiology* ; Pulmonary Circulation/drug effects ; Rats ; Tetraethylammonium/pharmacology ; Vasoconstriction/physiology* ; Vasoconstriction/drug effects ; Verapamil/pharmacology

The lungs are frequently the site of adverse drug reactions because of their higher oxygen concentration, the distinctive properties of the pulmonary circulation, and the close proximity of the alveolar epithelium to the blood. Amiodarone, an iodinated benzofuran derivative, is an effective antiarrhythmic drug commonly used for refractory tachyarrhythmia. However, it has a wide range of adverse effects, the most serious of which is lung disease. Most patients present with the insidious onset of dyspnea and a nonproductive cough, and generally recover after withdrawing the drug. We recently experienced four fatal cases of amiodarone pulmonary toxicity. Therefore, we discuss these unusual drug-induced pulmonary toxicity cases with a review of the relevant literature.
Amiodarone ; Cough ; Drug-Related Side Effects and Adverse Reactions ; Dyspnea ; Epithelium ; Humans ; Lung ; Lung Diseases ; Oxygen ; Pulmonary Circulation ; Tachycardia

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

OBJECTIVETo evaluate the beneficial effects of adenosine on myocardial no-reflow in a mini-swine model of acute myocardial infarction (AMI) and reperfusion.

METHODSTwenty-four animals were randomly assigned to 3 groups: 8 in controls, 8 in adenosine-treated and 8 in sham-operated. The groups were subjected to 3 hours of coronary occlusion followed by 60 minutes of reperfusion except the sham-operated group. Data on hemodynamics and coronary blood flow volume (CBV) were collected. The area of no-reflow was evaluated by both myocardial contrast echocardiography (MCE) in vivo and histopathological means and necrosis area was measured with triphenyltetrazolium chloride staining.

RESULTS(1) In control group, systolic and diastolic blood pressure (SBP and DBP), left ventricular systolic pressure, maximal rate of increase and decline in left ventricular pressure (+/- dp/dtmax) and cardiac output significantly declined (P < 0.05-0.01), while left ventricular end-diastolic pressure (LVEDP) and pulmonary capillary wedge pressure (PCWP) significantly increased at the end of 3 hours of LAD occlusion (both P < 0.01), with +/- dp/dtmax further significantly declined (both P < 0.05) at 60 minutes of reperfusion. In adenosine treated group, the changes of SBP and DBP, left ventricular systolic pressure, +/- dp/dtmax, cardiac output, LVEDP and PCWP were the same as those in the control group after AMI and reperfusion, while left ventricular systolic pressure, +/- dp/dtmax, cardiac output, LVEDP and PCWP recovered significantly at 60 minutes of reperfusion compared with those at 6 hours AMI. (2) In control group, the coronary ligation areas (LA) were similar (P > 0.05) detected by MCE in vivo and histopathological evaluation, and the areas of no-reflow were both as high as 67.5% and 69.3%, respectively. The final necrosis area reached 99% of LA. Compared with those in the control group, there was no significant difference in LA on both MCE and histopathological evaluation in the adenosine-treated group, though the areas of no-reflow on both methods were significantly decreased to 21% and 22% (both P < 0.01) and final necrosis area was also significantly decreased to 75% of LA (P < 0.05). (3) In the control group, CBV were significantly declined to 45.8% and 50.6% of the baseline at immediately after release of 3 hours occlusion and at 60 minutes of reperfusion, respectively (both P < 0.01). In the adenosine-treated group, CBV were also significantly declined at immediately after release of 3 hours occlusion, and at 60 minutes of reperfusion (both P < 0.05), though significantly increased to 79.5% and 79.9% of the baseline which were both significantly higher than those in the control group.

CONCLUSIONAdenosine has an effective role in preventing myocardial no-reflow, improving left ventricular function and reducing infarct area during AMI and reperfusion in mini-swine.

Adenosine ; pharmacology ; therapeutic use ; Animals ; Cardiac Output ; drug effects ; Coronary Circulation ; drug effects ; Disease Models, Animal ; Female ; Male ; Myocardial Infarction ; drug therapy ; physiopathology ; Myocardial Reperfusion Injury ; prevention & control ; Pulmonary Wedge Pressure ; drug effects ; Swine ; Swine, Miniature

OBJECTIVEAs an important method of hemodynamic assessment in idiopathic pulmonary arterial hypertension (IPAH), cardiac catheterization combined with pulmonary vasoreactivity testing remains with limited experience in children, and the acute pulmonary vasodilator agents as well as response criteria for vasoreactivity testing remain controversial. The aim of this study was to investigate the clinical importance, agent selection, and responder definition of cardiac catheterization combined with pulmonary vasoreactivity testing in pediatric IPAH.

METHODThe patients admitted to Department of Pediatric Cardiology of Beijing Anzhen Hospital between April 2009 and September 2013 with suspected IPAH, under 18 years of age, with WHO functional class II or III, were enrolled. All the patients were arranged to receive left and right heart catheterization and pulmonary vasoreactivity testing with inhalation of pure oxygen and iloprost (PGI2) respectively. Hemodynamic changes were analyzed, and two criteria, the European Society of Cardiology recommendation criteria (Sitbon criteria) and traditional application criteria (Barst criteria), were used to evaluate the test results.

RESULTThirty-nine cases of children with suspected IPAH underwent cardiac catheterization. In 4 patients IPAH was excluded; 4 patients developed pulmonary hypertension crisis. The other 31 patients received standard cardiac catheterization and pulmonary vasoreactivity testing. Baseline mean pulmonary artery pressure (mPAP) was (66 ± 16) mmHg (1 mmHg = 0.133 kPa), and pulmonary vascular resistance index (PVRI) (17 ± 8) Wood U · m². After inhalation of pure oxygen, mPAP fell to (59 ± 16) mmHg, and PVRI to (14 ± 8) Wood U · m² (t = 4.88 and 4.56, both P < 0.001) . After inhalation of PGI2, mPAP fell to (49 ± 21) mmHg, and PVRI to (12 ± 9) Wood U · m² (t = 7.04 and 6.33, both P < 0.001). According to the Sitbon criteria, the proportion of pure oxygen responders was 6.5% (3/31) , while PGI2 responders was 35.5%, and the difference was significant (P = 0.004). According to the Barst criteria, the proportion of pure oxygen responders was 16.1% (5/31), while PGI2 responders was 51.6% (16/31), and the difference was significant (χ² = 0.09, P = 0.001).

CONCLUSIONFor children with IPAH, cardiac catheterization combined with pulmonary vasoreactivity testing has important value in differential diagnosis, severity estimation, and treatment (including the emergency treatment) choices. Pulmonary hypertension crisis is an important complication of cardiac catheterization in pediatric IPAH. Younger age, general anesthesia, crisis history, and poor heart function are important risk factors for pulmonary hypertension crisis. PGI2 is a relatively ideal agent for vasoreactivity testing in children with IPAH, which has more responders than traditionally used pure oxygen.

RESULTSof responders are not completely consistent using different criteria, and comprehensive evaluation should be done according to the goals of treatment in clinical practice.

Administration, Inhalation ; Adolescent ; Anesthesia, General ; Cardiac Catheterization ; Child ; Child, Preschool ; Familial Primary Pulmonary Hypertension ; diagnosis ; physiopathology ; Female ; Hemodynamics ; Humans ; Iloprost ; administration & dosage ; Infant ; Male ; Pulmonary Artery ; physiopathology ; Pulmonary Circulation ; drug effects ; Pulmonary Wedge Pressure ; drug effects ; Severity of Illness Index ; Vascular Resistance ; drug effects ; Vasodilator Agents ; administration & dosage

BACKGROUNDThe RhoA/Rho kinase pathway may participate in the pathogenesis of hypoxia and monocrotaline induced pulmonary hypertension. This study tested whether RhoA/Rho kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension in rats.

METHODSMale Wistar rats (4 weeks) were randomly divided into 4 shunt groups, 4 treated groups and 4 control groups. Shunt and treated groups underwent left common carotid artery/external jugular vein shunt operation. Control groups underwent sham operation. Treated groups received fasudil treatment and the others received same dose of saline. At weeks 1, 2, 4 and 8 of the study, right ventricular systolic pressure was measured and blood gases were analysed to calculate Qp/Qs. The weight ratio of right ventricle to left ventricle plus septum and the mean percentage of medial wall thickness in moderate sized pulmonary arteries were obtained. RhoA activity in pulmonary arteries was detected using Rho activity assay reagent. Rho kinase activity was quantified by the extent of MYPT1 phosphorylation with Western blot. Proliferating cells were evaluated using proliferating cell nuclear antigen immunohistological staining.

RESULTSCarotid artery/jugular vein shunt resulted in high pulmonary blood flow, both an acute and a chronic elevation of right ventricular systolic pressure, significant medial wall thickening characterized by smooth muscle cells proliferation, right ventricular hypertrophy and increased activation of RhoA and Rho kinase. Fasudil treatment lowered pulmonary artery systolic pressure, suppressed pulmonary artery smooth muscle cells proliferation, attenuated pulmonary artery medial wall thickening and inhibited right ventricular hypertrophy together with significant suppression of Rho kinase activity but not Rho activity.

CONCLUSIONSActivated RhoA/Rho kinase pathway is associated with both the acute pulmonary vasoconstriction and the chronic pulmonary artery remodelling of high flow induced pulmonary hypertension. Fasudil treatment could improve pulmonary hypertension by inhibiting Rho kinase activity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; therapeutic use ; Animals ; Cell Proliferation ; drug effects ; Enzyme Activation ; drug effects ; Hypertension, Pulmonary ; drug therapy ; etiology ; Hypertrophy, Right Ventricular ; prevention & control ; Intracellular Signaling Peptides and Proteins ; antagonists & inhibitors ; physiology ; Male ; Muscle, Smooth, Vascular ; drug effects ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Serine-Threonine Kinases ; antagonists & inhibitors ; physiology ; Pulmonary Artery ; pathology ; Pulmonary Circulation ; drug effects ; Rats ; Rats, Wistar ; Systole ; drug effects ; Vasoconstriction ; drug effects ; rho-Associated Kinases ; rhoA GTP-Binding Protein ; physiology

BACKGROUND: Endogenous nitric oxide (NO) induces the peripheral vasodilation via the activation of guanylate cyclase in patients with septic shock. The purpose of this study was to assess the acute effects of methylene blue (MB), which is an inhibitor of guanylate cyclase, on the hemodynamics and on the production of pro-inflammatory cytokines and nitric oxide (NO) in patients with refractory septic shock. METHODS: Twenty consecutive patients with refractory septic shock, which was defined as shock refractory to a dopamine infusion of more than 20 microgram/kg/min with the appropriate use of antibiotics and adequate volume replacement, received MB infusion of 1 mg/kg intravenously. The hemodynamic and respiratory variables were measured at baseline, 30, 60 and 120 min after an infusion of MB (1 mg/kg). The blood levels of NO, IL-1, IL-10 and TNF-alpha were measured at baseline, 30 and 120 min after MB infusion. RESULTS: The administration of MB induced an increase in the systemic vascular resistance (SVR) that resulted in an increase of the mean arterial pressure (MAP) in patients with refractory septic shock, and this was without a decrease in cardiac output. The administered MB induced an increase in pulmonary vascular resistance (PVR) that resulted in an increase of pulmonary arterial pressure (PAP), without any deterioration of gas exchange. However, the increases in SVR and PVR were not associated with the alteration of endogenous production of NO, IL-1, IL-10 and TNF-alpha. CONCLUSION: MB transiently elevated the MAP by increasing the SVR without altering the endogenous productions of NO, IL-1, IL-10 and TNF-alpha during the study period in patients with refractory septic shock.
Anti-Infective Agents, Urinary/administration & dosage/*therapeutic use ; Blood Pressure/*drug effects/physiology ; Comparative Study ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Infusions, Intravenous ; Male ; Methylene Blue/administration & dosage/*therapeutic use ; Middle Aged ; Pulmonary Circulation/drug effects/physiology ; Research Support, Non-U.S. Gov't ; Retrospective Studies ; Shock, Septic/blood/*drug therapy/physiopathology ; Treatment Outcome ; Vascular Resistance/*drug effects/physiology