allopurinol and Hypertension--Pulmonary

Endothelial dysfunction and impaired nitric oxide bioavailability have been implicated in the pathogenesis of sickle cell anemia. Nitric oxide is a diatomic gas with a role in vascular homeostasis. Hemoglobin polymerization resulting from the HbS mutation produces erythrocyte deformation and hemolysis. Free hemoglobin, released into plasma by hemolysis scavenges on nitric oxide, and leads to reduced nitric oxide bioavailability. Pulmonary hypertension is a known consequence of sickle cell anemia. It occurs in 30-40% of patients with sickle cell anemia, and is associated with increased mortality. Several studies have implicated intravascular hemolysis, and impaired nitric oxide bioavailability in the pathogenesis of pulmonary hypertension. In this review, we summarize the mechanisms of altered nitric oxide bioavailability in sickle cell anemia and its possible role in the pathogenesis of pulmonary hypertension.

Topics: Anemia, Sickle Cell; Animals; Endothelium, Vascular; Genetic Predisposition to Disease; Hemoglobins; Hemolysis; Humans; Hypertension, Pulmonary; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase; Oxidants; Oxidative Stress; Xanthine Oxidase

Oxidative stress (OS) has been implicated in the development of pulmonary hypertension (PH) and ventricular hypertrophy. Xanthine oxidase is a well-recognised source of reactive oxygen species, which lead to OS. The aim of this proof of concept study was to assess whether allopurinol (xanthine oxidase inhibitor) would reduce right ventricular mass (RVM) in patients with PH-associated chronic lung disease (PH-CLD).. We conducted a randomised, double-blind, parallel-group, placebo-controlled trial in patients with PH-CLD (93% COPD, 7% IPF) who were randomly assigned to receive allopurinol or placebo for 12 months. The primary outcome was the mean change in RVM, as assessed by cardiac magnetic resonance imaging (CMRI). Secondary outcomes included quality of life (QOL), spirometry and six-minute walk test (6MWT).. Seventy-one patients were recruited: mean age 71 years, mean pulmonary arterial pressure 30 mm Hg, FEV. Allopurinol had no overall impact on patients with PH-CLD but had potential benefit in COPD patients with more severe airflow limitation.

Topics: Aged; Allopurinol; Double-Blind Method; Humans; Hypertension, Pulmonary; Pulmonary Disease, Chronic Obstructive; Quality of Life; Walk Test

The effect of allopurinol to inhibit purine metabolism via the xanthine oxidase pathway in neonates with severe, progressive hypoxemia during rescue and reperfusion with extracorporeal membrane oxygenation (ECMO) was examined. Twenty-five term infants meeting ECMO criteria were randomized in a double-blinded, placebo-controlled trial. Fourteen did not receive allopurinol, whereas 11 were treated with 10 mg/kg after meeting criteria and before cannulation, in addition to a 20-mg/kg priming dose to the ECMO circuit. Infant plasma samples before cannulation, and at 15, 30, 60, and 90 min, and 3, 6, 9, and 12 h on bypass were analyzed (HPLC) for allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid concentrations. Urine samples were similarly evaluated for purine excretion. Hypoxanthine concentrations in isolated blood-primed ECMO circuits were separately measured. Hypoxanthine, xanthine, and uric acid levels were similar in both groups before ECMO. Hypoxanthine was higher in allopurinol-treated infants during the time of bypass studied (p = 0.022). Xanthine was also elevated (p < 0.001), and uric acid was decreased (p = 0.005) in infants receiving allopurinol. Similarly, urinary elimination of xanthine increased (p < 0.001), and of uric acid decreased (p = 0.04) in treated infants. No allopurinol toxicity was observed. Hypoxanthine concentrations were significantly higher in isolated ECMO circuits and increased over time during bypass (p < 0.001). This study demonstrates that allopurinol given before cannulation for and during ECMO significantly inhibits purine degradation and uric acid production, and may reduce the production of oxygen free radicals during reoxygenation and reperfusion of hypoxic neonates recovered on bypass.

Topics: Allopurinol; Blood Gas Analysis; Double-Blind Method; Enzyme Inhibitors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Hypoxanthine; Hypoxia; Infant, Newborn; Purines; Respiratory Insufficiency; Xanthine Oxidase

Increased oxidative stress and high uric acid are implicated in the pathogenesis of pulmonary hypertension (PH). This provides opportunity to benefit from drugs like allopurinol which suppresses both contributing factors. Therefore, we aimed to investigate the effects of allopurinol in preventing as well as reversing the pathological changes occurring in monocrotaline (MCT)-induced rat model of PH. Male rats were assigned into three groups based on the follow-up time: 7, 21 and 35 days. Time-matched controls of each group received single injections of MCT (60 mg/kg) intraperitoneally. Test groups consisted of rats who were treated with MCT on day 0 plus oral allopurinol (60 mg/kg) daily for 7 or 21 days. 35-day group received allopurinol for two weeks starting on the 22nd day following MCT injection. At the end of all-time points, rats were killed and basal pulmonary perfusion pressure, Fulton index, pulmonary arterial wall thickness and pulmonary arterial relaxations along with oxidative stress markers (MDA, SOD, XO), NO and uric acid levels were measured in all groups. MCT-injected rats had evidence of raised oxidative stress (high MDA and XO, low SOD levels) which was reversed by allopurinol co-treatment in all-time groups. Marked elevation of uric acid seen in 21- and 35 day-groups was also reversed by allopurinol. Reduced NO levels of 21 and 35 days were unchanged in allopurinol treated groups. Apart from an increase in arterial wall thickening which was maintained in all-time groups, no alterations in other cardiovascular parameters were observed in 7-day group. However, basal lung perfusion pressure and Fulton index significantly increased, while arterial relaxations decreased in 21- and 35-day groups. Co-treatment with allopurinol for 21 days improved these functional alterations, whereas late allopurinol treatment failed to affect them. Our results indicate that early treatment of MCT-induced PH with allopurinol ameliorated the impaired functional characteristics via suppressing the increased oxidative stress and uric acid, while treatment started after progression of the disease had no significant effect.

Topics: Allopurinol; Animals; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Uric Acid; Vascular Remodeling

Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.

Topics: Animals; Cells, Cultured; DNA, Complementary; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Transgenic; Superoxide Dismutase; Transfection; Xanthine Oxidase

Pulmonary hypertension (PH) is a multifactorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH, and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO(3)(-)) and nitrite (NO(2)(-)) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity.. Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular remodeling in wild-type mice exposed to 3 weeks of hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma and lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase or treated with the xanthine oxidoreductase inhibitor allopurinol.. These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH.

Topics: Allopurinol; Animal Feed; Animals; Antibiotics, Antineoplastic; Bleomycin; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitric Oxide Synthase Type III; Nitrites; Pulmonary Circulation; Ventricular Pressure; Xanthine Dehydrogenase

Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients.. Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography.. PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P < .01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 μM, P < .01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P = .02, respectively) and decreased eSOD activity (235 ± 23 vs. 461 ± 33 AUC, P < .01). Iloprost improved right cardiac output (3.7 ± 0.6 to 4.1 ± 1.2 L/min, P = .02) and decreased pulmonary vascular resistance (4.1 ± 1.1 to 2.9 ± 0.9 Wood U, P = .01). Changes in right cardiac output after prostanoid inhalation correlated significantly with baseline eSOD activity and FMD (Rho: 0.61, P < .01 and Rho: 0.63, P = .01, respectively).. PAH patients show increased systemic oxidative stress and endothelial dysfunction markers. Response to inhaled prostanoid is inversely related to both parameters.

Topics: Acute Disease; Administration, Inhalation; Adult; Biomarkers; Brachial Artery; Case-Control Studies; Cross-Sectional Studies; Endothelium, Vascular; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Malondialdehyde; Oxidative Stress; Prostaglandins; Pulmonary Artery; Superoxide Dismutase; Xanthine Oxidase

Topics: Case-Control Studies; Endothelium, Vascular; Female; Gene Expression Regulation, Enzymologic; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Oxidative Stress; Pulmonary Artery; Xanthine Oxidase

Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O(2)) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg.kg(-1).day(-1) or Tempol 100 mg.kg(-1).day(-1) ip) or a XO inhibitor, Allopurinol (50 mg.kg(-1).day(-1) ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxia-exposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-dependent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.

Topics: Acetylcholine; Allopurinol; Animals; Animals, Newborn; Cell Proliferation; Chronic Disease; Cyclic N-Oxides; Dinoprost; Free Radical Scavengers; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Nitric Oxide Synthase Type III; Organ Size; Oxidative Stress; Pregnatrienes; Pulmonary Artery; Rats; Reactive Oxygen Species; Spin Labels; Superoxides; Time Factors; Xanthine Oxidase

Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid alpha-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice. We found increased levels of soluble cell adhesion molecules in sph/sph mice, suggesting activation of the vascular endothelium. We hypothesized that plasma hemoglobin released by intravascular hemolysis initiates endothelial injury through nitric oxide (NO) scavenging and oxidative damage. Likewise, electron paramagnetic resonance spectroscopy showed that plasma hemoglobin is much greater in sph/sph mice. Moreover, plasma from sph/sph mice had significantly higher oxidative potential. Finally, xanthine oxidase, a potent superoxide generator, is decreased in subpopulations of liver hepatocytes and increased on liver endothelium in sph/sph mice. These results indicate that vasoregulation is abnormal, and NO-based vasoregulatory mechanisms particularly impaired, in sph/sph mice. Together, these data indicate that sph/sph mice with severe HS have increased plasma hemoglobin and NO scavenging capacity, likely contributing to aberrant vasoregulation and initiating oxidative damage.

Topics: Animals; Disease Models, Animal; Hemoglobins; Hemolysis; Hypertension, Pulmonary; Liver; Mice; Mice, Mutant Strains; Nitric Oxide; Spectrin; Spherocytosis, Hereditary; Vasodilation; Xanthine Oxidase

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.

Topics: Acetylcysteine; Allopurinol; Animals; Antioxidants; Chronic Disease; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Oxidative Stress; Oxygen; Phosphatidylcholines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Tunica Media; Ventricular Function, Right; Xanthine Oxidase

1. Cyclic guanosine 3'-5'-monophosphate (cyclic GMP) is the second messenger of important physiologically active mediators controlling the pulmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertension. 2. Levels of cyclic GMP measured during baseline conditions at 5 and 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with time. Pretreatment with DMPPO (1 microM) induced a larger increase in cyclic GMP concentration in the perfusate from chronically hypoxic rat lungs (31+/-36 at 5 min to 1821+/-83 pmol ml(-1) at 60 min) than in normoxic rat lungs (329+/-20 to 1281+/-127 pmol ml(-1), P<0.05). 3. In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 microM) potentiated the vasodilator effects of atrial natriuretic peptide (100 pM-10 nM) and sodium nitroprusside (1 pM 10 nM), but did not alter vasodilation to isoproterenol. 4. In conscious rats previously exposed to 15 days hypoxia and studied under 10% O2, DMPPO (0.01, 0.05 and 0.1 mg kg(-1), i.v. bolus) caused a dose-dependent decrease in pulmonary arterial pressure (Pap) with no change in systemic artery pressure (Sap) and cardiac output. 5. Continuous infusion of DMPPO (0.1 mg kg(-1) h(-1) i.v. by osmotic pumps) in rats exposed to 10% O2 during 2-weeks reduced the Pap (P<0.05) and the degree of muscularization of pulmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrophy. 6. These results suggest that cyclic GMP phosphodiesterase inhibition may selectively dilate pulmonary circulation during chronic hypoxia.

Topics: Allopurinol; Animals; Atrial Natriuretic Factor; Cyclic GMP; Drug Interactions; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Nitroprusside; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Time Factors; Vasodilation

Protection of the failing right ventricle (RV) in the surgical treatment of massive pulmonary embolism is a keystone for myocardial recovery. This study evaluated whether cardioplegia should be used or avoided. In a modified Langendorff rat heart model pulmonary embolism was simulated by afterload elevation (20 cm H2O) for 30 min. Hearts were arrested with cardioplegic solutions [St. Thomas Hospital (ST); University of Wisconsin (UW); oxygenated Krebs-Henseleit-Potassium (KHP)] and stored for 10 min or were allowed to beat empty (NoCP) for 15 min. After reestablishing of baseline conditions groups were measured for 60 min. Cardiac index (CI) decreased in all groups to 20% during afterload elevation. Group NoCP showed 68 and Group ST 65% recovery after 10 min and deteriorated after 30 min. After 60 min CI was 37 (ST) and 39% (NoCP). UW and KHP showed a significantly better recovery (KHP 100%; UW 88%). At 60 min CI decreased to 60 (KHP) and 64% (UW), but was still significantly higher than corresponding values of NoCP and ST. Following increased pulmonary afterload cardioplegia with UW or KHP solution is beneficial for RV recovery. The composition of the cardioplegia is obviously important and needs further study.

Topics: Acute Disease; Adenosine; Allopurinol; Animals; Cardioplegic Solutions; Disease Models, Animal; Embolectomy; Evaluation Studies as Topic; Extracorporeal Circulation; Glucose; Glutathione; Heart Arrest, Induced; Heart Failure; Hypertension, Pulmonary; Insulin; Male; Myocardial Reperfusion Injury; Organ Preservation Solutions; Pulmonary Embolism; Raffinose; Rats; Rats, Inbred Lew; Tromethamine; Ventricular Function, Right

Topics: Animals; Capillary Permeability; Glucose Oxidase; Hydrogen Peroxide; Hypertension, Pulmonary; Lung; Perfusion; Pulmonary Alveoli; Pulmonary Edema; Purines; Rabbits; Xanthine Oxidase