u-62840 and Hypoxia

Topics: Administration, Inhalation; Administration, Oral; Animals; Collagen; Disease Models, Animal; Epoprostenol; Heart; Hemodynamics; Hypoxia; Indoles; Male; Myocardium; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrroles; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Topics: Animals; Antihypertensive Agents; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases; Down-Regulation; Epoprostenol; Humans; Hypertrophy; Hypoxia; Immunosuppressive Agents; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger; Sirolimus; Vascular Remodeling

Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH.. Male Sprague Dawley rats were injected with SU (20 mg·kg. At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4 weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs.. Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.

Topics: Angiogenesis Inhibitors; Animals; Antihypertensive Agents; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Indoles; Male; Protein Kinase Inhibitors; Pyrroles; Rats, Sprague-Dawley; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right

Pulmonary hypertension (PH) is a rapidly progressive disease that eventually leads to right heart failure and death. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs) play an important role in the survival, migration, and proliferation of vascular smooth muscle cells. However, the association between serum TRAIL levels and PH is unknown. In this study, we assayed the serum soluble TRAIL (sTRAIL) levels in 78 patients with PH and 80 controls. The sTRAIL concentrations were elevated in the PH patients compared with the controls (138.76 ± 6.60 pg/mL vs. 80.14 ± 3.38 pg/mL, p < 0.0001). The presence of sTRAIL levels of >103 pg/mL could discriminate PH patients from healthy individuals, with a sensitivity of 75.6% and specificity of 81.2%. Moreover, elevated sTRAIL concentrations were associated with eventual pathological complications; this is consistent with the finding that sTRAIL levels decreased in patients who responded to treatment. In a hypoxia-induced PH mouse model, sTRAIL levels were significantly higher compared with those in normoxia mice, and clearly decreased when the mice were treated with treprostinil. The sTRAIL levels were positively correlated with right ventricular systolic pressure and the index of right ventricular hypertrophy. In conclusion, serum sTRAIL could be a biomarker for diagnosis and effective therapy for PH patients.

Topics: Animals; Case-Control Studies; Disease Models, Animal; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Middle Aged; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; TNF-Related Apoptosis-Inducing Ligand

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.. Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.. CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).. Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Monocrotaline; Nitroprusside; Piperazines; Pulmonary Artery; Purines; Rats; Sildenafil Citrate; Smooth Muscle Myosins; Sulfones; Swine; Vascular Resistance; Vasoconstriction; Vasodilator Agents

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Blood Circulation; Blood Vessels; Bone Marrow Cells; Chimerism; Chronic Disease; Epoprostenol; Female; Fibroblasts; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Pulmonary Artery