ozagrel and Hypoxia

To study the effect of Thromboxane A2 (TXA2) inhibitor on the proliferation of hypoxic pulmonary artery smooth muscle cells (PASMC) of porcines.. The methods of 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), immunohistochemistry of Ki67 and TdT-mediated dUTP nick end labeling (TUNEL) were employed to measure the proliferation, inhibition rate and apoptosis of PASMC.. U46619, a thromboxane A2 agonist, could promote the proliferation and expression of Ki67 in PASMC under hypoxic and normal conditions. It could also inhibit the apoptosis of PASMC. Ozagrel, a thromboxane A2 inhibitor, inhibited the proliferation and the expression of Ki67 in PASMC under hypoxia. The inhibition rate was 71.4%, but it had no effect on the proliferation and expression of Ki67 in PASMC under normal conditions. It promoted the apoptosis of PASMC. Ozagrel could inhibit the action of U46619 in promoting the proliferation and expression of Ki67 in PASMC and inhibit the apoptosis of PASMC.. Ozagrel may be used in treating the pulmonary hypertension by inhibiting the proliferation of PASMC, pulmonary vascular remodeling, and promote the apoptosis of PASMC.

Topics: Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; Hypoxia; Methacrylates; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Swine

Topics: Animals; Arachidonic Acids; Disease Models, Animal; Dogs; Embolism, Fat; Epoprostenol; Female; Hypoxia; Indomethacin; Lung; Lung Injury; Male; Methacrylates; Microcirculation; Oleic Acid; Oleic Acids; Pulmonary Circulation; Pulmonary Embolism; Respiratory Distress Syndrome; Thromboxane A2; Vasoconstriction; Vasodilation

In monkey coronary artery strips contracted with prostaglandin (PG) F2 alpha or K+, exchange of entire N2 for O2 in the gas aerating the bathing media produced a contraction. Endothelium denudation did not alter the response. Aspirin, indomethacin, and ONO 3708, a PG receptor antagonist, markedly inhibited the hypoxia-induced contraction, whereas superoxide dismutase and OKY 046, a thromboxane (Tx) A2 synthesis inhibitor, were ineffective. Diltiazem depressed the contraction. Hypoxia increased the release of PGE2 but not 6-keto-PGF1 alpha and TxB2. Contractions induced by hypoxia of human coronary artery strips were also independent of the endothelium but were suppressed by indomethacin and diltiazem. On the other hand, dog coronary artery contractions induced by hypoxia were attenuated by endothelium denudation but were not influenced by indomethacin. It may be concluded that the hypoxia-induced contraction of monkey and human epicardial coronary arteries is associated with vasoconstrictor PGs released from subendothelial tissues; however, TxA2 and superoxide anion are not involved. The dog coronary artery contraction appears to be elicited by substance(s), other than cyclooxygenase products, released from the endothelium.

Topics: Animals; Aspirin; Coronary Vessels; Dinoprost; Dogs; Endothelium, Vascular; Female; Humans; Hypoxia; In Vitro Techniques; Indomethacin; Isometric Contraction; Macaca; Male; Methacrylates; Muscle Relaxation; Muscle, Smooth, Vascular; Papaverine; Prostaglandins; Species Specificity; Superoxide Dismutase; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

This study investigated the effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (ketoprofen) on hypoxic pulmonary vasoconstriction in conscious adult sheep in order to evaluate the physiological role of thromboxane and other cyclooxygenase products. In addition, we studied the effects of histamine H1 (chlorpheniramine) and H2 antagonists (cimetidine) on hypoxic pulmonary vascular tone. Hypoxia caused a 37% rise in pulmonary arterial pressure (p less than 0.05) and a 36% increase in pulmonary vascular resistance (p less than 0.05). Pretreatment with intravenous OKY-046 10 mg/kg or ketoprofen 2 mg/kg had no effect on normoxic pulmonary vascular tone and inhibited the increase in plasma TXB2 concentration during hypoxia without affecting the pulmonary pressor response to hypoxia. Cimetidine produced an increase in hypoxic pulmonary vascular tone when individual members of the group were compared, but there was no statistically significant difference when the group was compared to the control study. Chlorpheniramine had no effect on hypoxic pulmonary tone. These data suggest that hypoxic pulmonary vasoconstriction is not mediated by release of TXA2, that hypoxic vascular tone is not modulated by cyclooxygenase products, and that the histamine H2 receptor may play a modulating role in hypoxic pulmonary vasoconstriction in conscious adult sheep.

Topics: Acrylates; Animals; Consciousness; Female; Hypoxia; Ketoprofen; Lung; Male; Methacrylates; Phenylpropionates; Receptors, Histamine H2; Sheep; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 +/- 27 (mean +/- SD) to 35 +/- 13 mm HG (P less than .01). The mean arterial pressure (MAP) remained at 50 +/- 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 +/- 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 +/- 4 to 20 +/- 4 mm HG (P less than .01) whereas the PVR increased 70% (P less than .01). TxB2 rose from 147 +/- 85 to 271 +/- 154 pg/mL (P less than .05), and 6-keto-PGF1 alpha rose from 105 +/- 96 to 142 +/- 110 pg/mL. These substances are the hydrolysis products of TxA2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O2, values for MAP, CO, and PVR were similar to those of the nontreatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Epoprostenol; Female; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Methacrylates; Oxygen; Sheep; Thromboxane A2