metiamide and Hypoxia

In a minority of conscious sheep, the hypoxic pulmonary vasoconstrictor response is blunted ("nonresponders"). The purpose of this investigation was to determine if this blunted response is related to an increased activity of H2-histamine receptors, beta-adrenergic receptors, or the generation of inhibitory prostaglandins. We measured pulmonary arterial pressure, pulmonary arterial wedge pressure, and pulmonary blood flow for the calculation of pulmonary vascular resistance (PVR) in 5 "nonresponders" and 5 sheep with a typical hypoxic pulmonary vasoconstrictor response ("responders") while breathing room air and 13% O2 (balance, N2). Arterial oxygen tension (PaO2) was also determined as a measure of the severity of hypoxia. During hypoxia, mean PVR increased by 6% (p = NS) in the "nonresponders" (PaO2, 49 +/- 4 mmHg), and by 70% (p less than 0.01) in the "responders" (mean PaO2, 46 +/- 4 mmHg). Metiamide (H2-blocker) and propranolol (beta-adrenergic blocker) pretreatments did not restore the hypoxic pulmonary vascular response in the "nonresponders," whereas pretreatment with indomethacin (prostaglandin synthetase inhibitor) caused mean PVR to increase by 48% (p less than 0.01) during hypoxia, indicating a partial restoration of hypoxic pulmonary vasoconstriction. In the "responders," the hypoxic pulmonary vascular response was not potentiated by indomethacin pretreatment (68% increase in mean PVR). We conclude that some sheep exhibit a blunted hypoxic pulmonary vasoconstrictor response caused by enhanced production of inhibitory prostaglandins.

Topics: Animals; Female; Hemodynamics; Hypoxia; Indomethacin; Metiamide; Propranolol; Prostaglandins; Pulmonary Circulation; Sheep; Vasoconstriction

We used pharmacologic and histologic techniques to investigate the role of mast cells in the mediation of hypoxic pulmonary vasoconstriction in conscious sheep. Breathing a hypoxic gas mixture (13%, 02, 87% nitrogen) caused hypoxic pulmonary vasoconstriction (HPV) with increases in mean pulmonary artery pressure and pulmonary vascular resistance by 97 and 90%, respectively. Intravenous pretreatment with the mast cell membrane stabilizing agent cromolyn sodium (3 mg/kg/min) completely blocked HPV, whereas the H1-histamine receptor antagonist chlorpheniramine, alone or in combination with the H2-receptor antagonist metiamide and the prostaglandin synthetase inhibitor indomethacin, failed to prevent HPV. Cromolyn sodium failed to modify the pulmonary pressor response to infusions of norepinephrine (alpha-agonist), tyramine (catecholamine-releasing agent), and histamine, indicating the specificity of cromolyn sodium action on the mast cells. Electromicroscopic studies of pulmonary perivascular mast cells showed that a 90-min exposure to the hypoxic gas mixture reduced the total number of granules per mast cell to 75% of control. This was blocked by cromolyn sodium pretreatment. We conclude that in conscious sheep], HP[V is initiated by the liberation of a mast cell product (other than histamine) that either directly or indirectly causes pulmonary vasoconstriction.

Topics: Animals; Chlorpheniramine; Cromolyn Sodium; Cytoplasmic Granules; Female; Hemodynamics; Hypoxia; Indomethacin; Lung; Mast Cells; Metiamide; Sheep; Vasoconstriction

In vitro frog gastric mucosa was employed as a model for a combined physiological, biochemical, and ultrastructural study of the morphological changes which accompany the onset of acid secretion by the oxyntic cell. The histamine H2-receptor antagonist metiamide was used to provide a reproducible control state. Stimulation of acid production by theophylline resulted in a 10-fold increase in plasma membrane surface area and a distinct change in the conformation of mitochondrial cristae. Studies using the acid secretion inhibitors, thiocyanate and anoxia, demonstrated that neither acid production per se nor oxidative metabolism is essential for the theophylline-dependent changes in surface area. Increases in tissue cyclic AMP levels were observed under the conditions producing morphological changes. It is postulated that surface area changes induced by theophylline are controlled by cellular cyclic AMP levels.

Topics: Animals; Anura; Cyclic AMP; Gastric Mucosa; Hypoxia; Metiamide; Rana catesbeiana; Theophylline

Pulmonary vasomotor actions of histamine and the possible relationship of histamine to hypoxic pulmonary vasconstriction were studied in anaesthetized cats with one lobe of lung perfused at constant flow and in isolated perfused rat and ferret lungs. In the cat histamine caused dilatation, biphasic responses and constriction with increasing doses. Histamine induced dilatation was better demonstrated during hypoxic vasoconstriction and was reduced by an H2 histamine antagonist; constriction with histamine was abolished by an H1 antagonist. Histamine also caused both vasodilatation and vasoconstriction in ferret lungs. A mast cell stabilizing agent had no effect on hypoxic pulmonary vasoconstriction in cats or rats. This response was unaffected in cats but greatly reduced in rats and ferrets by cyproheptadine, a combined histamine and 5-hydroxy-tryptamine inhibitor. It was unaffected in cats but abolished in ferrets an H1 histamine inhibitor. It was again unaffected in cats but greatly reduced in rats and ferrets by an H2 histamine inhibitor. These species differences may reflect differences in mechanism but more probably reflect non-specific effects of the inhibitors in certain circumstances. However, when drugs nearly abolished hypoxic vasoconstriction, ATP still caused vasoconstriction.

Topics: Animals; Blood Vessels; Cats; Cyproheptadine; Dose-Response Relationship, Drug; Ferrets; Histamine; Hypoxia; Lung; Metiamide; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Species Specificity; Vasoconstriction

Topics: Animals; Chlorpheniramine; Dogs; Histamine; Hypoxia; Metiamide; Pulmonary Circulation; Receptors, Histamine; Vascular Resistance; Vasomotor System

Topics: Animals; Blood Pressure; Diphenhydramine; Dogs; Female; Femoral Artery; Hypoxia; Male; Metiamide; Microspheres; Pulmonary Alveoli; Pulmonary Artery; Pulmonary Circulation; Radionuclide Imaging; Thiourea

We sought to define the roles of H1-and H2-receptors in the cat and to evaluate the roles of these receptors during alveolar hypoxia. In pentobarbital anesthetized cats, we found that histamine infusion (1.1 microgram/kg/min for 3 min) increased cardiac output and decreased pulmonary and systemic vascular resistances. However, when cardiac output was held constant, histamine infusion induced pulmonary vasoconstriction. Histamine infusions after H1-and H2-receptor blockade (chlorpheniramine and metiamde, respctively) indicated that H2-receptors mediated systemic vasodilatation. In the lung, H1-receptors mediated vasoconstriction, and H2-receptors mediated vasodilatation. Hypoxia (10% O2) caused large increases in pulmonary vascular resistance which were not blocked by H1-, H2-, or combined H1- and H2-receptor blockade. In the intact cat, histamine does not appear to mediate hypoxic pulmonary hypertension.

Topics: Animals; Cardiac Output; Cats; Chlorpheniramine; Heart Rate; Histamine; Hypoxia; Lung; Metiamide; Pulmonary Alveoli; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Vascular Resistance; Vasomotor System

Five chronically instrumented healthy dogs were exposed to a 5-day period of breathing 10% oxygen in a chamber. The response to hypoxia was found to be time dependent. During the first 24 h of hypoxia the circulatory response was characterized by increases in cardiac output, heart rate, pulmonary and systemic arterial blood pressures, and pulmonary vascular resistance. Systemic vascular resistance increased; left atrial pressure decreased. During the early part of hypoxia the animals became hypocapnic; the arterial blood pH rose significantly. During the rest of the hypoxic period cardiac output, heart rate, and arterial blood pH returned to the control values; pulmonary and systemic arterial pressures and pulmonary vascular resistance remained significantly elevated. Systemic vascular resistance rose; left atrial pressure remained below control. This response to hypoxia was not substantially modified when the experiment was repeated during the administration of the antihistamine promethazine, an H1-receptor blocking agent, in a dose which blocked the pulmonary vasoconstrictor response to small doses of exogenous histamine. The circulatory response to acute hypoxia in five anesthetized dogs was not modified by intravenous administration of metiamide, an H2-receptor blocking agent.

Topics: Animals; Aorta; Blood Pressure; Dogs; Environment, Controlled; Female; Heart Rate; Hematocrit; Hemodynamics; Histamine; Histamine H1 Antagonists; Hydrogen-Ion Concentration; Hypoxia; Male; Metiamide; Oxygen; Promethazine; Pulmonary Artery; Regional Blood Flow; Time Factors