thromboxane-b2 and Hypotension

We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI2) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia.. In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGF1 alpha (stabile metabolite of PGI2), TXB2 (stabile metabolite of thromboxane A2) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection.. Following MT, arterial hypotension occurred along with a substantial PGI2 release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF1 alpha (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P = 0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB2 (164 (87) vs. 58 (1) ng/L, P = 0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P = 0.001), AVP (41 +/- (18) vs. 12 (7) ng/L, P = 0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients.. Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI2 release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A2, presumably contributing to hemodynamic stability within 30 min after MT.

Topics: Abdomen; Anesthesia, Epidural; Anesthesia, General; Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Catecholamines; Double-Blind Method; Epoprostenol; Female; Hemodynamics; Hormones; Humans; Hypotension; Ibuprofen; Male; Mesentery; Middle Aged; Prospective Studies; Renin; Thromboxane B2

Pigs are known to provide a sensitive model for studying complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction to liposomal and many other nanomedicines that limits their clinical use. The utility of rats as a CARPA model has, however, not been analyzed to date in detail. The present study compared the two models by inducing CARPA with i.v. bolus injections of two reactogenic liposomes that differed from each other in surface properties: one was AmBisome, a strong anionic, free-surface small unilamellar liposome (SUV), while the other was neutral, polyethylene glycol (PEG)-grafted SUV wherein the 2 kDa-PEG was anchored to the membrane via cholesterol (Chol-PEG). Both in pigs and rats AmBisome caused significant consumption of C3, indicating C activation, along with paralleling massive changes in blood pressure, white blood cell, platelet counts and in plasma thromboxane B2 levels, indicating CARPA. These processes were similar in the two species in terms of kinetics, but significantly differed in the doses that caused major hemodynamic changes (~0.01 and ~22 mg phospholipid (PL)/kg in pigs and rats, respectively). Pigs responded to AmBisome with pulmonary hypertension and systemic hypotension, and the reaction was not tachyphylactic. The major response of rats was systemic hypotension, leukopenia followed by leukocytosis, and thrombocytopenia. Chol-PEG liposomes caused severe reaction in pigs at 0.1 mg/kg, while the reaction they caused in rats was mild even at 300 mg PL/kg. Importantly, the reaction to Chol-PEG in pigs was partly tachyphylactic. These observations highlight fundamental differences in the immune mechanisms of porcine and rat CARPA, and also show a major impact of liposome surface characteristics, determining the presence or absence of tachyphylaxis. The data suggest that rats are 2-3 orders of magnitude less sensitive to liposomal CARPA than pigs; however, the causes of these differences, the PEG-dependent tachyphylaxis and the massive reactivity of Chol-PEG liposomes remain unclear.

Topics: Animals; Complement Activation; Drug Hypersensitivity; Heart Rate; Humans; Hypotension; Leukocyte Count; Lipids; Liposomes; Male; Platelet Count; Polyethylene Glycols; Rats, Wistar; Species Specificity; Surface Properties; Swine; Thromboxane B2

AMG X, a human neutralizing monoclonal antibody (mAb) against a soluble human protein, caused thrombocytopenia, platelet activation, reduced mean arterial pressure, and transient loss of consciousness in cynomolgus monkeys after first intravenous administration. In vitro, AMG X induced activation in platelets from macaque species but not from humans or baboons. Other similar mAbs against the same pharmacological target failed to induce these in vivo and in vitro effects. In addition, the target protein was known to not be expressed on platelets, suggesting that platelet activation occurred through an off-target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by preincubation of AMG X with its pharmacological target or with anti-human Fc antibodies or by preincubation of platelets with AMG X F(ab')(2) or human immunoglobulin (IVIG). AMG X F(ab')(2) did not activate platelets. Thus, platelet activation required both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet Fc receptors (i.e., FcγRIIa) with the Fc domain. These findings reflect the complexity of the mechanism of action of mAbs and the increasing awareness of potential for unintended effects in preclinical species.

Topics: Administration, Intravenous; Animals; Antibodies, Monoclonal; Blood Platelets; Humans; Hypotension; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Macaca fascicularis; Male; Papio; Platelet Activation; Platelet Aggregation; Protein Binding; Serotonin; Syncope; Thrombocytopenia; Thromboxane B2

Anaphylactic shock accidents after allergen exposure are frequent. After immunization with ovalbumin (OVA), a common dietary constituent, we evaluated the efficacy of pretreatment with histamine-receptor or serotonin-receptor blockers administered alone or in combination with a nitric oxide synthase inhibitor (L-NAME) on OVA-induced anaphylactic shock in Brown Norway rats. Animals were allocated to the following groups (n = 6 each): control (0.9% saline); diphenydramine (15 mg kg(-1)); cimetidine (20 mg kg(-1)); diphenydramine + cimetidine; dihydroergotamine (50 microg kg(-1)); diphenydramine + cimetidine + dihydroergotamine; L-NAME (100 mg/kg) alone or associated with diphenydramine, cimetidine, diphenydramine + cimetidine, dihydroergotamine, or diphenydramine + cimetidine + dihydroergotamine. Mean arterial blood pressure (MABP), heart rate (HR), and survival time were monitored for 60 min following treatment. The shock was initiated with i.v. OVA. The MABP drop after i.v. OVA was worsened by diphenydramine and was modestly attenuated by cimetidine, dihydroergotamine, or both together. L-NAME potentiated slightly the effects of cimetidine and dihydroergotamine by lessening the initial MABP decrease, but this transient effect was not sufficient to prevent the final collapse or to improve survival time. Decreased vasodilatory (prostaglandins E2), increased vasoconstrictory (thromboxane B2) prostaglandins, and unchanged leukotriene C4 concentrations were contributory to the overall hemodynamic changes. Thus, the combined blockade of vasodilator mediators (histamine, serotonin, and nitric oxide) slowed the MABP drop in anaphylactic shock, but did not improve survival. More studies are needed to understand these discordant effects.

Topics: Anaphylaxis; Animals; Arteries; Cimetidine; Dihydroergotamine; Dinoprostone; Eicosanoids; Enzyme Inhibitors; Heart; Histamine; Hypotension; Leukotriene C4; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Ovalbumin; Pressure; Rats; Rats, Inbred BN; Receptors, Serotonin; Serotonin; Thromboxane B2; Time Factors

Impairment in cardiovascular functions sometimes manifested in astronauts during standing postflight, may be related to the diminished autonomic function and/or excessive production of endothelium-dependent relaxing factors. In the present study, using the 30 degrees head-down tilt (HDT) model, we compared the cardiovascular and biochemical effects of 7 days of suspension and a subsequent 6-h post-suspension period between suspended and non-suspended conscious female Sprague-Dawley rats. Mean arterial pressure (MAP) and heart rate were measured prior to suspension (basal), daily thereafter, and every 2h post-suspension. Following 7 days of suspension, MAP was not different from their basal values, however, upon release from suspension, MAP was significantly reduced compared to the non-suspended rats. Nitric oxide levels were elevated while thromboxane A(2) levels declined significantly in both plasma and tissue samples following post-suspension. The levels of prostacyclin following post-suspension remained unaltered in plasma and aortic rings but was significantly elevated in carotid arterial rings. Therefore, the post-suspension reduction in mean arterial pressure is due mostly to overproduction of nitric oxide and to a lesser extent prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Blood Pressure; Carotid Arteries; Epoprostenol; Female; Heart Rate; Humans; Hypotension; In Vitro Techniques; Nitric Oxide; Prostaglandins; Rats; Rats, Sprague-Dawley; Space Simulation; Thromboxane A2; Thromboxane B2; Weightlessness; Weightlessness Simulation

Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 micro m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B(2) (TxB(2)) in bronchoalveolar lavage fluid and increased urinary dinor TxB(2). Furegrelate and ketorolac treatments reduced TxB(2) and dinor TxB(2) to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB(2). Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE.

Topics: Angiography; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Disease Models, Animal; Extravascular Lung Water; Hypotension; Isoenzymes; Ketorolac; Membrane Proteins; Microspheres; Pleural Effusion; Polystyrenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Circulation; Pulmonary Embolism; Rats; Rats, Sprague-Dawley; Respiratory Dead Space; Survival Rate; Thromboxane B2; Thromboxane-A Synthase

Because some patients with Streptococcus pneumoniae bacteremia may present with shock, we reasoned that this organism may produce substances that cause shock. To test this hypothesis, type III pneumococcus supernatant, suspended in 10 ml of sterile water, was infused over 1 min in 8 adult anesthetized sheep. Normal saline was used as a control and had no effect on any of the hemodynamic parameters. Infusion of supernatant resulted in a precipitous fall in cardiac output from a control value of 4.25 +/- 0.54 to 2.80 +/- 0.43 (SE) l/min, a fall in mean systemic arterial pressure from 70 +/- 4 to 49 +/- 8 mmHg, and an increase in the mean pulmonary arterial pressure from 13 +/- 2 to 23 +/- 4 mmHg within 1 min after the infusion was completed. The peak hemodynamic effects were observed at approximately 3 min and returned to normal within 10 min after the infusion was completed. The thromboxane B2 level increased from a control value of 10 +/- 5 to 156 +/- 43 pg/ml at 3 min after the infusion was completed and decreased to 63 +/- 34 pg/ml at 20 min. A second identical dose of pneumococcal supernatant, repeated within 2 h of the first dose, had no effect on hemodynamic variables. Pretreatment with indomethacin, 5 mg/kg body wt, completely blocked the hemodynamic effects of pneumococcal supernatant (n = 3 sheep). Thus, we conclude that S. pneumoniae supernatant contains substances that cause septic shock syndrome through the synthesis of arachidonic acid metabolites and that a sublethal dose of the supernatant causes rapid tachyphylaxis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cardiac Output; Hypertension, Pulmonary; Hypotension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Pneumococcal Infections; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sheep; Shock, Septic; Streptococcus pneumoniae; Thromboxane A2; Thromboxane B2

The effects of CIS-19 (cis-2-(3,4-dimethoxyphenyl)-6-isopropoxy-7-methoxyl-1-(N-methylforma mido)-1,2, 3,4-tetrahydronaphthalene) was determined in vitro in rabbit platelets and in vivo in rats and guinea-pigs. CIS-19 inhibited in a selective and concentration-dependent manner the aggregation and ATP release reaction of rabbit platelets induced by PAF (4 nM). The IC50 values of CIS-19 on PAF-induced aggregation of washed platelets and platelet-rich plasma were 11.3 +/- 2.7 and 16.8 +/- 3.0 microM respectively. BN52021 also inhibited PAF-induced aggregation of washed platelets with an IC50 value of 11.7 +/- 2.8 microM. CIS-19 inhibited [3H]PAF (4 nM) binding to washed rabbit platelets with an IC50 value of 1.5 +/- 0.2 microM. The concentration-response curve of PAF-induced aggregation of washed platelets was shifted rightwards by CIS-19 with pA2 and pA10 values of 7.1 (6.8-7.3 for 95% confidence limit) and 6.1 (5.8-6.2) respectively. The thromboxane B2 formation of washed platelets caused by AA, collagen or thrombin was not affected by CIS-19 of concentrations below 400 microM. CIS-19 (25 microM) completely blocked PAF-induced, but not collagen- or thrombin-induced [3H]inositol monophosphate formation of washed platelets. When CIS-19 (2.5 and 5 mg/kg) was injected i.v. into the femoral vein, it did not affect the blood pressure of rats, but antagonized PAF (2.5 micrograms/kg, i.v.)-induced hypotensive shock either preventively or curatively. CIS-19 (2.5 and 5 mg/kg) also blocked PAF (50 ng/kg)-induced, but not AA (50 micrograms/kg)-induced, bronchoconstriction in guinea-pigs. It is concluded that CIS-19 is an effective PAF receptor antagonist not only in vitro, but also in vivo.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Bronchoconstriction; Diterpenes; Dose-Response Relationship, Drug; Ginkgolides; Guinea Pigs; Hypotension; Inositol Phosphates; Lactones; Male; Platelet Activating Factor; Rabbits; Rats; Rats, Wistar; Receptors, Cell Surface; Tetrahydronaphthalenes; Thromboxane B2

To determine the effects of reduced cerebral perfusion pressures produced by hemorrhage alone or in combination with intracranial hypertension on thromboxane A2 (TxA2) production, we undertook a randomized study in 38 anesthetized, mongrel dogs. Animals were subjected to 30 mins of hemorrhagic shock with normal (group 1) or increased (group 2) intracranial pressure (ICP). Group 1 animals (n = 22) were hemorrhaged to reduce cerebral perfusion pressure to 40 mm Hg for 30 mins. In group 2 (n = 16), cerebral perfusion pressure was reduced by the combination of less severe hypotension and intracranial hypertension (20 mm Hg). Cerebral and systemic hemodynamic measurements were recorded, including cerebral blood flow (sagittal sinus outflow method); ICP; cerebral perfusion pressure; and arterial and cerebral venous concentrations of TxB2 (double-antibody radioimmunoassay technique), the major metabolite of TxA2. Data were obtained at baseline and at the beginning and end of the 30-min shock period.. Hemorrhagic shock significantly (p less than .05) decreased cerebral blood flow in both groups. At the beginning of the shock period, cerebral blood flow was higher in group 1 than in group 2 (p less than .05) and venous-arterial differences in TxB2 increased significantly (p less than .05) in group 2, but not in group 1. At the end of the 30-min shock period, venous-arterial levels of TxB2 remained significantly (p less than .05) higher in group 2.. Increased cerebral production of TxA2 during hypotension accompanied by intracranial hypertension may contribute to the severity of neural damage produced by the combination of head trauma and shock.

Topics: Animals; Brain; Brain Injuries; Cerebrovascular Circulation; Dogs; Female; Hypotension; Intracranial Pressure; Male; Multivariate Analysis; Shock, Hemorrhagic; Thromboxane A2; Thromboxane B2

Clinical and animal data suggest that the pathogenesis of CO poisoning extends beyond the inhibition of hemoglobin function, but no mechanism has been identified. Evidence of neurological compromise, particularly loss of consciousness, has been implicated as a marker for increased mortality and morbidity in clinical reports. Experiments were carried out with rats to assess whether CO exposure may cause brain lipid peroxidation. With the use of two methods, measurement of conjugated dienes and thiobarbituric acid reactivity, brain lipid peroxidation could be documented as a result of exposure to CO at a concentration sufficient to cause unconsciousness. Products of lipid peroxidation were increased by 75% over the base-line values 90 min after CO exposure. Unconsciousness was associated with a brief period of hypotension, so brief that in itself it caused no apparent insult. Lipid peroxidation occurred only after the animals were returned to CO-free air, and there was no direct correlation with the carboxyhemoglobin level. This work may provide an explanation for a number of currently poorly understood clinical observations regarding CO poisoning.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiovascular System; Disease Models, Animal; Hemorrhage; Hypotension; Lipid Peroxidation; Male; Rats; Rats, Inbred Strains; Thromboxane B2

Mesenteric traction syndrome consists of sudden tachycardia, hypotension, and cutaneous hyperemia, and frequently occurs during mesenteric traction in patients undergoing abdominal aortic aneurysm (AAA) reconstructive surgery. The etiology and clinical impact of this phenomenon are unknown, but the symptoms suggest a release of vasoactive materials from the mesenteric vascular bed. Thirty-one patients who underwent AAA surgery were studied. Mesenteric traction was accompanied by a decrease in systolic (p = 0.005) and diastolic (p less than 0.05) blood pressures, and in systemic vascular resistance (p less than 0.005), and was accompanied by an increase in heart rate (HR) (p less than 0.005), and cardiac output (p = 0.01). These hemodynamic changes coincided with an increase (p less than 0.001) in plasma concentrations of 6-keto-prostaglandin F1 (6-K-PGF1). No apparent change was found in prostaglandin E2, thromboxane B2, and histamine concentrations. The concentration of 6-K-PGF1 was correlated with diastolic blood pressure (r = -0.52, p less than 0.005) and HR (r = 0.65, p less than 0.001). Cutaneous hyperemia was observed in 58% of the patients. In an additional six patients, who had taken aspirin daily before AAA surgery, no significant changes were observed in the hemodynamic measurements or 6-K-PGF1 concentrations. These data suggest that mesenteric traction syndrome may be mediated at least in part by a selective release of prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Anesthesia, General; Aortic Aneurysm; Epoprostenol; Female; Flushing; Humans; Hypotension; Intraoperative Complications; Male; Mesenteric Arteries; Mesenteric Veins; Middle Aged; Syndrome; Tachycardia; Thromboxane B2

The effects of lysine vasopressin (LVP) on pial arteriolar diameter and cortical periarachnoid fluid prostanoid concentrations were investigated in newborn pigs. Chloralose-anesthetized piglets were equipped with closed cranial windows over the parietal cortex for observation of pial arterioles and collection of cerebrospinal fluid (CSF) passing over the cerebral surface. Prostanoids in the CSF were determined by radioimmunoassay. LVP (10-1,000 microU/ml) elicited concentration-dependent increases in pial arteriolar diameter associated with increased levels of 6-keto-prostaglandin (PG)F1 alpha, PGE2, thromboxane B2, and PGF2 alpha. LVP-induced pial arteriolar dilation was unchanged after intravenous indomethacin (5 mg/kg). Conversely, LVP constricts pial arterioles previously dilated by physiological (hemorrhagic hypotension) and pharmacological (topically applied PGE2 or isoproterenol) intervention. This constriction is potentiated by indomethacin. Vascular and biochemical changes elicited by LVP were blocked by intravenous [1-(beta-mercapto-beta beta-cyclopentamethylene propionic acid),2,(O-methyl)-Tyr-AVP] (5 micrograms/kg), a putative V1 receptor antagonist, whereas vascular effects of norepinephrine and U46619, a thromboxane A2 mimic, were unchanged. Therefore, the degree of vascular tone appears to influence responses of the newborn pig cerebral circulation to LVP.

Topics: Animals; Animals, Newborn; Arginine Vasopressin; Arterioles; Blood Pressure; Hemorrhage; Hypotension; Isoproterenol; Lypressin; Pia Mater; Prostaglandins; Swine; Thromboxane B2; Vasoconstriction; Vasodilation

Pulmonary insufficiency is a major cause for mortality and morbidity following shock and sepsis. We studied the effect of hemorrhagic shock and retransfusion on endotoxin-induced lung dysfunction. Eighteen unanesthetized sheep with chronic lung lymph fistulae were divided into 3 groups. In Group I (n = 5) hemorrhagic shock of 50 torr was induced by arterial bleeding. Shed blood was retransfused after 4 h, and the animals were observed for 5 h. In Group II (n = 7) 1 microgramg/kg E. coli endotoxin was injected intravenously, and the animals were observed for 5 h. In Group III (n = 6) hemorrhagic shock was induced similarly to Group I. After 2 h of hypotension, E. coli endotoxin was injected similarly to Group II. Blood was retransfused after 4 h. During hemorrhagic shock arterial oxygen tension (PaO2) increased from 78.0 to 94.0 torr (P less than 0.005), lymph flow (QL) decreased from 7.2 to 5.2 ml/h (P less than 0.05) and lymph protein clearance (L/P.QL) from 4.6 to 3.3 ml/h (P less than 0.05). Calculated pulmonary microvascular pressure (Pmv) decreased from 11.1 to 7.0 torr (P less than 0.05). Plasma TXB2 increased from 197 to 967 pg/ml (P less than 0.05) and lymph TXB2 from 272 to 833 pg/ml (P less than 0.05). Endotoxin infusion was followed by a fall in WBC to 2,900/microliters (P less than 0.001), rise in pulmonary artery pressure (Ppl) from 17.5 to 49.7 torr (P less than 0.005), and Pmv from 12.1 to 23.7 torr (P less than 0.01). PaO2 decreased from 78.0 to 61.0 torr (P less than 0.01), QL increased to 36.9 ml/h (P less than 0.001), and L/P.QL to 24.3 ml/h (P less than 0.001). Plasma TXB2 increased to 7,600 pg/ml (P less than 0.005) and 6-Keto PGF1 alpha to 1,519 pg/ml (P less than 0.01). Infusion of endotoxin during hemorrhagic shock was followed by a comparable fall in WBC, pulmonary hypertensive response and hypoxemia, while Pmv increased only to 19.2 torr which was significantly lower than Group II (P less than 0.05). The rise in QL to 17.4 and L/P.QL to 10.6 ml/h in response to endotoxin was also significantly lower than Group II (P less than 0.05 and P less than 0.05, respectively). Plasma and lymph TXB2 and 6-Keto PGF1 alpha were unchanged. It is concluded that hemorrhagic shock reduced endotoxin-induced pulmonary microvascular pressure, pulmonary lymph production and protein flux, while the fall in WBC, early pulmonary hypertensive phase, hypoxemia, and prostanoid production were not altered by the hypotensive insult.

Topics: Animals; Endotoxins; Hemodynamics; Hypotension; Leukocyte Count; Lung; Lung Injury; Lymph; Oxygen; Pulmonary Circulation; Sheep; Shock, Hemorrhagic; Thromboxane B2

Effects of hypotensive hemorrhage on pial arteriolar diameter and cortical subarachnoid fluid prostanoid concentrations were investigated in newborn pigs. Chloralose-anesthetized piglets were equipped with closed cranial windows over the parietal cortex for observation of pial arterioles and collection of cerebrospinal fluid (CSF) passing over the cerebral surface (cortical subarachnoid CSF). Prostanoids in the CSF were determined by radioimmunoassay. Measurements of pial arterioles were made during normotension (63 +/- 4 mmHg) and hypotension (28 +/- 3 mmHg). Hypotension caused pial arteriolar diameters to increase from 162 +/- 22 to 193 +/- 22 microns. During normotension, the cortical subarachnoid prostanoid concentrations were (in ng/ml) prostaglandin E2 (PGE2) 2.6 +/- 0.7, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) 1.7 +/- 0.4, thromboxane B2 (TXB2) 0.25 +/- 0.02. Hypotension caused 6-keto-PGF1 alpha to increase 245 +/- 104% and PGE2 to increase 132 +/- 38%. TXB2 increased slightly (37 +/- 21%). Topical application of PGE2 and prostacyclin caused marked dilation of pial arterioles. Treatment of hypotensive newborn pigs with indomethacin caused constriction of pial arterioles to diameters not significantly different from the normotensive diameters. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow during hypotension in piglets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arterioles; Cerebral Arteries; Cerebrovascular Circulation; Dinoprostone; Epoprostenol; Female; Hypotension; Indomethacin; Male; Prostaglandins; Prostaglandins E; Swine; Thromboxane B2; Vasodilation

Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.

Topics: Adolescent; Adult; Aged; Cell Aggregation; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Epoprostenol; Female; Granulocytes; Humans; Hypotension; Infections; Male; Middle Aged; Prospective Studies; Prostaglandins; Radioimmunoassay; Shock, Septic; Thromboxane B2

Perinatal cerebral infarction is a not uncommon finding in newborn babies surviving intensive care. Asphyxia, with its attendant hypotension, is the most common cause of this problem and may result in neuropathological changes in the periventricular white matter. Previous studies have demonstrated uncoupling of cerebral blood flow and metabolism in the periventricular white matter regions of newborn beagle pups exposed to hemorrhagic hypotension. This work examines the effects of hypotension on serum and regional cerebral prostaglandin levels in the newborn beagle pup. The animals were anesthetized, tracheostomized, and paralyzed. Pups were randomly assigned to two groups: one was subjected to hemorrhagic hypotension and the other received no insult. Hypotension was induced by slow venous hemorrhage calculated to maintain a mean arterial blood pressure at 20 to 30 mm Hg. Serum prostaglandin determinations were made immediately before and 15 minutes after random assignment to hypotension or control groups. In addition, regional cerebral prostaglandin determinations were performed 15 minutes after randomization. Analysis of the serum prostaglandin data revealed that there were no significant differences in the values for thromboxane B2 or 6-keto-prostaglandin (PG) F1 alpha, which are the stable breakdown products of thromboxane A2 and prostacyclin, respectively. Prostaglandin E2 levels increased in response to hemorrhagic hypotension insult. Regional cerebral prostaglandin determinations demonstrated decreases in thromboxane B2 and 6-keto-PGF1 alpha in both gray and white matter. Although gray matter PGE2 was increased in pups exposed to hemorrhagic hypotension, this increase was not found in the periventricular white matter of injured pups. This regional difference in PGE2 synthesis in response to insult may explain the periventricular white matter neuropathological changes attributed to it.

Topics: Animals; Animals, Newborn; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Hypotension; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane B2

The effect of haemorrhagic hypotension on the levels of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical tissue of rats was studied. Lightly anesthetized rats were subjected to steady-state hypotension for 15 min, with a mean arterial blood pressure of 80, 60, and 40 mm Hg, and compared to a control group of normotensive rats. No significant change was found in the levels of PGE2 and TXB2. The level of 6-keto-PGF1 alpha increased from 7.8 +/- 0.9 to 14.1 +/- 1.9 pg/mg protein (p less than 0.02) at 80 mm Hg. Our findings suggest that prostacyclin, which is a potent vasodilator, might play a role in setting the lower limit of the autoregulation range.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Brain; Dinoprostone; Epoprostenol; Hemorrhage; Homeostasis; Hypotension; Male; Prostaglandins E; Rats; Thromboxane B2

Embolisation of blood clots produced an increased pulmonary artery pressure in vitro and systemic hypotension in vivo. In control anaesthetized animals, systemic blood pressure fell by 44.9 +/- 28.0 mm Hg following embolisation and 40% of the animals died within 5 minutes of embolisation. Plasma concentrations of thromboxane B2 (TXB222222 2) and 6-keto-prostaglandin F 1 alpha (6-keto-PGF 1 alpha) were increased by 0.54 +/- 0.13 ng/ml and 0.41 +/- 0.25 ng/ml, respectively. Pretreatment of animals with aspirin (ASA), 5 mg/kg or 250 mg/kg, reduced the hypotensive response and the TXB 2 and 6-keto-PGF 1 alpha release. Embolisation of isolated lungs perfused with blood-free medium induced an increase in pulmonary artery pressure of 32.7 +/- 21.0 mm Hg and significantly increased the content of TXB 2 and 6-keto-PGF 1 alpha in the perfusate. Pretreatment of lungs with indomethacin, 10 micrograms/ml, reduced the mean pulmonary pressure response to embolisation to 10.6 +/- 4.9 mm Hg and blocked the appearance of TXB 2 in the perfusate. Embolisation with an agarose clot induced only a 2.58 +/- 0.8 mm Hg increase in pressure and no detectable TXB 2 release. These results indicate that embolisation of lungs with a blood clot induces the release of TXB 2 and 6-keto-PGF 1 alpha. The release of these mediators, the hemodynamic responses and mortality were blocked by ASA pretreatment.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia, General; Animals; Aspirin; Hypotension; Indomethacin; Lung; Male; Perfusion; Pressure; Pulmonary Artery; Pulmonary Embolism; Rabbits; Thromboxane B2; Thromboxanes