Plasma Prostanoid Research Articles

Role of Prostanoids in the Regulation of Cerebral Blood Flow During Normoxia and Hypoxia in the Fetal Sheep

The fetal cardiovascular responses to hypoxia include decreased peripheral blood flow and increased cerebral, cardiac, and adrenal blood flow. Prostanoids, metabolites of cyclooxygenase enzyme activity, have potent effects on vascular tone in both the adult and the fetus. To examine the role of prostanoids in the regulation of fetal cerebral blood flow (CBF) during acute hypoxic stress, eight near term fetal sheep were studied after infusing vehicle or diclofenac, a cyclooxygenase inhibitor, followed by a 30-min period of hypoxia (arterial Po(2) 12 Torr). In the control experiments, CBF, measured continuously with laser Doppler flowmetry, increased to 148% of baseline values (p < 0.01) and cerebral vascular resistance decreased to 70% of baseline values after 30 min of hypoxic stress. During diclofenac infusion, hypoxia resulted in a CBF increase to only 129% of baseline, a significant attenuation (p < 0.05), accompanied by decreased plasma prostanoid concentrations. Increases in mean arterial blood pressure during hypoxia were also attenuated by diclofenac infusion. Flow and pressure responses were not accompanied by changes in cerebral vascular resistance. These results indicate that prostanoids indirectly modulate fetal CBF responses to hypoxia, but that their effects are mediated through modulation of systemic rather than cerebral vascular tone.

An imbalance in plasma prostanoids in patients with Raynaud's phenomenon and pulmonary vasospasm.

Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p<0.01) and decreased significantly in responders (p<0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p<0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p<0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon.

Serial changes of the plasma prostanoids during myocardial ischemia — reperfusion in swine. Effects of magnesium, diltiazem, and a novel Mac-1 inhibitor

The key role of prostanoids has been recognized in patients with ischemic heart disease. However, serial changes of thromboxane and prostacyclin during both brief and prolonged ischemia-reperfusion are poorly known. These plasma prostanoids were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on the level of the stable metabolites of thromboxane (TXB 2) and prostacyclin (6-keto-PGF 1α) were elucidated. Forty-nine swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. The occlusion phase was associated with a decline of plasma prostanoids, followed by a significant increase during reperfusion. Mg and diltiazem similarly affected plasma prostanoids by reducing TXB 2 release at 1 h of reperfusion. There was, however, no effect on plasma 6-keto-PGF 1α. The Mac-1 inhibition was associated with stabilization of both antagonistic prostanoids as well. Ability of Mg, diltiazem, and leumedins to favorably modulate plasma prostanoid levels have direct clinical implications for the use of these agents in patients with coronary artery disease.

健常小児における尿中１１−ｄｅｈｙｄｒｏ−ｔｈｒｏｍｂｏｘａｎｅ Ｂ２および２，３−ｄｉｎｏｒ−６−ｋｅｔｏ‐ｐｒｏｓｔａｇｌａｎｄｉｎ Ｆ１αの測定

We measured levels of 11-dehydro-thromboxane B2 (11DT) and 2, 3-dinor-6-ketoprostaglandin F1α (23D6) in samples of urine collected at rest early in the morning from 72 normal children (36 boys and 36 girls), ranging in age from 1 to 18 years. Prostaglandins (PGs) were extracted from acidified sample by octadecylsilyl silica (Fuji Gel, Tokyo) suspension. After deproteinization and defattation were performed, PGs were eluted by ethylacetate. Then the dried residue containing PGs were fractionated by silica minicolumn BOND ELUT Si (Varian, Harbor City, Calif.) . We assayed PGs using RIA method.No significant sex-related differences were observed in urinary 11DT or 23D6 levels. Urinary levels of 11DT and 23D6 were significantly high during the latter half of infancy (between 1 and 3 years after birth), and they tended to decrease gradually with age thereafter, without showing any further particularly marked change until puberty.11DT and 23D6 are major metabolites of thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) eliminated by way of urine, respectively. Their levels in urine are promising as indicators of systemic TXA2 and PGI2 production and replace the place of plasma prostanoid levels, a less reliable indicator conventionally used.

Sickle cell vaso-occlusive crisis is associated with abnormalities in the ratio of vasoconstrictor to vasodilator prostanoids.

Plasma levels of 6-keto-prostaglandin F1 alpha (6kPGF1 alpha) and thromboxane (Tx) B2 have been assessed in sickle cell disease (SCD) with discrepant results. Inasmuch as direct measurement of plasma prostanoids is fraught with the problem of interfering substances, we assessed plasma 6kPGF1 alpha and TxB2 levels in patients with SCD by RIA after extraction of eicosanoids and separation by HPLC. We demonstrate that the 6kPGF1 alpha and TxB2 levels in children with SCD in steady state as well as in vaso-occlusive crisis (VOC) are significantly lower when compared with those from age-matched controls. The VOC plasma 6kPGF1 alpha and TxB2 levels were, however, significantly elevated when compared with those from children in steady state. Changes similar to those noted with unpaired plasma samples were also observed when paired steady state and VOC plasmas from the same patients were assessed. The ratio of TxB2 to 6kPGF1 alpha was, however, significantly elevated in patients with SCD in crisis when compared with eicosanoid ratios obtained during steady state. In an attempt to understand whether the abnormality in 6kPGF1 alpha was due to an impairment in endothelial cell prostacyclin-regenerating ability, we compared the ability of plasma from controls and children with SCD to activate arachidonic acid (AA) release and prostacyclin production by [14C]AA-prelabeled bovine aortic endothelial cells. Our results suggest that the decreased 6kPGF1 alpha levels in plasma from children with SCD was not due to an effect on substrate AA release but rather a modulatory effect of sickle plasma components on endothelial cell cyclooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of dietary fatty acids and vitamin E on plasma prostanoids and liver microsomal alkane production in broiler chickens with regard to nutritional encephalomalacia.

Nutritional encephalomalacia (NE) in broiler chicken is considered as a peroxidative dysfunction caused by vitamin E-deficient diets. A feeding experiment was performed to investigate the consequences of feeding different fats in combination with increasing amounts of vitamin E on liver lipid peroxidation and plasma prostanoid pattern. Newly hatched chicks from hens on a vitamin E-poor diet were fed with either mainly linolenic, linoleic or oleic acid-rich oils in a vitamin E-deficient (5 ppm) basic diet. The animals were supplemented with vitamin E on three levels (0, 20 or 120 ppm). On appearance of the first symptoms of NE after 8 days post-hatching, the animals were examined. Typical symptoms with a high incidence only occurred in the group fed linoleic acid and 5 ppm vitamin E. Plasma prostanoids and microsomal alkane production in liver as a measure of endogenous lipid peroxidation were determined. The dietary conditions affected plasma prostaglandin E2 and thromboxane A2, but not prostacyclin. However, it seems unlikely that the prostanoids are involved in the pathogenesis of NE. Liver lipid peroxidation increased in vitamin E deficiency. The level of alkanes depended on the type of fat supplied. The consequences of the different dietary fats in combination with vitamin E deficiency on peroxidative metabolism of broiler chickens are evident, indicating that a high level of oxidative stress is imposed by the linoleic acid-rich fat.

Time Course of Systemic and Renal Plasma Prostanoid Concentrations and Renal Function in Ovine Hyperdynamic Sepsis

1. We continuously recorded systemic and renal haemodynamic changes, and arterial, renal venous and urinary concentrations of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2, and determined their relationship to renal function in an ovine model of progressive hyperdynamic sepsis. 2. Nine chronically instrumented unanaesthetized sheep were given a continuous intravenous infusion of Escherichia coli endotoxin (20 ng min-1 kg-1) for 3 days. 3. Within the first 12 h of infusion, endotoxin induced a major hypotensive septic syndrome, including a persistent 30% reduction in mean arterial pressure, a 50% decrease in systemic vascular resistance and a 50% increase in mean pulmonary artery pressure, associated with severe lactacidaemia. 4. Renal blood flow decreased by 40%, and creatinine clearance, urine flow, and fractional sodium excretion decreased by more than 75%, of baseline values. After 12 h of endotoxin infusion, cardiac output increased two-fold and renal blood flow recovered to baseline values, whereas creatinine clearance remained depressed. Four sheep died between 13 and 22 h of endotoxaemia; these animals (allocated to group 1) presented a significantly and persistently more reduced renal blood flow (-23%) and creatinine clearance (-77%) after 4 h than the remaining five sheep (allocated to group 2), which survived more than 36 h (-16% and -21%, respectively), whereas systemic and pulmonary haemodynamic and gas exchange data remained similar in both groups. 5. The more pronounced decreases in renal blood flow, creatinine clearance and urine flow in group 1 were associated with higher plasma renin activity and plasma 6-keto-prostaglandin F1 alpha concentrations and a lower fractional urinary excretion of 6-keto-prostaglandin F1 alpha than in group 2, whereas plasma thromboxane B2 concentrations were similarly increased in both groups. Plasma prostaglandin E2 concentrations and urinary excretion were not notably affected by endotoxin infusion in either group. 6. Our results are not in favour of a significant renal production of any of these three prostanoids during endotoxaemia. In both groups, values of creatinine clearance were linearly correlated with simultaneous mean arterial pressure values after starting endotoxin infusion (group 1: creatinine clearance = 1.99 x mean arterial pressure--105, r = 0.95; group 2: creatinine clearance = 2.06 x mean arterial pressure--104, r = 0.80).(ABSTRACT TRUNCATED AT 400 WORDS)

Normalization of impaired response of platelets to prostaglandin [formula omitted] and synthesis of prostacyclin by insulin in unstable angina pectoris and in acute myocardial infarction

The minimal inhibitory concentration of prostaglandin e 1 (used as a probe for prostacyclin [PGI 2]) needed to inhibit platelet aggregation (36 ± 16 nM) in normal volunteers (n = 40) increased (64 ± 30 nM) in patients (n = 46) with acute coronary artery disease. Bolus injection of insulin in 20 patients, 0.1 U/kg body weight 4 times a day (every 6 hours) for 7 days decreased the minimal inhibitory concentration of prostaglandin E 1 from 64 ± 30 to 26 ± 12 nM (p < 0.001). Twenty other patients who received only saline solution had no decrease in minimal inhibitory concentration of the prostanoid. The bolus injection of insulin also increased the plasma level of PGI 2 (9 ± 2 pM) two-fold in these patients (28 ± 10 pM). Administration of aspirin inhibited the insulin-induced increase of plasma prostanoid level. Patients in the placebo group had no increase in plasma PGI 2 level. The bolus injection of insulin administered only once to another group of patients (n = 6) demonstrated that the hormonal effects were maximally increased within an hour of insulin administration, and were directly related to the increased insulin level in plasma. These results indicated the feasibility of using physiologic quantities of insulin for controlling of platelet aggregation through resensitization of platelet response to prostaglandin and increased synthesis of PGI 2 in vivo in acute coronary artery disease.

Effect of glutathione depletion on tissue and plasma prostacyclin and thromboxane in rats

Experiments were designed to determine the effects of glutathione (GSH) depletion with l-buthionine sulfoximine (BSO) or diethyl maleate (DEM) on tissue and plasma prostacyclin (6-ketoPGF 1α) and thromboxane (TxB 2) levels in male Sprague-Dawley rats. Despite depleting hepatic GSH to as much as 34% of control, BSO at various levels (0.4, 0.8 and 1.2 g/kg body wt) had no effect on hepatic, renal, pulmonary or cardiac tissue levels of 6-ketoPGF 1α and TxB 2 or circulating levels of 6-ketoPGF 1α in portal or arterial plasma. When rats were pretreated with 3-methylcholanthrene (3-MC) to induce cytochrome P450, BSO (0.8 g/kg body wt) also had no effect on tissue or plasma prostanoid levels with the exception of a slight, but significant, increase in hepatic 6-ketoPGF 1α in non-induced rats. In contrast, depletions of hepatic, renal and pulmonary tissue GSH by DEM (1 mL/kg body wt) to 12, 50 and 30% of control, respectively, were associated with elevations of 6-ketoPGF 1α in these tissues and in plasma obtained by right ventricular heart puncture. Pretreatment of rats with 3-MC had no significant effect on tissue GSH or prostanoid levels in controls or DEM-treated rats but plasma levels of 6-ketoPGF 1α were lower in comparison to non-induced rats. DEM with or without 3-MC pretreatment was associated with increased TxB 2 in renal tissue, whereas DEM elevated TxB 2 only in pulmonary tissue from non-induced rats. It appears that factors besides GSH depletion may be required to raise plasma and/or tissue 6-ketoPGF 1α levels in vivo.

Sustained effects of endothelin-1 on rabbit, dog, and rat pulmonary circulations

Effects of endothelin-1 (10(-8) M) on the pulmonary vascular resistance-compliance profile were examined in isolated blood-perfused rabbit, dog, and rat lungs using occlusion techniques. Capillary permeability was assessed by filtration coefficient (Kfc). Cyclooxygenase products were assessed by radioimmunoassay. In rabbit lungs, endothelin-1 increased all resistances except large vein; ibuprofen reversed the constriction. Endothelin-1 decreased total vascular compliance (CT), which was reversed by ibuprofen. Cyclooxygenase products were unchanged by endothelin-1 or endothelin-1 plus ibuprofen. In dog lungs, large vein resistance increased after endothelin-1; ibuprofen increased large arterial resistance. Endothelin-1 decreased CT and middle compartment compliance, and endothelin-1 plus ibuprofen decreased large vessel compliance (CLV). Ibuprofen reversed the endothelin-1 increase in plasma 6-oxo-prostaglandin F1 alpha. In rat lungs, ibuprofen reversed the endothelin-1 increase in small arterial resistance. Endothelin-1 decreased CLV, and endothelin-1 plus ibuprofen returned the compliance to baseline values. Ibuprofen potentiated the endothelin-1 increase in plasma prostanoids. Endothelin-1 plus indomethacin increased vascular resistance and blocked prostaglandin production. Kfc was increased only in rat lung after endothelin-1 plus ibuprofen. In summary, endothelin-1 increased pulmonary vascular resistance, which was attenuated by prostacyclin in dogs and rats. In rabbits, the resistance increase was reversed by ibuprofen.

The Complex Pattern of Cytokines in Sepsis Association Between Prostaglandins, Cachectin, and Interleukins

Although the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are important mediators of hemodynamic, metabolic, and immunologic alterations in the host during sepsis, it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p less than 0.05) of plasma TNF until 10 hours, steadily increasing (p less than 0.05) IL-1 plasma levels, and enhanced (p less than 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p less than 0.05) at 5 hours (153 +/- 29 pg/mL; control: 47 +/- 11 pg/mL) and 10 hours (96 +/- 16 pg/mL; control: 21 +/- 5 pg/mL). Prostaglandin E2 production by splenic macrophages (sM phi) from septic animals was increased (p less than 0.05) at 5 hours (9.1 +/- 2.2 ng/mL) and 10 hours (5.6 +/- 1.5 ng/mL) compared to controls (3.3 +/- 0.3 ng/mL at 5 hours; 1.3 +/- 1.3 ng/mL at 10 hours). Incubation of sM phi from septic animals with ibuprofen enhanced (p less than 0.05) IL-1 and TNF synthesis, while IL-6 production was reduced (p less than 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis.

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Plasma prostanoids in neonatal extracorporeal membrane oxygenation: Influence of meconium aspiration

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.

Plasma 6-keto-PGF 1α, thromboxane B 2 and PGE 2 during diabetic ketoacidosis

In 10 patients admitted to hospital with diabetic ketoacidosis plasma prostanoids 6-keto-PGF ∞ thromboxane B 2 and PGE 2 were studied before treatment and following recovery. During ketoacidosis the median plasma 6-keto-PGF 1α and PGE 2 were significantly increased compared to those of a normal reference group: 5.2 pg/ml and 3.9 pg/ml versus 1.7 pg/ml and 0.4 pg/ml (p< 0.01and p<0.05). In response to therapy both prostanoids decreased significantly towards a normal level, 6-keto-PGF 1α: 0.5 pg/ml p<0.01 and PGE 2: 0.08 p<0.05 respectively. The changes in plasma 6-keto-PGF 1α were negatively correlated to changes in pH, rho: −0.7788 p = 0.0135, whereas the changes in PGE 2 were positively correlated to serum creatinine at admittance, rho: 0.6976, p = 0.0368 and to the amount of intravenous fluid and insulin used during treatment, rho: 0.7500 p = 0.0126 and rho: 0.8424, p = 0.0023 respectively. Plasma thromboxane B 2 concentrations were not elevate and did not change after treatment of the ketoacidosis.

5‐Hydroxytryptamine and arachidonic acid metabolites modulate extensive platelet activation induced by collagen in cats in vivo

1. The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2. The intra-aortic infusion of collagen (100 micrograms kg-1 in 1 min) caused an extensive activation of platelets, as evidenced by the time-dependent drop of free platelet numbers in whole blood, and the increases of 5-hydroxyindoles (5-HI), 5-hydroxytryptamine (5-HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3. 5-HT2 receptor blockade with ketanserin (0.63 mg kg-1 i.v., 10 min) and cyclo-oxygenase inhibition with aspirin (10 mg kg-1 i.v., 10 min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5-HI. Aspirin, but not ketanserin, reduced the collagen-induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K-PGF1 alpha. 4. Dual TXA2 synthetase inhibition/TXA2-prostaglandin endoperoxide receptor antagonism with ridogrel (5 mg kg-1 i.v., 10 min) halved the drop in free platelets, reduced the release of platelet 5-HI, inhibited the increase in plasma TXB2 and elevated that of 6K-PGF1 alpha and PGE2 in response to collagen. 5. Combined treatment with ketanserin and aspirin reduced the collagen-induced drop of free platelets and the release of platelet 5-HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 6. Combined administration of ketanserin and ridogrel virtually eliminated the collagen-induced platelet adhesion/aggregation response and release of 5-HI; prostanoids were affected as with ridogrel alone. 7. The results indicate that the interplay between 5-HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.

Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.

Sperm function and structure and seminal plasma prostanoid concentrations in men with IDDM.

Semen from 18 men with insulin-dependent diabetes mellitus (IDDM) aged 20-40 yr was compared with that from 15 age-matched control subjects. Although semen volume, sperm count, and spermatozoal motility were similar in the two groups, semen from diabetic men had significantly greater numbers of abnormal spermatozoa and significantly lower ability to penetrate hamster eggs. Concentrations of prostaglandins E2, F2 alpha, and I2 and thromboxane A2 were significantly elevated in the seminal plasma from semen of diabetic subjects compared with control subjects. These observations indicate the need for a careful assessment of fertility in diabetic men, the mechanisms underlying the abnormalities in spermatozoa, and the relationship of these abnormalities to the increase in prostanoid concentrations in diabetic men.

Prostanoids and catecholamines after oral administration of natural progesterone.

Natural exogenous progesterone has been shown to affect the functioning of the central nervous system in man, inducing dizziness and sedation by unknown mechanisms. Seven postclimacteric women known to suffer from dizziness during natural progesterone therapy were treated with a single oral dose of 200 mg of natural progesterone on 2 occasions, with and without preceding administration of indomethacin. Cardiovascular responses, vasoactive prostanoids and catecholamines in the blood, and excretion of prostanoids in the urine were measured. Serum progesterone concentrations increased in each subject, and all the women experienced dizziness or tiredness after progesterone intake. Blood pressure and heart rate did not change. Urine excretion of immunoreactive prostaglandin E2 and 6-keto-prostaglandin1 alpha decreased significantly in the experiment without pretreatment with indomethacin, whereas indomethacin pretreatment reduced the basal excretion of prostanoids and abolished the progesterone-induced decrease in their excretion. The plasma concentrations of prostanoids and catecholamines did not change. The results confirm that natural progesterone can cause dizziness and tiredness in man. The appearance of these symptoms is not related to peripheral vasodilation or to changes in plasma prostanoid or catecholamine levels. Neither are the symptoms related to the alteration in the urinary excretion of prostanoids, since the women still suffered from tiredness and dizziness after pretreatment with indomethacin.

Thromboxane Mediation of Pulmonary Hemodynamic Responses after Neutralization of Heparin by Protamine in Pigs

Protamine neutralization of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension and systemic hypotension. Because prostanoids may be involved, the authors studied the role of arachidonic acid metabolites, especially thromboxane A2, in this process. During anesthesia with enflurane and fentanyl, four groups of pigs were studied: Group 1 (n = 10) received heparin (250 IU/kg), followed by protamine (100 mg) after 15 minutes to neutralize the heparin. The same protocol was used in group 2 (n = 11), except that the thromboxane A2 receptor antagonist BM 13.177 (10 mg/kg) was infused 5 minutes before the protamine. The protocol for group 1 was also used for group 3 (n = 7) except that these animals were pretreated with indomethacin (10 mg/kg). Animals in group 4 (n = 10) were given protamine only (100 mg). Pulmonary artery pressure and pulmonary vascular resistance increased significantly in group 1 after protamine neutralization of heparin. This was accompanied by significant increases in plasma concentrations of the cyclooxygenase products thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin F2 alpha. Cyclooxygenase products increased to comparable degrees in group 2, but without hemodynamic effects. Leukocyte counts decreased comparably in both groups. Hemodynamic reactions, as well as changes in plasma prostanoid levels were absent in group 3, and group 4, but leukocyte counts were less affected in animals that received protamine alone. The results indicate that the hemodynamic side-effects of protamine are mediated by prostanoids and that thromboxane A2 release is the pivotal step, because side effects were effectively prevented by pretreatment with a thromboxane receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement activation and membrane lipids in lung vascular injury.

Intravascular complement activation induces a rapid neutropenia and transient hypotension in laboratory animals such as rabbits. Injection of purified C5a causes similar hemodynamic events, and the hematologic changes suggest involvement of components such as polymorphonuclear leukocyte (PMN) and mediators including vasoamines and prostanoids. The anaphylatoxin-induced hypotension coincided with an increase in central venous pressure (CVP), decreased cardiac output (CO), increased plasma prostanoid levels, and neutropenia. These phenomena were repeatable in the animals when C5a was administered as a bolus 45 min after the initial treatment. Animals pretreated with indomethacin failed to exhibit the hypotensive response to C5a but still exhibited the transient neutropenia. Indomethacin effectively eliminated prostanoid release into plasma as expected. Administration of H2, but not H1, histamine-receptor antagonists reduced both C5a-induced hypotension and prostanoid release, suggesting that histamine may contribute to the C5a response in rabbits. Animals rendered neutropenic with nitrogen mustard prior to C5a challenge respond normally to C5a infusion (i.e., elevated prostanoid release and hypotension). The mechanism that we proposed for C5a-induced hypotension requires vascular smooth muscle contraction to be predominant over peripheral vasodilation in affecting cardiac output. Neutropenia occurs as a parallel event to hypotension but seemingly has little influence on the hemodynamic response. Prostacyclin (PGI2) levels were elevated in C5a-treated animals, and this lipid mediator contributes to hypotension by enhancing peripheral vasodilation. Because plasma TGxB2, levels were also elevated and central venous pressure increased as cardiac output decreased in treatment animals, we concluded that thromboxane-dependent pulmonary vasoconstriction contributes significantly to the C5a hypotensive response.