The concentration of 6-keto-PGF1α and TXB2 in plasma samples from patients with benign and malignant tumours of the breast

Peripheral plasma concentrations of 6-keto-PGF_1α and TXB₂ were measured in patients with benign and malignant tumours of the breast, in patients with nongynecological disease,a nd in healthy female controls. The values were significantly higher in female patients with maligants tumours of the breast than in healthy controls (146 ± 28 vs 13 ± 2.5 pg/ml for 6-keto-PGF_1α p<0.01 and 78 ± 17 vs 11 ± 2 pg/ml for TXB₂, p<0.01). Benign tumours of the breast were also associated with significantly raised plasma levels of 6-keto-PGF_1α and TXB₂ compared to normal controls (52 ± 5 vs 13 ± 2.5 pg/ml for 6-keto-PGF_1α, p < 0.01 and 26 ± 5 vs 11 ± 2 pg/ml for TXB₂, p < 0.05). The high levels of 6-keto-PGF_1α and TXB₂ were not found to be correlated with clinical and histopathological data. The surgical removal of the primary tumour has apparently no effect on the plasma concentration of 6-keto-PGF_1α and TXB₂ over a follow-up period of 9 days after operation. The lack of alterations in the ratio of TXB₂: 6-keto-PGF_1α in the cancer patients and other subjects studied before and after surgery is indicative of the regulatory power of metabolic systems to preserve the homeostatic balance.     

Circulating prostacyclin and thromboxane in patients with graves' disease

We measured plasma levels of PGI₂ as 6-keto-prostaglandin F_la (6-keto-PGFla) and thromboxane A₂ (TXA₂) as thromboxane B₂ (TXB₂) in patients with Graves' disease and in normal subjects. The levels of plasma 6-keto-PGFla were significantly elevated and correlated with those of serum T₄ and T₃, respectively, in hyperthyroid patients with Graves' disease. Significant reduction of 6-keto-PGF_1a levels was observed after antithyroid drug therapy. In contrast, the levels of plasma TXB₂ were significantly lower in untreated patients with Graves disease than in normal subjects. These data suggest that an elevation of plasma 6-keto-PGF_1a may play some additional role in pathophysiology of Graves disease.     

Comparison of umbilical vein models for measurement of relative prostacyclin and thromboxane production

There is growing evidence that blood vessels generate TXA₂ in addition to PGI₂. We examined effluents from continously perfused human umbilical vein and supernatants from umbilical vein rings for TXB₂ and 6-keto-PGF_1α measurements (stable metabolites of TXA₂ and PGI₂, respectively). TXB₂ and 6-keto-PGF_1α were identified in all samples. 6-keto-PGF_1α to TXB₂ ratio was higher in intact vein effluents than in the venous ring supernatants (112:1 and 28:1, respectively, P<0.01). Arachidonate stimulation increased 6-keto-PGF_1α and TXB₂ levels similarly in the intact vein effluent. In contrast, stimulation of the venous rings resulted in a relatively larger increase in TXB₂ than in 6-keto-PGF_1α. This caused 6-keto-PGF_1α to TXB₂ ratio to decline (p<0.01). The identity of TXB₂ was confirmed in several different ways. These data suggest that 1) human umbilical veins produce TXA₂ in addition to PGI₂, 2) TXA₂ release is more by venous rings than by the intact vein probably reflecting contribution from non-endothelial layers, and 3) arachidonate stimulation causes relatively greater release of TXA₂ than of PGI₂ from the venous rings, whereas release of PGI₂ and TXA₂ is similar from the intact vein.     

Plasma prostaglandin levels and circulating fuel levels in rats with diabetic ketoacidosis: Effects of cyclooxygenase inhibitors and of alpha and beta adrenergic blockade

We studied the effects of two structurally unrelated inhibitors of the fatty acid cyclooxygenase and of alpha and beta adrenergic blockade on the elevated plasma levels of 13,14-dihydro-15-keto-prostaglandin (PG)E₂, 6-keto-PGF_1α and thromboxane(TX)B₂, the stable derivatives of PGE₂, PGI₂ (prostacyclin) and TXA₂, respectively, in rats with streptozotocin-induced diabetic ketoacidosis (DKA). Meclofenamic acid and indomethacin each produced a significant decrease in the elevated plasma levels of 13,14-dihydro-15-keto-PGE₂, 6-keto-PGF_1α and TXB₂. Phentolamine significantly reduced the plasma level of TXB₂ but had no effect on the elevated circulating levels of glucose, free fatty acids, total ketones, 13,14,-dihydro-15-keto-PGE₂ or 6-keto-PGF_1α. Propranolol significantly reduced the elevated circulating levels of glucose, free fatty acids and total ketones but had no effect on the levels of the three prostaglandin derivatives. The ability of meclofenamic acid and indomethacin to reduce the plasma levels of 13,14-dihydro-15-keto-PGE₂, 6-keto-PGF_1α and TXB₂ confirms that the plasma levels of these three derivatives are elevated in rats with DKA. Since abnormalities in the production of PGI₂ and perhaps other cyclooxygenase derivatives may contribute to the pathogenesis of certain important hemodynamic and gastrointestinal features of DKA, cyclooxygenase inhibitors may play a role in the management of selected patients with this disorder. Alpha adrenergic activity is essential for the maintenance of the elevated plasma TXB₂ level in rats with DKA. The fall in the plasma TXB₂ level during alpha adrenergic blockade appears to reflect inhibition of platelet aggregation and platelet TXA₂ production, but other sources of the elevated plasma TXB₂ level in DKA are not excluded. Beta adrenergic activity contributes to the maintenance of elevated circulating levels of glucose, free fatty acids and total ketones in experimental DKA but not to the elevated plasma levels of the prostaglandin derivatives.     

Modulation of the platelet thromboxane A2 and aortic prostacyclin synthesis by dietary selenium and vitamin E

Vitamin E and selenium (Se) interact synergistically as an important antioxidant defense mechanism. Se, an essential component of glutathione peroxidase (GSH-Px) and vitamin E decompose fatty acid hydroperoxides and hydrogen peroxides generated by free radical reactions. Vitamin E and GSH-Px may modulate arachidonic acid metabolism and the activity of cyclooxygenase enzymes by affecting peroxide concentration. The balance between arterial wall prostacyclin (PGI₂) production and platelet thromboxane (TX)A₂ directly influences platelet activity. In order to elucidate the differential role of dietary vitamin E and Se in aortic PGI₂ and platelet TXA₂ synthesis, 1-mo-old F344 rats were fed semipurified diets containing different levels of vitamin E (0, 30, 200 ppm) and Se (0, 0.1, 0.2 ppm) for 2 mo. Thromboxane B₂ (TXB₂) and 6-keto-PGF₁α, were measured by radioimmunoassay (RIA) after incubation of whole blood and aortic rings at 37°C for 10 and 30 min, respectively. Vitamin E deficiency reduced plasma vitamin E to 5–17% of control-fed rats, and supplementation increased it to 53% of the control-fed rats. Se supplementation in vitamin E-supplemented animals increased plasma GSH-Px by 17%, compared to vitamin E-deficient rats. Se and vitamin E supplementation did not have a similar effect on TXB₂ and PGI₂ synthesis. Se deficiency did not alter platelet TXB₂ synthesis, but significantly decreased aortic PGI₂ synthesis. It was necessary to supplement with both antioxidants in order to increase, PGI₂ synthesis. Se and vitamin E deficient groups had a higher TXB₂/PGI₂ ratio (0.17±0.08) compared to Se- and vitamin E-supplemented groups (0.03±0.01). These results confirm previous reports in humans and animals and are in accordance with epidemiological data indicating an inverse relationship between plasma Se and platelet aggregation. Thus, further suggesting that vitamin E and Se may have a specific role in controlling TXA₂ and PGI₂ synthesis.     

Atherosclerosis decreased prostacyclin formation in rabbit lungs and kidneys

Metabolism of arachidonic acid (AA) was studied in perfused lungs and kidneys of normal and atherosclerotic rabbits by determination of PGE₂, PGF_2α and the stable metabolites of PGI₂ (6-keto-PGF_1α) and TXA₂ (TXB₂). PGI₂ was the main AA metabolite formed by normal lungs and kidneys. Atherosclerosis reduced the formation of PGI₂ by about 50 % in both organs. TXA₂ formation was similarily decreased in lungs. In kidneys, the decrease in PGI₂ formation was accompanied by an increase in PGE₂ formation.     

Pulmonary formation of prostacyclin in man

The pulmonary formation of prostacyclin (PGI₂), as reflected by the difference in concentration of pulmonary and systematic arterial radioimmunoassayed 6-keto-PGF_1α, was determined in six healthy waking subjects. The systematic arterial 6-keto-PGF_1α levels were low (50 pg/ml), and no evidence of pulmonary formation and release of the compound was noted. In other experiments systemic arterial 6-keto-PGF_1α levels were determined in patients prior to and during artificial ventilation, as well as during and after occlusion of the pulmonary circulation (extra-corporeal circulation, ECC). The arterial 6-keto-PGF_1α concentration prior to artificial ventillation was 17±4 pg/ml, i.e. within the range observed in the healthy subjects. During artificial ventilation the arterial levels of 6-keto-PGF_1α increased to 191±21 pg/ml, suggesting that pulmonary formation of PGI₂ was stimulated. In the patients subjected to ECC with occluded pulmonary circulation the arterial content of 6-keto-PGF_1α was stabilised at an elevated level (120−170 pg/ml). Following re-establishment of the pulmonary circulation the arterial concentrations of 6-keto-PGF_1α increased markedly, to 284±50 pg/ml. It is suggested that the basal pulmonary formation of PGI₂ in man is low or non-existent, and that enhanced formation of the compound in the lungs is a consequence of intervention with normal pulmonary ventilation or perfusion.     

Consequences of long-term selenium-deficient diet on the prostacyclin and thromboxane release from rat aorta

It is known that peroxides, which are increased during Se deficiency because of reduced glutathione peroxidase (GSH-Px) activity, can influence the prostacyclin I₂/thromboxane A₂ (PGI₂/TXA₂) ratio. In this study we analyzed the PGI₂ and TXA₂ formation of aortas of long-term Se-deficient rats. Despite low GSH-Px activity in the Se-deficient group, the basal PGI₂ and TXA₂ formation was not different versus control animals (PGI₂: 2295 ± 1134 pg/mg vs 2940 ± 1134 pg/mg; TXA₂: 3.83 ± 1.06 pg/mg vs 5.67 ± 2.99 pg/mg). However, we checked the capacity of the aortas of Se-deficient rats to compensate for a suddenly increased peroxide concentration. After peroxide stimulation, the PGI₂ release was significantly lower in the Se-deficient group compared to the control group (PGI₂: 3507 ± 1829 pg/mg vs 7986 ± 2636 pg/mg). Again, the TXA₂ release did not show any differences. The release ratio of PGI₂/TXA₂ decreased under peroxide stress in Se-deficient animals. Although long-term Se deficiency showed a relatively well-balanced metabolism under resting conditions, sudden stress, accompanied by an excessive radical production, cannot be compensated.     

Prostacyclin and thromboxane formation in human umbilical arteries following stimulation with vasoactive autacoids

The formation of prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) (measured as the stable metabolites 6-keto-PGF_1α and TXB₂) during stimulation with vasoactive autocoids was registered in human umbilical arteries perfused . Responses were registered within 3–4 minutes after addition of the subtances. Both angiostensin I and II were found to increase the formation of PGI₂ while depressing that of TXA₂. Serotonin increased the formation of TXA₂ but not that of PGI₂. Both PGE₂ and PGF_2α stimulated the PGI₂ formation. The TXA₂ mimetic U46619, increased PGI₂ production, whereas PGI₂ slighlty increased the formation of TXA₂. All responses were found to be completely inhibited by indomethacin.     

Myocardial prostacyclin and thromboxane A2 synthetase activities during ischemia and reperfusion in isolated rabbit heart

The aim of the study was to determine the prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) synthetase activities of myocardial tissue and their variation during ischemia and reperfusion. Regional ischemia was induced by 10 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of PGI₂ and TXA₂ were carried out by using arachidonic acid as substrate and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as sources of PGI₂ and TXA₂ synthetase. 6-keto-PGF_1α and TXB₂, stable metabolites of PGI₂ and TXA₂ respectively, were determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM were able to synthetise PGI₂ as well as TXA₂ from arachidonic acid. On the other hand, ischemia depressed both PGI₂ and TXA₂ synthetase activities of cardiac tissue: the depression was more pronounced on TXA₂ synthetase than on PGI₂ synthetase with no significant difference between ischemic and non-ischemic regions. Moreover, ischemia increased the ratio indicating therefore that it can facilitate the formation of PGI₂. The post ischemic reperfusion of the heart counteracted the decrease in PGI₂ synthetase induced by ischemia which returned to the normal level: reperfusion also slightly reversed the decrease in TXA₂ synthetase. However, the diminution in TXA₂ synthetase of non-ischemic myocardium was attenuated but it remained lower than the normal level. These results suggested that the whole left ventricle is affected by regional ischemia. Furthermore it appears that myocardial TXA₂ synthetase is more vulnerable than PGI₂ synthetase to a lack of oxygen and nutrients.     

Release of 6-KETO-PGF1α and thromboxane B2 in late appearing cardioprotection induced by the stable PGI analogue: 7-OXO-PGI

We have shown earlier that prostacylin (PGI₂) and its stable analogue: 7-oxo-prostacyclin(7-OXO) may induce a prolonged, late appearing (24–48 h after drug administration), dose dependent protection of the heart from harmful consequences of a subsequent severe ischaemic stress, such as myocardial ischaemia, life-threatening ventricular arrhythmias and early ischaemic morphological changes. In an other study we observed that a similar but shortlived (less than 1 h) cardioprotection, induced by preconditioning brief coronary artery occlusions, is greatly reduced by blockade of the cyclooxygenase pathway, suggesting that prostanoids might play a role in this shortlasting protection.Objective of our present study was to elucidate the importance of some arachidonic acid (AA) metabolites, such as PGI₂ and thromboxane A₂ (TXA₂) in the mechanism of the late appearing, prolonged cardioprotection. Estimation of the metabolites: 6-keto-PGF₁ (6-KETO) and thromboxane B₂ (TXB₂) was made from the perfusate of isolated Langendorff hearts of guinea-pigs pretreated with 50 g/kg 7-OXO, 24 and 48 h before preparation. Pretreatment alone produced a slight, but significant elevation of 6-KETO (from 206±11 to 284±19 pg/ml/min after 24 h, and to 261±18 pg/ml/min after 48 h). No change was seen in TXB₂ production. Global ischaemia for 25 min (followed by 25 min reperfusion) markedly increased the release of both AA metabolites; maximal values were observed in the third min of reperfusion (6-KETO from 206±11 to 1275±55 pg/ml/min and TXB₂ from 29±4 to 172±12 pg/ml/min). All values returned to the preischaemic level by the 25th min of reperfusion. Ischaemic increase in 6-KETO level was significantly higher in the perfusate of hearts from pretreated animals (1507±73 pg/ml/min after 24 h, and 1398±54 pg/ml/min after 48 h) that in those of untreated controls. There was no difference in TXB₂ values. Thus both basal and ischaemic release of PGI₂ increased 24 and 48 h after pretreatment with 7-OXO but not TXA₂ production. Results suggest that endogenous prostanoids might play a role in late appearing cardioprotection.     

Hyperglycemia promotes elevated generation of TXA2 in isolated rat uteri

The relationship between high glucose concentrations and arachidonic acid metabolism in uterine tissue from control and diabetic ovariectomized rats was evaluated. Uterine tissue from diabetic rats produced amounts of PGE₂ and PGF_2α similar to controls, while a lower production of 6-keto-PGF_1α (indicating the production of prostacyclin) and a higher production of TXB₂ (indicating the generation of TXA₂) was found in the diabetic group. A group of diabetic rats was treated with phlorizin to diminish plasma glucose levels. Phlorizin treatment did not alter production of PGE₂, PGF_2α, and 6-keto-PGF_1α in the diabetic group. A diminished production of TXB₂ was found in the treated diabetic uteri when compared to the non-treated diabetic group. Moreover, a positive correlation between plasma glucose levels and uterine TXB₂ generation was observed. When control uterine tissue was exposed in vitro to high concentrations of glucose (22 mM) and compared to control tissue incubated in the presence of glucose 11 mM alterations in the generation of PGE₂, PGF_2α, and 6-keto-PGF_1α were not found, but a higher production of TXB₂ was observed and values were similar to those obtained in the diabetic tissue. Alteration in the production of the prostanoids evaluated were not observed when diabetic tissue was incubated in the presence of high concentrations of glucose. These results provide evidence of a direct relationship between plasma glucose levels and uterine production of TXA₂.     

Prostacyclin,thromboxane and prostaglandin F2αin suction blister fluid of human skin: Effect of systemic aspirin and local glucocorticosteroid treatment

Changes in prostaglandin (PG) metabolism are known to be involved in various skin diseases. To elucidate the behavior of hree vasoactive PGs in human skin, namely prostacyclin (PG1₂), thromboxane A₂ (TxA₂) and PGF_2α, their stable metabolites, 6-keto-PGF_1α. TxB₂, and 13, 14 dihydro-15-keto PGF_2α (MPGF_2α), respectively, were measured by radioimmunoassays in suction blister fluids of 29 healthy male subjects. Nine of them were treated with acetylsalicylic acid (0.5 g × 4/day for one day beforehand), eight with local glucocorticoid (clobetasol-17-propionate, Dermovat^R Cream, twice a day for seven days) and 12 served as controls. All three PGs were detected in blister fluid. In controls the mean (±SD) concentration of 6-keto-PGF_1α was 1160 ± 470 pg/ml (n=12) that of TxB₂ 1590 ± 610 pg/ml (n=12) and that of MPGF_2α 1800 ± 710 pg/ml (n=12), levels which are higher than the respective concentrations in human plasma. The preceding aspirin treatment decreased the 6-keto-PGF_1α levels by 40 % (P<0.005), the TxB₂ levels by 80 % (P<0.001) and MPGF_2α levels by 35 % (P<0.05), whereas the preceding local glucocorticoid caused no changes in these PG levels. The results show that 1) PG1₂, TxA₂, and PGF_2α are locally released in the suction blister fluid of healthy human skin, 2) systemic treatment with a PG synthesis inhibiting drug, acetysalicylic acid, reduces this release, and 3) locally applied clobetasol-17-propionate does not affect the levels of prostaglandins and thromboxane as measured by our methods.     

Effects of Danshensu on Platelet Aggregation and Thrombosis: In Vivo Arteriovenous Shunt and Venous Thrombosis Models in Rats

Danshensu, a type of dihydroxyphenyl lactic acid, is one of the most abundant active phenolic acids in the dried root of Salvia miltiorrhizae (Lamiaceae)—widely used traditional Chinese medicine. The effects of danshensu on platelet aggregation and thrombus formation in rats were examined using various methods. It was found that danshensu significantly reduced thrombus weight in 2 experimental thrombosis models; dose-dependent inhibition of adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation occurred in normal and blood stasis-induced rats; Danshensu also significantly mitigated blood viscosity, plasma viscosity and hematocrit levels. Moreover, danshensu significantly inhibited venous thrombosis-induced expression of cyclooxygenases-2 (COX-2) rather than cyclooxygenases-1(COX-1) in the venous walls, down regulated thromboxane B₂ (TXB₂) and up regulated 6-keto prostaglandin F_1α (6-keto-PGF_1α), normalizing the TXB₂/6-keto-PGF_1α ratio. In addition, danshensu did not induce gastric lesions and even had protective effects on aspirin-induced ulcer formation at doses as high as 60 mg/kg. These findings suggest that the antithrombotic and antiplatelet aggregation effects of danshensu are attributed to its highly selective inhibition of COX-2 and ability to normalize the thromboxane A₂(TXA₂)/prostacyclin(PGI₂) balance. These findings suggest that danshensu have great prospects in antithrombotic and antiplatelet therapy.     

Selective inhibition of thromboxane synthesis partially protected while inhibition of angiotensin II formation did not protect rats against acute renal failure induced with glycerol

Acute renal failure (ARF) was induced in 35 week-old conscious female Wistar rats, by intramuscular (IM) injection of glycerol. Intraperitoneal (IP) injection of imidazole, an inhibitor of thromboxane (TXA₂) synthesis, partially protected the animals against ARF. This protection was accompanied by a significant decrease in renal TXB₂ (the stable chemical metabolite of TXA₂) and a significant increase in renal 6-keto-PGF₁α (the stable chemical metabolite of PGI₂) synthesis. Intraperitoneal injection of captopril (SQ 14225) an angiotensin-converting-enzyme inhibitor, did not protect the animals against ARF. This lack of protection was accompanied by a significant increase in renal TXB₂ and a significant decrease in renal 6-keto-PGF₁α synthesis. The results suggest that: (a) the renin-angiotensin (R-A) system does not play a role, or has only a secondary one in the development of ARF; (b) thromboxane A₂ (the most potent vasoconstrictor and platelet aggregator agent known) is the preponderant agent responsible for the development of this pathological syndrome.     

Effect of angiotensin II and norepinephrine on release of prostaglandins E2 and I2 by the perfused rat mesenteric artery

Prostaglandin E₂ (PGE₂) and 6 keto-PGF_1α, the stable metabolite of prostacyclin (PGI₂), have been measured in the effluent of perfused rat mesenteric arteries by the use of a sensitive and specific radioimmunoadday (RIA) method. The PGE₂ and 6-keto-PGF_1α were continuousyl released by the unstimulated mesenteric artery over a period of 145 min. After 100 min of perfusion the release of PGE₂ and 6-keto-PGF_1α was 4.5 ± 8.4 pg/min and 254 ± 75 pg.min respectively, which is in accord with the general belief that PGI₂ is the major PG synthesized by arterial tissue. Angiotensin II (AII) 5 ng/ml) induced an increased of PGE₂ and 6-keto-PGF_1α release without changing the perfusion pressure. The effect of norepinephrine (NE) injections on release of PGs depended on the duration of the stabilization period. The changes of perfusion pressure induced by NE were not related to changes in release of PGs. Thus, it seems that the increase of PG release induced by AII and NE was due to a direct effect of the drugs on the vascular wall. This may represent an important modulating mechanism in the regulation of vascular tone.     

The effects of prostacyclin (PGI2) and 6-keto-PGF1α on bovine plasma progesterone and LH concentrations

Injections of 1 mg PGI₂ directly into the bovine corpus luteum significantly increased peripheral plasma progesterone concentrations within 5 min. Concentrations were higher in the PGI₂-treated heifers than in saline-injected controls between 5 and 150 min and at 3.5, 4, 5, and 7 h post-treatment. Levels tended to remain elevated through 14 h. Saline and 6-keto-PGF_1α were without effect on plasma progesterone levels. The luteotrophic effect of PGI₂ was not due to alterations in circulating LH concentrations. An $\text{in vitro}$ experiment assessed the effects of either PGI₂ alone or in combination with LH on progesterone production by dispersed luteal cells. Progesterone accumulation over 2 h for control, 5 ng LH, 1 μg PGI₂, 10 μg PGI₂, and 10 μg PGI₂ plus 5 ng LH averaged 99 ± 42, 353 ± 70, 152 ± 35, 252 ± 45, and 287 ± 66 ng/ml (n=4), respectively. Thus PGI₂ has luteotrophic effects on the bovine CL both $\text{in vivo}$ and $\text{in vitro}$.     

Effect of dipyridamole of prostaglandin generation by human platelets and vessel walls

These experiments were conducted to determine the effects of dipyridemole on human platelet aggregation, platelet thromboxane A₂ (TXA₂) and human vessel wall prostacyclin (PGI₂) generation. Dipyridamole in varying concentrations (5 to 50 μg/ml) had no direct effect on ADP-induced platelet aggregation in vitro, but it potentiated PGI₂-induced platelet aggregation inhibition at these concentrations. Dipyridamole also inhibited arachidonic acid-induced platelet TXA₂ generation at these concentrations. In continuously perfused umbilical vein segments, dipyridamole treatment resulted in stimulation of PGI₂ release determined by bioassay and by measurement of its stable metabolite 6-keto-PGF_1α. Minimum concentration of dipyridamole causing PGI₂ release was 50 μg/ml. These in vitro studies suggest that anti-thrombotic effects of dipyridamole in man are mediated mainly by potentiation of PGI₂ activity and to some extent by TXA₂ suppression. Stimulation of PGI₂ release by human vessels may not be seen in usual therapeutic concentrations.     

Effects of nitrogen dioxide exposure on the contents of prostaglandins and thromboxane B2 in broncho alveolar lavage

Effects of 10 ppm nitrogen dioxide (NO₂) exposure on the contents of prostaglandins (PGs) and thromboxane (TX) B₂ in broncho-alveolar lavage (BAL) of rats were studied. In the BAL of normal rats, the amounts of PGs and TXB₂ in the whole lavage were 6-keto-PGF_1α (38.0 ± 6.4 ng) > TXB₂ (11.8 ± 4.0 ng) > PGF_2α (5.7 ± 1.6 ng) PGE (0.5 ± 0.3 ng). Rats were exposed to NO₂ for 1, 3, 5, 7 and 14 days. The NO₂ exposure decreased in the level of 6-keto-PGF_1α by about 35% throughout the exposure. The level of TXB₂ was higher in the day 5 exposure group (155%). The contents of PGF_2α and PGE first, decreased and then transiently increased on days 3 and 5. PG 15-hydroxy-dehydrogenase activity of lung homogenate decreased correspondingly on day 3 and 5. Then the contents PGF_2α and PGE decreased on day 7 and 14.6-keto-PGF_1α and TXB₂ are stable metabolites of PGI₂, a strong bronchorelaxant and TXA₂, a strong bronchoconstrictor respectively. Therefore the results suggested that the decrease in 6-keto-PGF_1α, a major prostanoid in the BAL and the increase in TXB₂ may correlate with broncho constriction by NO₂ exposure.     

Hypercalcemia in association with a Leydig cell tumor in the rat: A model for tumor-induced hypercalcemia in man

The etiology of tumor-induced hypercalcemia was investigated in a transplantable Leydig cell tumor of the Fischer rat. In this model, serum calcium rose from a baseline of 10.4 ± 0.3 m mg/dl to 12.5 ± 0.4 mg/dl at day 10 and 16.4 ± 1.3 mg/dl (p<0.001) at day 13 post transplant. Urinary calcium also increased from 1.52 ± 0.17 mg/d to 3.52 ± 0.72 mg/d (Day 12, p<0.01). Serum phosphate decreased from a baseline of 7.5 ± 0.3 mg/dl to 5.5 ± 0.6 mg/dl at day 13 (p<0.05). At day 13 serum immunoreactive parathyroid hormone levels fell 76% from baseline (p<0.01). Calcitonin increased from 59 ± 2 pg/ml to 88 ± 9 pg/ml (p<0.01). The plasma prostaglandin E metabolite, 13, 14-dihydro-15-keto-PGE₂ increased from 407 ± 103 pg/dl to 647 ± 62 pg/ml (p<0.05) and the active Vit D compound 1, 25(OH)₂D increased from 94.8 ± 5.2 pg/ml to 162.3 ± 11.8 pg/ml (p<0.01). Urinary cyclic AMP did not decrease in parallel with the parathyroid hormone level and, in fact, increased from 146 ± 3 nmol/d to 172 ± 27 nmol/d (NS). Administration of the cyclooxygenase inhibitor indomethacin (20 mg/Kg/d) or hydrocortisone (50 mg/Kg/d) did not prevent the development of hypercalcemia. This model is similar to many patients with humoral hypercalcemia of malignancy who demonstrate suppression of parathyroid hormone with elevated urinary cyclic AMP excretion and may prove useful in the understanding of the responsible mechanisms.