Species dependent relaxation of intrapulmonary arteries (IPA) of rabbits, dogs and humans by prostacyclin

Helically cut strips of successive IPA segments of rabbits, dogs and human patients were set up for isometric recording in vitro. High tone was produced by norepinephrine (NE, 3 microM). This tone was markedly reduced by prostacyclin (PGI2) in the secondary, tertiary and quaternary branches of human and canine pulmonary trunk. The IC50 values for PGI2 ranged from 22 to 503 nM, the human vessels being more sensitive to prostacyclin than canine IPA. Under these conditions, the primary and secondary branches of the rabbit pulmonary trunk were not relaxed by PGI2. The contractile potency of NE was determined in each pulmonary vessel studied. The secondary segments of rabbit IPA were about ten times as sensitive to NE (EC50 for NE: 38 +/- 7 nM) as compared to the secondary IPA from dogs and humans (EC50 values: 370 +/- 84 and 440 +/- 50, respectively). When high tone was induced by equieffective contractile concentrations of NE (3 microM for canine and human IPA and 0.3 microM for rabbit vessels), PGI2 was still less effective (P less than 0.01) in relaxing secondary IPA of rabbits (IC25: 220 +/- 55) than the corresponding segments of dogs and humans (IC25: 51 +/- 12 and 17 +/- 4, respectively). The difference between canine and human vessels was also significant (P less than 0.02). These results indicate that there is an interspecies difference in the sensitivity of IPA to NE and PGI2.     

Effects of uterine stimulant drugs on prostacyclin production by the pregnant rat myometrium. I. Oxytocin, bradykinin and PGF2α

The release of prostacyclin from chopped myometrial fractions of 18–20 day pregnant rats was assayed by inhibition of ADP-induced aggregation of citrated rabbit platelet-rich plasma. Preincubation of myometrial tissue with oxytocin 10 mU/ml increased prostacyclin generation from 2.25 ± 0.48 (control) to 3.75 ± 0.73 ng/mg over 15 minutes. Bradykinin 20 μg/ml also caused a significant increase in myometrial prostacyclin output from 2.26 ± 0.19 to 4.26 ± 0.64 ng/mg. PGF_2α 1 μg/ml did not increase prostacyclin release significantly. Pretreatment of myometrial tissue with the phospholipase inhibitor mepacrine significantly reduced the peptide-stimulated release of prostacyclin. The results suggest that prostacyclin production may play an important role in modulating the actions of oxytocin and bradykinin in the pregnant rat myometrium.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance(PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance (PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Pulmonary vascular response to prostacyclin in fetal lambs

Eighteen prostacyclin injections (19.4±1.5 μg/kg) were performed in five chronically instrumented, intact fetal lambs in order to study the effects on pulmonary blood flow. These resulted in a brief period of bradycardia followed by a more prolonged period of increased pulmonary blood flow. In this latter phase, pulmonary blood flow increased from a baseline value of 49±4 ml/(kg min) to 122±10 ml/(kg min). Systolic/diastolic pulmonary arterial pressure simultaneously fell from to mm Hg. Flow through the ductus arteriosus was unchanged and right ventricular output increased to account for the increased pulmonary blood flow. Thus, prostacyclin causes pulmonary vasodilation in intact fetal lambs and may participate in the control of fetal pulmonary blood flow and the circulatory adjustments to extra-uterine life.     

A nitric oxide synthesis inhibitor decreased prostaglandin production in rat mesenteric vasculature

Endothelial cells synthesize and release nitric oxide (NO) and prostacyclin (PGI₂) which are involved in the regulation o f vascular tone and blood pressure. Our objective was to evaluate the effects of inhibiting NO synthesis on vascular prostaglandin (PG) and cyclic nucleotide production, as well as the pressor response to norepinephrine (NE). Isolated mesenteric arterial beds were perfused with Krebs-Henseleit solution containing 100 μM N^G-monomethyl-L-arginine (L-NMMA), 100 μM L-arginine (LA), or vehicle. After a 30 min equilibration 0.1, 0.5, 1, or 5 μM NE was infused into the superior mesenteric artery and the perfusion pressure was monitored. The basal perfusion pressure did not differ significantly between groups. The pressure-response curve was shifted to the right in the L-NMMA group vs. the LA and control groups. Perfusion was similarly performed with a Krebs-Henseleit solution containing 100 μM L-NMMA, LA, D-arginine, or vehicle. Perfusates were collected before and after NE infusion for the measurement of PGE₂, 6-keto-PGF_1α, TxB₂, cAMP, and cGMP. In the L-NMMA group the release of PGE₂ and 6-keto-PGF1α was decreased, and the release of cGMP was prevented. Production of cAMP did not differ between the four groups before NE infusion, and NE increased cAMP release in the L-NMMA group and controls. The results indicate that inhibition of NO synthesis by L-NMMA enhanced the pressor response to NE, possibly mediated by the decreased cGMP and PGI₂ production in resistance vessels.     

Effect of hypoxia on prostacyclin production in cultured pulmonary artery endothelium

Exposure of cultured bovine pulmonary artery endothelial cells to varying levels of hypoxia (10% or 0% O₂) for 4 hours resulted in a significant dose-dependent inhibition in endothelial prostacyclin synthesis (51% and 98%, at the 10% and 0% O₂ levels respectively, p <0.05, compared to 21% O₂ exposure values). Release of ³H-arachidonic acid from cellular pools was not altered by hypoxia. Some of the cells were incubated with arachidonic acid (20 μM for 5 min) or PGH₂ (4 μM for 2 min) immediately after exposure. Endothelium exposed to 0% O₂, but not to 10% O₂, produced significantly less prostacyclin after addition of either arachidonic acid (25 ± 5% of 21% O₂ exposure values, n=6, p <0.01) or PGH₂ (31 ± 3% of 21% O₂ exposure values, n=6, p <0.05). These results suggest that hypoxia inhibits cyclooxygenase at the 10% O₂ level and both cyclooxygenase and prostacyclin synthetase enzymes at the 0% O₂ exposure levels. Exposure of aortic endothelial cells resulted in a 44% inhibition of prostacyclin at the 0% exposure level. No significant alteration in prostacyclin production was found in pulmonary vascular smooth muscle cells exposed to hypoxia. These data suggest that the increased prostacyclin production reported in lungs exposed to hypoxia is not due to a direct effect of hypoxia on the main prostacyclin producing cells of the pulmonary circulation.     

Cardioprotective effect of prostacyclin and 7-oxo-PGI2 in rats against chronic isoproterenol damage

Isoproterenol (ISO) was injected in 5 mg/kg i.p. doses to rats, daily for two weeks. We evaluated the developed myocardial hypoxia and necrosis quantitatively by histological methods. To follow the time course of cardioprotection prostacyclin or 7-oxo-PGI₂ were injected daily, i.p. 5, 30 min and 1, 2, 3, 4 hours before or after the ISO to groups of ten rats, respectively. Cardioprotection was defined as the reduction of necrotized areas and was expressed as percentage change compared to the control (saline treated) group. 1 μg/kg PGI₂ and 50 μ/kg 7-oxo-PGI₂₊ showed nearly equipotent cardioprotection (37.3±7.9% and 38.3±6.8%, respectively). The peak effect of both compounds appeared when injected prior to ISO in the 120. min but the action of 7-oxo-PGI₂ was more prolonged. The different doses of prostacyclin analogs given after the ISO injection were ineffective with the exception of 50 μ/kg 7-oxo-PGI₂ (29.75± 5.2 %).     

A prostacyclin analogue, iloprost, augments the ovulatory response of the LH-stimulated in vitro perfused rat ovary

Ovaries from immature rats, primed with pregnant mare's serum gonadotropin (PMSG; 20 IU, on day 28), were perfused in vitro in a recirculating system for 21 h from the morning of day 30 of age. Stimulation with luteinzing hormone (LH; 0.1 μg/ml) in vitro at 0 h of perfusion resulted in 2.4 ± 0.75 (mean ± SEM) ovulatioons per treated ovary, whereas no ovulations occured in the unstimulated group. When the addition of LH was supplemented hourly for 10 h with a stable prostacyclin analogue, Iloprost, at concentrations of 0.01 μM or 0.1 μM, the ovulation rate increase significantly (p<0.05) to 6.6 ± 1.3 and 10.2 ± 2.4 ovulations per treated ovary, respectively. Iloprost (0.1 μM) did not cause any follicular ruptures when added by itself at every hour up to 10 h. The addition of Iloprost did not affect the release of cyclic adenosine 3′,5′-monophosphate or LH-stimulated ovaries. All ovulated oocytes had resumed meiosis as judged from the absence of a germinal vesicle. These data indicate a positve modulatory role of prostacyclin in the LH-induced ovulatory process for the rat.     

Determination of histamine, methylhistamines and histamine—o-phthaldialdehyde complexes by two high-performance liquid chromatographic procedures : Application to biological samples

Two high-performance liquid chromatographic procedures were proposed to measure histamine. The first, with UV detection and a strong acid cation exchanger (Partisil 10, SCX Whatman), made it possible to isolate histamine and some methylated derivatives. The second, with a C₁₈ sorbent (μBondapak, Waters, 10 μm particle size) eluted with ion-pairing phases, made it possible to isolate the histamine—o-phthaldialdehyde complexes. This last procedure allied with a chromatographic purification step gave lower or identical amounts of histamine than those described in human urine (16 ± 7 μg per 24 h), canine whole blood (1.5 ± 1 ng/ml) and human gastric juice (2.3 ± 1.4 ng/ml). The two procedures gave the concentration of a histamine-like compound isolated from the antral mucosa.     

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68, 215

U-68,215 [15-Cyclohexyl-9-deoxo-13, 14-dihydro-2′, 9a-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(′1,′3-interphenylene)-PGE₁] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED₅₀: 0.8 μg/kg) and the intestine (ED₅₀: 22 μg/kg), is gastric antisecretory (ED₅₀: 35 μg/kg) and antiulcer (aspirin) (ED_{50: 5 μg/kg}). The oral antisecretory ED₅₀ in dogs in 50 μg/kg. It has a long duration of gastric cytoprotection: 8–10 hours compared to 3 hours for 16, 16-dimethyl PGE₂ Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induced cellular proliferation of the gastroeintestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It ihibits platelet aggregation (ED₅₀: 300 μg/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at a n oral dose correponding to 1–5 time the antisecretory ED₅₀ in rats and dogs, and to 150 times the cytoprotective ED₅₀ in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.     

Evaluation of prostaglandin-receptors in human and rat liver: Interspecies differences at the prostaglandin receptor-level

The properties of PGE1-, PGE2- and iloprost (stable PGI2-analogue)-binding sites on normal human and rat liver surface cell membranes were investigated. The specific binding of [3H]PGE1 to human (rat) liver surface cell membranes could be displaced most effectively by unlabeled PGE1 (IC-50: 2.5±1.7, (6.1±2.1) μM) and the specific binding of [3H]PGE2 by unlabeled PGE2 (IC-50: 1.9±0.9 (2.0±0.8) μM. The Scatchard analysis on [3H]PGE1- as well as on [3H]ilioprost-binding was curvilinear whereas it was clearly linear on [3H]PGE2-binding in both the species. The high-affinity [3H]PGE1-sites showed a Bmax of 36.3±5.2 (21.3±4.3) fmol/mg protein and a Kd of 2.1±1.8 (1.9±0.7) nM, the low-affinity [3H]PGE1-sites a Bmax of 93.4±18.2 (86.1±13.2) fmol/mg protein and a Kd of 10.5±2.9 (15.3±3.2) nM. The high-affinity [3H]iloprost-sites exhibited a Bmax of 71.4±13.9 (35.9±8.2) fmol/mg protein and a Kd of 4.1±1.2 (1.7±1.8) nM, the low-affinity [3H]iloprost-sites a Bmax of 217.3±42.1 (142.9±17.8) fmol/mg protein and a Kd of 16.3±4.9 (9.2±7.2) nM. The [3H]PGE2-sites showed a Bmax of 135.4±51.9 (38.8±7.4) fmol/mg protein and a Kd of 16.2±3.2 (2.5±1.2) nM.It is assumed that prostaglandins of the E-series are promising substances in the regulation of human and rat liver function since liver cells are stable to bind reasonable amounts of these substances in a high affinity manner. However, interspecies differences in the affinity of the prostaglandins to their receptor-sites make it strange to assume that the same biological findings claimed several times for the rat liver are relevant for human too.     

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α₁-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.     

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.     

The development of tone in the smooth muscle of guinea-pig isolated tracheal preparations may be influenced by prostanoids released from the adjacent airway cartilage

Guinea-pig tracheal strip preparations containing cartilage, placed under an applied load , develop tone spontaneously. The finding that spontaneous tone is reduced by indomethacin suggests that one or more prostanoids are involved in the development of spontaneous tone in this species. In this study we examined the effects of removing the cartilage component of the preparations on changes in tone induced by indomethacin and isoproterenol. In contrast to preparations containing cartilage, tissues devoid of cartilage, did not develop tone after the application of an initial 1 g resting load. Indomethacin (1 μM) reduced resting tone by 0.62 ± 0.14 g in cartilage-containing tissues but, in contrast, reduced tone by only 0.03 ± 0.01 g in tissues devoid of cartilage. Furthermore, relaxation responses (0.38 ± 0.05 g) to isoproterenol (1 μM) could be produced in cartilage-containing preparations but not in cartilage-free preparations. Radioimmunoassays indicated that the release of PGE₂, PGF_2α and 6-keto PGF_1α, the end-product of PGI₂ breakdown, was diminished in preparations lacking cartilage. Thus, in guinea-pig airway preparations cartilage is apparently a source of sufficient prostanoids to induce spontaneous tone     

Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse

Background

Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies.

Methodology/Principal Findings

Following our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre-treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 μg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 μg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 μg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 μg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 μg/mL allopurinol).

Conclusions

This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs.     

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

These experiments were conducted to determine the effects of dipyridamole on human platelet aggregation, platelet thromboxane A2 (TXA2) and human vessel wall prostacyclin (PGI2) generation. Dipyridamole in varying concentrations (5 to 50 micrograms/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-PGF1 alpha. Minimum concentration of dipyridamole causing PGI2 release was 50 micrograms/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.     

The efficacy of the extraovular “Prostaglandin-Impact” in provoking first trimester abortion

In good agreement with earlier findings (1–8) legal abortion had been induced successfully with Csapo's method of “Prostaglandin Impact” (PGI) in 44 out of 50 sedated patients. They were 25±1.1 years of age, 11.3±0.2 weeks pregnant, para 1.1±0.2. Only a PGI (10 mg PG F2α) was delivered into the extraovular space. In 44 women, this single PGI provoked 40% progesterone (P)-withdrawal in 3 hours (P < 0.001) and 64% P-withdrawal (P < 0.001) in 15.3±0.9 hours, when the patients aborted. The remaining 6 women, whose P-withdrawal was only 14% at 3 hours without continuation during 24 hours, failed to abort. Thus in PG-induced abortions the regulatory significance of rapid and continued P-withdrawal (1–8) had been verified.The side effects were mild, transient and acceptable. The “Abortion Score” was 86. There were no serious complaints or complications during the study and followup. Since even in the 6 cases of failure the cervix dilated sufficiently to allow curettage (without surgical dilatation), the therapeutic benefits of the single PGI technique should be further examined in those services, where constant medical supervision (for determining the necessity and timing of repeated PGI) is not available.     

Inhibition of adenosine diphosphate-induced intravascular aggregation of rat platelets by 6-oxo-prostaglandin E1

The antiaggregatory effects of 6-oxo-PGE1 were evaluated in the rat using a minimally invasive technique involving 111-Indium labelling of platelets. The antiaggragatory effects on adenosine diphosphate-induced aggregation were compared with those of prostacyclin (PGI2) and prostalandin E1 (PGE1) following slow infusions and bolus injections. The rank order of antiaggregatory potency was PGI2 > 6-oxo-PGE1 > PGE1 while the rank order of duration of antiaggregatory effects was PGE1 > 6-oxo-PGE1 > PGI2. The kinetics of the antiaggregatory effects of these prostaglandins suggests that such action are not mediated by direct effects on platelets, but through a secondary mechanism.