Neuroeffector actions of prostaglandin D2 on isolated dog mesenteric arteries

Treatment with prostaglandin (PG) D2 in concentrations (10(-8) to 10(-7) M) insufficient to alter the basal tone potentiated the contractile response of helical strips of dog mesenteric arteries to transmural electrical stimulation but did not influence the response to norepinephrine. The potentiating effect of PGD2 was not prevented by treatment with diphloretin phosphate, a PG antagonist, whereas contractions of dog cerebral arteries induced by PGD2 were suppressed. The 3H-overflow evoked by transmural stimulation in superfused mesenteric arterial strips previously soaked in 3H-norepinephrine containing media was significantly increased in PGD2. It is concluded that PGD2 increases the stimulation-evoked release of norepinephrine from adrenergic nerves innervating the arterial wall. PGD2 appears to act differently on receptive sites responsible for increasing the release of norepinephrine and for producing arterial contraction.     

Histophysiological studies of prostaglandin F2alpha on isolated organs. I. Effect of prostaglandin F2alpha on the heart.

The physiological and histochemical effects of PGF2alpha on isolated rabbit hearts were examined. The results showed a positive inotropic effect. The coronary flow increased. From the histochemical studies, adenosine triphosphatase (ATP-ase) and succinic dehydrogenase activities were increased while that of alkaline phosphatase was decreased. Glycogen granules were depleted. These findings were discussed on a histophysiological basis.     

Oxytocin-stimulated production of prostaglandin F2alpha by isolated endometrium of rabbit: modulation by ovarian steroids

To test the hypothesis that ovarian steroid hormones modulate oxytocin-induced release of prostaglandin F2alpha (PGF2alpha) from uterine endometrium, 2 ovariectomized rabbits were pretreated with progesterone (5 mg/day for 10 days), 2 with estradiol-17 beta (25 microgram/day for 10 days), 2 with both steroids, and one with sesame oil only. On the last day of treatment, endometrial fragments were excised and incubated in vitro with or without oxytocin (100 muU/ml). Although endometrium from rabbits pretreated with combined steroids released more PGF2alpha immediately after excision than did tissue from animals pretreated with either steroid by itself, endometrium from animals pretreated with estradiol-17 beta alone released the most PGF2alpha during sustained incubation in vitro. Moreover, only this tissue exhibited significant oxytocin-dependent release of PGF2alpha. At the dosages used, progesterone completely antagonized both of these effects of estradiol-17 beta. The results support the hypothesis that ovarian steroid hormones regulate oxytocin-dependent release of PGF2alpha from endometrial cells. A posible mechanism of action is suggested.     

A comparison of prostaglandin F2alpha and three 16-aryloxy analogues on the isolated rabbit jejunum

Three 16-aryloxy analogues of PGF2alpha are potent, full agonists on the isolated rabbit jejunum. Their actions are more prolonged than that of PGF2alpha, and radioactive tracer studies with one of the analogues reveal a slower wash-out of the analogue compared to PGF2alpha, under superfusion conditions. During the prolonged contractile response diminished responses to PGF2alpha were obtained: this effect was investigated in terms of receptor desensitization. The actions of these analogues were also investigated on the isolated guinea-pig ileum and the rabbit oviduct in vivo.     

Neuroeffector actions of prostaglandin D2 on isolated dog mesenteric arteries

Treatment with prostaglandin (PG) D₂ in concentrations (10⁻⁸ to 10⁻⁷ M) insufficient to alter the basal tone potentiated the contractile response of helical strips of dog mesenteric arteries to transmural electrical stimulation but did not influence the response to norepinephrine. The potentiating effect of PGD₂ was not prevented by treatment with diphloretin phosphate, a PG antagonist, whereas contractions of dog cerebral arteries induced by PGD₂ were suppressed. The ³H-overflow evoked by transmural stimulation in superfused mesenteric arterial strips previously soaked in ³H-norepinephrine containing media was significantly increased by PGD₂. It is concluded that PGD₂ increases the stimulation-evoked release of norepinephrine from adrenergic nerves innervating the arterial wall. PGD₂ appears to act differently on receptive sites responsible for increasing the release of norepinephrine and for producing arterial contraction.     

Effect of prostaglandin F3 alpha on gastric mucosal injury by ethanol in rats: comparison with prostaglandin F2 alpha

In humans eicosapentaenoic acid can be converted to 3-series prostaglandins (PGF3 alpha, PGI3, and PGE3). Whether 3-series prostaglandins can protect the gastric mucosa from injury as effectively as their 2-series analogs is unknown. Therefore, we compared the protective effects of PGF3 alpha and PGF2 alpha against gross and microscopic gastric mucosal injury in rats. Animals received a subcutaneous injection of either PGF3 alpha or PGF2 alpha in doses ranging from 0 (vehicle) to 16.8 mumol/kg and 30 min later they received intragastric administration of 1 ml of absolute ethanol. Whether mucosal injury was assessed 60 min or 5 min after ethanol, PGF3 alpha was significantly less protective against ethanol-induced damage than PGF2 alpha. These findings indicate that the presence of a third double bond in the prostaglandin F molecule between carbons 17 and 18 markedly reduces the protective effects of this prostaglandin on the gastric mucosa.     

Passive smoking impairs endothelium-dependent relaxation of isolated rabbit arteries

The aim of the present study was to examine the effect of prolonged passive smoking (lasting 3 weeks) on plasma catecholamine levels and reactivity of isolated rabbit arteries. Plasma noradrenaline, adrenaline and dopamine levels were determined radioenzymatically. Isolated rings of the thoracic aorta and carotid artery were suspended in organ chambers and connected to a force transducer for the recording of isometric tension. Plasma noradrenaline levels were found to be significantly elevated in rabbits subjected to passive smoking for 3 weeks. Plasma adrenaline and dopamine levels were not changed. Transmural nerve stimulation of arterial rings evoked frequency-dependent contractions. Prolonged passive smoking did not affect neurogenic contractions of the arteries tested. On the other hand, endothelium-dependent relaxations of phenylephrine-precontracted arteries were significantly impaired. Furthermore, hypertrophy of the left ventricle was observed. In conclusion, passive smoking impairs endothelium-dependent relaxations but not neurogenic contractions of systemic arteries. The impaired relaxations of arteries may be, at least in part, mediated through the degradation of released nitric oxide by superoxide anions derived from cigarette smoke.     

Mechanism of relaxant action of prostaglandin F2alpha on the guinea-pig isolated trachea

Prostaglandin F2alpha consistently produced a dose-related triphasic response in guinea-pig isolated tracheal chain preparations. The response consisted of an initial transient contraction followed by a transient relaxation, followed by a further contraction. The relaxant action was not due to adrenergic or histaminergic transmission, but might be due to a PG-like material released by the PGF 2alpha-induced contraction.     

Role of prostaglandin F2alpha in ovulation.

Using radioimmunoassay procedures, the levels of plasma, uterine and ovarian prostaglandin (PG) F2alpha, and those of plasma estradiol and progesterone were measured in intact, hysterectomized or ovariectomized immature female rats pretreated with PMS and subsequent HCG. Occurrence of ovulation was confirmed at 8 hours after the HCG administration not only in the intact rats but also in the hysterectomzied rats. The levels of plasma estradiol and progesterone, and of uterine and ovarian PGF2alpha rose with the PMS injection alone, but they did not reach the peaks before the HCG administration. Both plasma estradiol and uterine PGF2alpha showed a peak at 2 hours after the HCG injection. These peaks were antecedent 2 or 6 hours before the peaks of ovarian and plasma PGF2alpha, respectively. However, such increase of uterine PGF2alpha does not seem to be indispensable for ovulation, because ovulation could occur in the hysterectomized rats. The levels of ovarian PGF2alpha showed a high plateau from 4 to 8 hours after the HCG injection, and then rapidly decreased after ovulation. The levels of plasma PGF2alpha peaked not only in the intact rats but also in the hysterectomized rats at 8 hours after the HCG treatment. But in the ovariectomized rats, this plasma PGF2alpha peak at 8 hours disappeared and there was no statistical change of plasma PGF2alpha throughout the PMS-HCG treatment. Plasma progesterone gradually increased and reached the maximum at 10 hours after the HCG injection. These results conclude that the main source of increased plasma PGF2alpha during the ovulatory process induced with the PMS-HCG treatment is the ovary, and it is strongly suggested that a rapid increase of PGF2alpha in the ovary may play some important role(s) in the ovulatory process.     

Effects of arachidonic acid and prostaglandin F2 alpha in isolated rat lungs

Isolated rat lungs were ventilated and perfused by saline-Ficoll perfusate at a constant flow. The baseline perfusion pressure (PAP) correlated with the concentration of 6-keto-PGF1 alpha the stable metabolite of PGI2 (r = 0.83) and with the 6-keto-PGF1 alpha/TXB2 ratio (r = 0.82). A bolus of 10 micrograms exogenous arachidonic acid (AA) injected into the arterial cannula of the isolated lungs caused significant decrease in pulmonary vascular resistance (PVR) which was followed by a progressive increase of PVR and edema formation. Changes in perfusion pressure induced by AA injection also correlated with concentrations of the stable metabolites (6-keto-PGF1 alpha: r = -0.77, TxB2: -0.76), and their ratio: (6-keto-PGF1 alpha/TXB2: r = -0.73). Injection of 10 and 100 micrograms of PGF2 alpha into the pulmonary artery stimulated the dose-dependent production of TXB2 and 6-keto-PGF1 alpha. No significant correlations were found between the perfusion pressure (PAP) which was increased by the PGF2 alpha and the concentrations of the former stable metabolites. The results show that AA has a biphasic effect on the isolated lung vasculature even in low dose. The most potent vasoactive metabolites of cyclooxygenase, prostacyclin and thromboxane A2 influence substantially not only the basal but also the increased tone of the pulmonary vessels.     

Peroxisomal chain-shortening of prostaglandin F2 alpha

We have recently reported that prostaglandin F2 alpha can be chain-shortened by isolated rat liver peroxisomes. In the present study it is further established by cell fractionation experiments that the enzymes involved in this reaction are localized to peroxisomes. Under the conditions employed, the highest activity was found in the light mitochondrial fraction. Further fractionation of the light mitochondrial fraction by sucrose density gradient centrifugation showed that the prostaglandin oxidation activity comigrated with peroxisomal marker enzymes. Di(2-ethylhexyl)phthalate treatment resulted in a tenfold increased capacity for the conversion of prostaglandin F2 alpha into tetranorprostaglandin F1 alpha. The reaction was not inhibited by KCN. The reaction was further characterized with respect to cofactor requirements. The prostaglandin oxidation was found to be completely dependent on NAD, CoA, ATP, Mg2+ and was stimulated by FAD. Incubation of prostaglandin E2 with peroxisomes resulted in conversion into several products. After alkaline hydrolysis, one of these was identified as tetranorprostaglandin B1.     

Evaluation of prostaglandin F2 alpha and prostacyclin interactions in the isolated perfused rat lung.

To characterize the interactions between prostaglandin F2 alpha and prostacyclin in controlling tone in the pulmonary circulation, isolated rat lungs were ventilated, perfused with blood, and subjected to challenge by prostaglandin F2 alpha in increasing doses. The pulmonary resistance was evaluated using occlusion techniques that separate the resistance into segments of large and small arteries and veins. The total vascular compliance was evaluated using outflow occlusion. Resistance increased after prostaglandin F2 alpha, and this resistance change was primarily in the small artery segment. The maximum resistance increase by prostaglandin F2 alpha (Rmax,PGF2 alpha), calculated from the Michaelis-Menton equation, was 16.6 +/- 3.6 cmH2O.l-1.min.100 g-1 for total vascular resistance with a concentration required to produce 50% Rmax (K0.5) of 5.26 +/- 3.57 nM. The Rmax,PGF2 alpha for small artery resistance was 13.5 +/- 2.4 cmH2O.l-1.min.100 g-1 with a K0.5 of 2.35 +/- 1.57 nM. The vascular compliance decreased during vasoconstriction by prostaglandin F2 alpha, and the maximum decrease in compliance (Cmin,PGF2 alpha) was -0.43 +/- 0.12 ml/cmH2O with a K0.5 of 2.84 +/- 2.99 nM. At each dose of prostaglandin F2 alpha, prostacyclin was administered in increasing doses to reverse the vasoconstriction caused by prostaglandin F2 alpha. For each concentration of prostaglandin F2 alpha, prostacyclin almost completely reversed the resistance increases and approximately one-half the compliance decrease. The maximum change in vascular resistance or compliance produced by prostacyclin was dependent on the dose of prostaglandin F2 alpha; yet the K0.5 for prostacyclin was within the picomolar range for all doses of prostaglandin F2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different responses to prostaglandin F2 alpha and E2 in human extra- and intramyometrial arteries

Tubal segments of the ascending uterine arteries and of intramyometrial arteries were obtained from 18 women who underwent hysterectomy at various phases of the menstrual cycle. Ring preparations of the vessels were mounted in organ baths and isometric tension was recorded. In extramyometrial arteries (outer diameter 2-3 mm) prostaglandin (PG) F2 alpha most potently, but also PGE2 caused concentration-related contractions. In contrast, the contractant effects of both PGs on intramyometrial arteries (outer diameter 0.5-0.6 mm) were negligible. Both extra- and intramyometrial vessels were relaxed to a moderate degree (10-25%) by low concentrations of PGF2 alpha and PGE2. No significant differences between the responses to vasopressin and noradrenaline were found between the vessel preparations. Thus human uterine arteries seem to change their responses to PGF2 alpha and PGE2 as they enter the myometrium and decrease in diameter, and the results raise doubt about the view that direct vasoconstrictor effects of these PGs contribute to the regulation of myometrial blood flow. Such effects of vasopressin and noradrenaline cannot be excluded.     

Chain-shortening of prostaglandin F2 alpha by rat liver peroxisomes

Liver peroxisomes were isolated from di(2-ethylhexyl)phthalate treated rats by isopycnic sucrose gradient centrifugation of a light mitochondrial fraction. Incubation of prostaglandin F2 alpha with purified peroxisomes resulted in conversion into a more polar product(s). In contrast, incubation with mitochondrial fractions and microsomal fractions under the same conditions did not result in any detectable conversion. The polar material obtained from a preparative incubation was purified by high performance liquid chromatography and characterized by radio-gas chromatography and gas chromatography-mass spectrometry. The structure of the polar compound was shown to be 5,7,11-trihydroxy-tetranorprost-9-enoic acid (tetranor-prostaglandin F1 alpha). Prostaglandin F2 alpha was thus chain-shortened by four carbon atoms.     

The effect of the prostaglandin F2alpha analogue ICI 81008 on uterine small arteries and on blood pressure.

The effects of PGF2alpha and its analogue ICI 81008 have been compared on the small arteries of the omentum uteri on the rat. The vessels measured 20-80 mum in diameter and were examined by intra-vital-microscopy. While the maximum responses of PGF2alpha and ICI 81008 were similar, the duration of the effect of ICI 81008 was significantly longer (P is less than 0.001). At 15 minutes after the administration of the drugs the effect of ICI 81008 was still almost maximal, while the PGF2alpha response disappeared.