A calcitonin-like action of prostaglandin E1

The pharmacological effects of PGE1 (6 and 9 days, 2-1,250 micrograms/kg per day subcutaneously) upon the growth and the bone resorption of mammals were studied using the proximal tibia and upper incisor of immature rats along with lead acetate as a time marker, and upon the serum calcium and inorganic phosphorus levels. The following results were obtained. 1. PGE1 hardly affected the body weight or the weight of organs of the rats but apparently inhibited the longitudinal growth of proximal tibia in a dose related manner. 2. PGE1 clearly inhibited not only the longitudinal growth (incisor growth) but also the appositional growth (dentin formation) of incisal dentin. 3. The grade of the inhibitory effect on the growth was in the order of bone growth greater than dentin formation greater than incisor growth. 4. The occurrence of osteoporosis due to a low calcium diet was inhibited by the simultaneous administration of PGE1, the mechanism being considered to be mainly due to the inhibitory effect on the bone resorption. 5. PGE1 lowered the level of serum calcium and the lowering effect was not observed in the thyro-parathyroidectomized rat. From the facts that the above effects were exactly the same as those of calcitonin (1), the possibility that the subcutaneous injection of PGE1 may induce a calcitonin-like action, a part of which may dependent on the calcitonin secretion is suggested.     

Studies on the mechanism of action of prostaglandin F2 alpha induced luteolysis in rats

The effects of prostaglandin F2 alpha (PGF2 alpha) administration on the utilization of low density lipoprotein (LDL) and progesterone secretion were examined in dispersed luteal cells from rat ovaries. Immature rats were rendered pseudopregnant with administration of pregnant mare serum gonadotropin and human chorionic gonadotropin. Animals were sacrificed at different times after PGF2 alpha (5 mg/kg) or vehicle administration on day-5 of pseudopregnancy. Administration of PGF2 alpha in vivo decreased human chorionic gonadotropin (hCG) binding to luteal cell membranes in vitro but enhanced binding of LDL. Utilization of labelled cholesterol for steroid synthesis from reconstituted LDL [(3H)-CL-LDL] by dispersed luteal cells was enhanced following PGF2 alpha administration. This suggests that the LDL pathway is not suppressed during prostaglandin induced luteolysis. Progesterone and total progestin secretion in response to N6-2'-0-Dibutyryladenosine 3'5'-cyclic monophosphate (cAMP) was decreased at 2, 4 and 24 hours following PGF2 alpha administration demonstrating a post-cAMP defect in steroidogenesis. Addition of the hydroxylated sterols, 20 or 25-OH cholesterol as substrate stimulated progesterone secretion in vehicle treated rats in a dose dependent fashion with 20-OH cholesterol being more potent. Progesterone secretion in response to stimulation with luteinizing hormone (LH) and cAMP from vehicle treated rats was less than that observed with 20 or 25-OH cholesterol, indicating that endogenous substrate may be a limiting factor in steroid synthesis. The maximal capacity of luteal tissue to produce progestins following PGF2 alpha administration was determined with 20-OH cholesterol as the substrate. The results suggest that the post-cAMP defect at 4 hours following PGF2 alpha administration may be due to failure of the cells to mobilize endogenous cholesterol. However at 24 hours following PGF2 alpha administration the decreased ability of luteal cells to convert cholesterol to pregnenolone may contribute to decreased progesterone synthesis.     

Decrease of prostaglandin E2 receptor binding is accompanied by reduced antilipolytic effects of prostaglandin E2 in isolated rat adipocytes

The effect of treatment of isolated rat adipocytes with prostaglandin E2 (PGE2) on subsequent [3H]PGE2 binding was studied. In addition, the antilipolytic effects of was studied. In addition, the antilipolytic effects of PGE2, adenosine, and insulin were studied in control and PGE2-treated adipocytes. Treatment of adipocytes with PGE2 (1 microM) decreased the binding of [3H]PGE2 by 61% (from 11.0 to 4.6 fmol/10(6) cells, P less than 0.005). Scatchard analysis of the binding data demonstrated that the decrease of PGE2 receptor binding was due to a decrease in the apparent number of PGE2 receptors while the apparent receptor affinity was unaltered. Reduction of the PGE2 receptor binding was specifically regulated inasmuch as structurally related compounds such as PGF2 alpha and arachidonic acid had only minor effects on subsequent [3H]PGE2 receptor binding. Reduction of the available receptor number was associated with a significant decrease in the antilipolytic effect of PGE2 on the isoproterenol-stimulated lipolysis (P less than 0.05). The maximal antilipolytic effect of PGE2 was decreased by 45%. Desensitization of the biological effect of PGE2 (antilipolysis) was only partially specifically regulated inasmuch as the antilipolytic compound phenylisopropyladenosine also had reduced antilipolytic effect in PGE2-treated cells. However, the antilipolytic effect of insulin was similar in control and PGE2-treated cells. It was found that the PGE2-induced decrease of [3H]PGE2 receptor binding may be due to a very tight coupling between the PGE2 molecule and its specific receptor. This tight coupling may then represent an occupancy of the receptor rather than a true loss of receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

The mechanism of prostaglandin action on the pregnant human uterus

The concentrations of 15 methyl PGF2α, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action.The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.     

The mechanism of prostaglandin action on the early pregnant human uterus

To extend observations in 11 weeks pregnant patients⁽¹⁾ the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 g (15S)-methyl PGF2α methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 g 16-phenoxy-ω-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 ± 154 g.The PGF2α and PGE₂-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversibly compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the “ideal” method of non-surgical menstrual induction.     

The mechanism of prostaglandin action on the early pregnant human uterus

To extend observations in 11 weeks pregnant patients the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 microgram (155)-methyl PGF2 alpha methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 microgram 16-phenoxy-omega-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 +/- 154 microgram. The PGF2 alpha and PGE2-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversible compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the "ideal" method of non-surgical menstrual induction.     

The mechanism of prostaglandin action on the pregnant human uterus.

The concentrations of 15 methyl PGF2 alpha, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action. The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.     

Islet-activating protein discriminates the antilipolytic mechanism of insulin from that of other antilipolytic compounds

In vivo administration of islet-activating protein to rats resulted in an increase in fat cell lipolysis in vitro, which was associated with almost complete resistance of adipocytes towards the antilipolytic effects of N6-phenylisopropyladenosine, prostaglandin E2 and nicotinic acid. Concomitantly, the inhibitory effects of these compounds on adenylate cyclase activity in membranes were impaired. In contrast, the antilipolytic action of insulin was not only preserved, but even augmented in cells from rats treated with islet-activating protein. The data suggest that insulin exerts its antilipolytic effects via mechanisms which are different from those involved in the effects of prostaglandin E2, N6-phenylisopropyladenosine and nicotinic acid.     

Temperature and benzyl alcohol as probes of the antilipolytic mechanism of insulin action in adipocytes.

The temperature dependence of cAMP accumulation and glycerol release in response to epinephrine and insulin in adipocytes is examined. (1) Glycerol release in the presence of epinephrine demonstrated linear Arrhenius kinetics to 41 degrees C, and above 45 degrees C glycerol release was progressively inhibited. (2) In contrast, incubation of the cells with both epinephrine and insulin resulted in glycerol release rates that were relatively temperature insensitive. (3) Calculation of the efficacy of insulin to inhibit epinephrine-stimulated glycerol release as a function of temperature yielded a biphasic response, with a distinct optimum around 41 degrees C, in a similar manner to the effects of insulin on hexose transport activation determined previously. (4) A saturating dose of insulin (40 ng/ml) was found to have no significant effect on epinephrine-stimulated intracellular cAMP over the temperature range studied. (5) Addition of benzyl alcohol (to 40 mM) resulted in substantial inhibition of basal, epinephrine stimulated, and insulin inhibited glycerol release, without affecting the magnitude of insulin inhibition. We conclude from these studies that (a) insulin inhibition of glycerol release can not be mediated directly by intracellular cAMP modulation, (b) as in the case of hexose transport activation, the signalling mechanism by the occupied insulin receptor appears to be relatively independent of the membrane lipid environment.