E2 Alpha Research Articles

Response of human coronary arteries to aggregating platelets: importance of endothelium-derived relaxing factor and prostanoids.

Epicardial human coronary arteries (HCA) were obtained during heart transplantation. Strip preparations were mounted for isometric tension recording. Tension was induced with prostaglandin F2 alpha (0.3-3 microM). Aggregating human platelets (10(7)/ml and 10(8)/ml) caused marked relaxation if the endothelium of the HCA was intact, but produced modest additional constriction if the endothelium was removed. The endothelium-dependent relaxations to platelets were slightly enhanced in the presence of methysergide (1 microM) or after treatment of the platelets with the thromboxane synthase inhibitor dazmegrel (1 mM, 30 minutes). Relaxations to platelets were markedly inhibited or abolished in the presence of apyrase (1 unit/ml), after selective pretreatment of HCA with gossypol or methylene blue (both 30 microM, 30 minutes), or after addition of hemoglobin (20 microM) to the organ bath. Pretreatment of HCA (not the platelets) with aspirin (30 microM, 30 minutes) had no significant effect on platelet-induced relaxations. Adenosine 5'-diphosphate (0.1-100 microM) induced marked relaxations in endothelium-intact and much smaller relaxations in endothelium-denuded HCA. A low concentration (10 nM) of serotonin (5-HT) produced modest endothelium-dependent relaxations, higher concentrations (0.1-1 microM) led to increases in tension (also in the presence of endothelium). The thromboxane A2 mimetic U44069 (1-100 nM) was the most potent constrictor of HCA irrespective of the presence or absence of endothelium. After inhibition of thromboxane synthase, platelets produced large amounts of prostaglandins E2 and F2 alpha. Both prostaglandins constricted HCA, which can explain the limited effects of dazmegrel.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential role for prostaglandin F2 alpha, D2, E2 and thromboxane A2 in mediating the metabolic and hemodynamic actions of sympathetic nerves in perfused rat liver.

In isolated rat liver perfused at constant pressure perivascular nerve stimulation caused an increase of glucose and lactate output and a reduction of perfusion flow. The metabolic and hemodynamic nerve effects could be inhibited by inhibitors of prostanoid synthesis, which led to the suggestion that the effects of nerve stimulation were, at least partially, mediated by prostanoids [Iwai, M. & Jungermann, K. (1987) FEBS Lett. 221, 155-160]. This suggestion is corroborated by the present study. 1. Prostaglandin D2, E2 and F2 alpha as well as the thromboxane A2 analogue U46619 enhanced glucose and lactate release and lowered perfusion flow similar to nerve stimulation. 2. The extents, the kinetics and the concentration dependencies of the metabolic and hemodynamic actions of the various prostanoids were different. Prostaglandin F2 alpha and D2 caused relatively stronger changes of metabolism, while prostaglandin E2 and U46619 had stronger effects on hemodynamics. Prostaglandin F2 alpha elicited greater maximal alterations than D2 with similar half-maximally effective concentrations. Prostaglandin F2 alpha mimicked the nerve actions on both metabolism and hemodynamics best with respect to the relative extents and the kinetics of the alterations. 3. The hemodynamic effects of prostaglandin F2 alpha could be prevented completely by the calcium antagonist nifedipine without impairing the metabolic actions of the prostanoid. Apparently, prostaglandin F2 alpha influenced metabolism directly rather than indirectly via hemodynamic changes. The present results, together with the previously described effects of prostanoid synthesis inhibitors, suggest that prostanoids, probably prostaglandin F2 alpha and/or D2, could be involved in the actions of sympathetic hepatic nerves on liver carbohydrate metabolism. Since prostanoids are synthesized only in non-parenchymal cells, nervous control of metabolism appears to depend on complex intra-organ cell-cell interactions between the nerve, non-parenchymal and parenchymal cells.

Effects of alpha-tocopherol, its carboxylic acid chromane compound and two novel antioxidant isoflavanones on prostaglandin H synthase activity and autodeactivation.

The natural antioxidant alpha-tocopherol has repeatedly been described to inhibit platelet aggregation and thromboxane formation, whereas its influence on prostaglandin H synthase in vivo and in vitro is a matter of controversy. In the present study the effects of different antioxidative compounds on ram vesicular gland microsomal prostaglandin H synthase activity were investigated in vitro: d,l-alpha-tocopherol, its carboxylic acid chromane compound (Trolox), phytol, alpha-tocopherol-acetate and two novel antioxidative isoflavanones, obtained by methylation and/or hydrogenation of naturally occurring isoflavones from fermented soybeans (6,7-dihydroxy-4'-methoxyisoflavanone and 6,7,4'-trihydroxyisoflavanone). Alpha-tocopherol, -acetate and phytol revealed no significant influence on the enzyme activity when applied in concentrations up to 1 mM. Trolox (100-1000 mu mumol/l) and the two isoflavanones (5-50 and 10-100 mumol/l) dose-dependently augmented the initial rate of oxygen consumption and the total oxygen uptake during prostaglandin H synthase incubation with arachidonic acid (AA). In parallel, these compounds increased the formation of prostaglandin E2 and F2 alpha from 14C-labelled AA, and they markedly protected the prostaglandin H synthase from rapid autodeactivation as revealed by repetitive application of AA in small doses. We suggest that these compounds serve as cosubstrates to which the oxidizing equivalents are transferred which arise during the hydroperoxidase reaction of the enzyme.

Prostaglandin D2, a cerebral sleep-inducing substance in monkeys.

The sleep-inducing effect of prostaglandin D2 (PGD2) was studied in five conscious male rhesus monkeys (Macaca mulatta) maintained in a 12-hr light/dark cycle. PGD2 was infused into the lateral or the third ventricle of the cerebrum slowly and continuously for 6 hr in the light period. Infusion of PGD2 into the lateral ventricle at 15-2250 pmol/min induced natural sleep as identified by electroencephalogram, electromyogram, electrooculogram, body temperature, heart rate, and animal behavior. Although sensitivity to PGD2 was slightly different among individual animals, the amount of total sleep time increased maximally up to 3- to 4-fold over the control level. PGD2 infused into the third ventricle induced effects similar to those observed for the lateral ventricular route, but infusion into the third ventricle was about 1000 times more effective than infusion into the lateral ventricle. In three monkeys, PGD2 increased the amount of sleep in a dose-dependent manner. Bell-shaped dose-response curves were observed for the other two monkeys. Infusion of prostaglandin E2 or F2 alpha into the lateral ventricle caused sedation but slightly reduced the amount of slow-wave sleep and produced increases in heart rate and body temperature. These findings suggest that endogenous PGD2 may be involved in the regulation of sleep by acting on the brain structures surrounding the third ventricle in the rhesus monkey.

Regulation of the proliferation of primary rat hepatocytes by eicosanoids.

DNA synthesis in primary adult rat hepatocyte cultures was promoted by epidermal growth factor (EGF), arachidonic acid, and prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha). Growth promotion by EGF was blocked by 0.1 mM indomethacin and 1 mM aspirin, without affecting cell viability. If verapamil was present in the medium when EGF was added, the growth response was inhibited. Hepatocytes stimulated by EGF or arachidonic acid released PGE2 and PGF2 alpha into the culture medium. This was diminished if 0.1 mM indomethacin was also in the medium. The importance of autocrine regulation of hepatocyte growth by prostaglandins is discussed.

Histamine dilates pial arterioles of newborn pigs through prostanoid production.

To test the hypothesis that histamine would dilate pial arterioles via a prostanoid mechanism, histamine was placed on the brain surface of anesthetized newborn pigs via a closed cranial window. Pial arteriolar diameters were measured after topical application of 10(-7), 10(-6), 10(-5), 10(-4), and 10(-3) M histamine. In addition, cortical cerebrospinal fluid (CSF) was collected for radioimmunoassay of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), and prostaglandin F2 alpha (PGF2 alpha). The animals were then randomized to receive either indomethacin trihydrate (5 mg/kg, iv) or an equal volume of saline (vehicle). The protocol then was repeated. Histamine (before indomethacin or vehicle infusion) caused concentration-dependent vasodilation. This vasodilation was accompanied by a significant increase in cortical CSF 6-keto-PGF1 alpha and PGE2. Concentrations of TxB2, PGD2, and PGF2 alpha were not altered significantly by histamine application. Pretreatment with indomethacin blocked the histamine-induced cerebral vasodilation, but vasodilation after vehicle was intact. These data imply that histamine dilates the pial arterioles of newborn pigs by stimulating the synthesis of vasodilator prostanoids.

Bovine Placental Prostaglandin Synthesis: Principal Cell Synthesis as Modulated by the Binucleate Cell1

Bovine placentomes were collected during late gestation, prepartum, and immediately postpartum. Postpartum tissues were collected prior to fetal placental release. A procedure for separating fetal placental principal cells from fetal binucleate cells (BNC) was developed. Dispersed fetal placental cells (mixed types), principal cells, and BNC were each examined for their ability to produce prostaglandins (PGs) from arachidonic acid (AA) and to metabolize prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in vitro. Dispersed fetal placental cells obtained prepartum produced predominantly PGs of the E series (PGEs) from AA (p less than 0.05). PGE synthesis predominated (p less than .05) in cells from postpartum tissue if the fetal placental membranes were subsequently retained, whereas synthesis of PGs of the F series (PGFs) predominated (p less than 0.05) if the fetal membranes were subsequently released. Principal cells were the primary source of fetal placental PG synthesis from AA (p less than 0.05). BNC exhibited a lesser ability to synthesize PGs from AA (p less than 0.05), but were able to convert PGF2 alpha to PGE2. Dispersed fetal placental cells exhibited greater ability to convert PGF2 alpha to PGE2 (p less than 0.05) than did the separated cells. These data suggest the function of a two-cell system within the fetal villi such that the BNC modulate the output of principal cell PG synthesis and/or metabolism.

Evidence for specific binding of 15 hydroxyeicosatetraenoic acid to pituitary rat cells

Specific receptors for [3H]-15 HETE have been identified on GH3 cells, a cloned strain of rat pituitary cells. With incremental inputs of radioligand and a constant cell number, specific [3H]-15 HETE binding reached a plateau indicative of saturable binding sites. Ligand analysis of the Scatchard plot demonstrated a single class of high affinity binding sites with a dissociation constant (Kd) of 0.75 nM. 12 HETE competed with radiolabeled 15 HETE (IC50 = 1 x 10(-6) +/- 0.8 M). In contrast, arachidonic acid, leukotriene B4, prostaglandins E2 and F2 alpha did not compete with [3H]-15 HETE.

Vasoactive Prostaglandins in the Impending No-Reflow State

The impending no-reflow (NRF) state was studied in the rat hindlimb to identify possible biochemical mediators producing the no-reflow phenomenon. After 5 hours of ischemia, the venous effluents draining the ischemic limb and the contralateral nonischemic limb were collected for three 30-minute time periods. Thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-ketoprostaglandin F1 alpha, the stable metabolite of prostacyclin (PGI2), were measured by radioimmunoassay. Venous outflow rate, distal skin perfusion assessed by dermofluorometry, and histology of muscle and skin were examined in control limbs, ischemic limbs, and limbs with impending no reflow. The no-reflow state was characterized by a significantly decreased venous outflow (less than 0.01 ml per minute), decreased skin perfusion (index of fluorescence of 15 percent in no-reflow limbs versus 70 percent in reflow limbs), and absence of thrombosis of the vasculature. The no-reflow state also was associated with 2.4 times more thromboxane B2 and 1.5 times more 6-ketoprostaglandin F1 alpha than that observed in ischemic limbs with reflow. The biosynthesis of vasodilating prostaglandin E2 in the no-reflow state, however, was only 40 percent of the prostaglandin E2 measured in limbs with reflow. We propose that the impending no-reflow state may reflect a state of global microcirculatory "agonal" vasoconstriction, most probably due to an overabundant release of the vasoconstrictor thromboxane relative to the vasodilating prostaglandin E2 and prostacyclin. The likelihood of specific biochemical mechanisms producing the no-reflow state suggests that pharmacologic agents may be able to reverse the impending no-reflow state to improve tissue survival.

Gonadotropic regulation of prostaglandin production by ovarian follicular cells of the pig.

Prepubertal gilts were treated with 750 IU pregnant mare's serum gonadotropin (PMSG) and 72 h later with 500 IU human chorionic gonadotropin (hCG) to induce follicular growth and ovulation. Dispersed granulosa cells (GC) and theca interna cells (TC) from follicles of gilts 72 h (GC-72 and TC-72, respectively) and 108 h (GC-108 and TC-108 h, respectively) after PMSG treatment were cultured for 0, 12, 24, and 36 h in medium with or without luteinizing hormone (LH), dibutyryl cyclic adenosine 3',5'-monophosphate [Bu)2cAMP), calcium ionophore (A23187), and/or arachidonic acid (AA), and the production of prostaglandin E2 (PGE) and prostaglandin F2 alpha (PGF) was measured by radioimmunoassay. TC-72 was the principal source of PGs 72 h after PMSG. At 108 h, the production of PGE and PGF by GC was increased 10- and 30-fold, respectively, whereas corresponding increases by TC were 2-fold. LH and A23187 significantly stimulated PGE and PGF production by both GC-72 and TC-72, but only thecal PG production was stimulated by (Bu)2cAMP. LH had minimal or no effect on PG production by GC-108 and TC-108, but A23187 (GC-108, TC-108) and (Bu)2cAMP (TC-108) were stimulatory. Basal PG production by GC-72, GC-108, and TC-108 was stimulated by AA. However, production by GC and TC cultured in medium containing AA and LH, A23187, or (Bu)2cAMP was not different from that produced by AA alone. These findings suggested that GC and TC can synthesize PGs in vitro, but AA availability is rate-limiting in GC. After exposure to hCG in vivo, the capacity of both cell types to produce PGs is increased but is limited by AA availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple control of fever production in the central nervous system of rabbits.

1. The effects of microinjection of prostaglandin D2, E2 and F2 alpha and of endogenous pyrogen on the rectal temperature of rabbits were extensively examined in sixty-eight brain regions and in the third cerebral ventricle. 2. Intracerebroventricular injection of both prostaglandins E2 and F2 alpha produced dose-dependent fever over a range of 100-1000 ng. The selective brain regions, the nucleus broca ventralis, preoptic area, anterior hypothalamus and the ventromedial hypothalamus, responded to microinjections of a small dose (less than 200 ng) of prostaglandins E2 and F2 alpha by producing fever. Furthermore, the lateral hypothalamus, ventral thalamus, substantia nigra and the trigeminal nucleus were also sensitive to high concentrations of prostaglandins E2 and F2 alpha, fever being produced. It is likely that prostaglandin D2 is not involved in fever induction. 3. The ventricular injection of endogenous pyrogen also produced fever. However, brain regions sensitive to microinjection of endogenous pyrogen were exclusively localized to regions near the organum vasculosum laminae terminalis (OVLT), such as the nucleus broca ventralis and the preoptic area. In contrast to the monophasic fever induced by prostaglandins E2 and F2 alpha, about 30 min after ventricular or cerebral injection of endogenous pyrogen the rectal temperature gradually started to rise and the fever was prolonged over 4 h. 4. We investigated the effect of an inhibitor of prostaglandin synthesis, sodium salicylate, on biphasic fever induced by intravenous injection of bacterial endotoxin. The microinjections of sodium salicylate into the bilateral regions near the OVLT suppressed the second peak but had no effect on the first peak. 5. The present study clarifies that there exist two separate mechanisms of induction of biphasic fever. Correlating with the first peak of biphasic fever, prostaglandins synthesized outside the blood-brain barrier act on multiple sites in the central nervous system to induce fever. Correlating with the second peak, endogenous pyrogen acts on regions near the OVLT to synthesize and release pyrogenic prostaglandins.

Effects of dietary protein intake on branched-chain keto acid dehydrogenase activity of the rat. Immunochemical analysis of the enzyme complex.

Polyclonal antibodies directed against the dihydrolipoyl transacylase (E2) and alpha subunit of branched-chain alpha-keto acid decarboxylase (E1 alpha) components of the bovine branched-chain keto acid dehydrogenase complex were shown to cross-react with the E2 and E1 alpha polypeptides of the enzyme complex of different rat tissues. Phosphorylation of the branched-chain keto acid dehydrogenase complex resulted in inhibition of enzyme activity concomitant with phosphate incorporation into the E1 alpha polypeptide. Phosphorylation of E1 alpha slowed its rate of migration through sodium dodecyl sulfate-polyacrylamide gels. This permitted resolution of the phosphorylated and unphosphorylated forms of E1 alpha on immunoblots. Liver and skeletal muscle mitochondria were prepared from rats consuming 6, 20, or 50% casein diets. The enzyme complex in mitochondria was measured by radioisotopic enzyme assay and immunoassay. Liver branched-chain keto acid dehydrogenase was 25% active in rats consuming 6% casein diets; whereas in rats consuming 20 or 50% casein diets, the liver enzyme was 82 or 100% active, respectively. Branched-chain keto acid dehydrogenase of muscle was 10, 13, and 22% active, respectively, in rats consuming 6, 20, and 50% casein diets. The amount of protein consumed by rats did not affect the total amount of the enzyme complex per unit of mitochondrial protein as measured by either the radioisotopic assay (enzyme activity) or the immunoassay. However, the protein intake of rats did affect activity of the enzyme kinase in liver. Liver branched-chain keto acid dehydrogenase kinase was more active in rats consuming 6% casein than in those fed chow or 50% casein diets. The amount of protein consumed by rats thus influences the enzyme activity in liver and muscle by affecting the reversible phosphorylation mechanism and not by induction of branched-chain keto acid dehydrogenase.

Disturbed relationship between urinary prostaglandin E2 excretion, plasma arginine vasopressin and renal water excretion after oral water loading in early hepatic cirrhosis.

An oral water load of 20 ml kg-1 body weight was given to 11 patients with early hepatic cirrhosis and to 16 healthy control subjects. Urinary output (V), free water clearance (CH2O), urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), and plasma concentration of arginine vasopressin (AVP) were determined before and during the first 4 h after loading. During basal conditions, PGE2 excretion was the same in patients (75 pg min-1, median, range 15-569) and controls (78 pg min-1, range 22-262), but during the first hour after water loading, PGE2 increased to a significantly higher level in cirrhotic patients (423 pg min-1, median) than in control subjects (162 pg min-1) (P less than 0.05). No difference in PGF2 alpha excretion was found between the two groups. Urinary output and CH2O were significantly lower after water loading in patients than in controls. Arginine vasopressin before water loading did not differ between patients and control subjects, but after loading it was unchanged in the patients, whereas a significant reduction (1.9 to 1.4 pmol l-1, P less than 0.01) was found in the control subjects. In controls, but not in patients, PGE2 was significantly positively correlated to V and CH2O, and negatively correlated to AVP after water loading. Thus, renal PGE2 excretion is increased and CH2O is decreased after water loading in patients with early hepatic cirrhosis, and a disturbed relationship seems to exist between PGE2 on the one hand, and AVP and renal water excretion, on the other, in these patients after water loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Mediation of augmented monocyte adhesiveness by thromboxane.

We examined the potential contribution of thromboxanes in human monocyte adherence to plastic. Monocyte adherence to plastic could be augmented by various stimuli including lipopolysaccharide, chemotactic peptide, and supernates of antigen-stimulated lymphocytes. Increments in monocyte adhesiveness were suppressed by inhibition of cyclooxygenase, thromboxane synthetase, or by antiserum to thromboxane B2. Neither prostaglandin E2 or F2 alpha significantly affected baseline or lipopolysaccharide-stimulated monocyte adherence. Additional experiments confirmed incremental production of thromboxane B2 by monocytes after incubation with lipopolysaccharide. Thromboxane B2 itself did not stimulate monocyte adhesiveness. These data demonstrate that monocytes release thromboxane A2 following stimulation and suggest that thromboxane A2 may play a significant role in monocyte-substrate attachment.

Neonatal and maternal prostaglandin in the ontogenic response of rat gastric mucosa to H+.

We have previously demonstrated that neonatal rat stomach is less susceptible to luminal H+ when compared with the adult. In the present study we investigate the role of endogenous prostaglandins (PG) in the ontogeny of gastric permeability responses to H+. Responses to luminal instillation of 250 mN HCl were measured in rats at 10, 15, 20, and 25 days after birth. Mucosal responses were measured in terms of loss of H+ and appearance of Na+, K+, and protein in the luminal instillate. Indomethacin (IM; 8 mg/kg sc) administration to rat pups reduced mucosal levels of prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha). In response to intraluminal HCl, the reduction of mucosal PG did not significantly affect transmucosal fluxes of ions and protein when compared with control pups. IM was also given to lactating dams on days just prior to the pups being 10, 15, 20, and 25 days old. IM treatment significantly reduced the content of PGE2 and 6-keto-PGF1 alpha in maternal milk. Permeability responses in pups from IM-treated dams were increased over pups from control dams. This effect was not observed in 25-day-old rats. Treatment of pups from IM-injected dams with PGE2 but not PGI2 partially restored the permeability responses to luminal H+ to levels observed in pups from control dams.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary prostaglandin E2 and F2 alpha excretion in nephrotic syndrome during basal conditions, after water loading, and after remission of the syndrome.

The urinary excretion rate of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) was determined in patients with the nephrotic syndrome both before and after an oral water load in 21 patients and 17 control subjects, and before and after remission of the syndrome in 8 of the patients. In the nephrotic syndrome PGE2 excretion rate varied considerably during basal conditions, remission was accompanied by an increase in the PGE2 excretion, and both basal PGF2 alpha excretion rate and the normal response in PGF2 alpha water loading were reduced. A significant, positive correlation was found between urine flow rate and excretion rate of PGE2 in the periods with the largest urine flow rate in both patients and control subjects. It is suggested that a relatively suppressed renal prostaglandin production may be a pathogenetic factor for sodium and water retention in the nephrotic syndrome, although it cannot be excluded that the abnormal prostaglandin excretion pattern is secondary, at least partially, to the reduction of urine flow rate.

Effect of angiotensin-converting enzyme inhibitor YS980 on prostaglandin synthesis in rabbit kidney medulla slices.

The effect of YS980, an angiotensin-converting enzyme inhibitor, on the generation of medullary prostaglandins E2 and F2 alpha was examined. At concentrations of 0.2 mM and below, YS980 enhanced prostaglandin F2 alpha synthesis at the expense of prostaglandin E2. At concentrations of 0.4 mM or more, YS980 inhibited synthesis of both prostaglandins E2 and F2 alpha markedly. These results suggest that YS980 has the potential to modulate prostaglandins E2 and F2 alpha synthesis by the kidney and that this effect may represent some pharmacological action of the drug.

Adenosine 3',5'-monophosphate, prostaglandins, and epinephrine stimulate the secretion of immunoreactive gonadotropin-releasing hormone from cultured human placental cells.

Cell culture and biochemical procedures were used to identify and study the possible mechanisms regulating the secretion of GnRH-like immunoreactivity (GnRH-LI) from human placenta. Monolayer primary cultures of trophoblasts were established after mechanical and enzymatic dispersion of normal human term placenta. The cultured cells stained immunocytochemically positive with anti-GnRH serum, and GnRH-LI extracted from the cells eluted from high performance liquid chromatography with the same retention time as authentic GnRH. One week after plating, exposure to high concentrations of K+ or to various doses of veratridine, a Na+ ionophore, increased GnRH-LI release into the culture medium. This effect was reversed by Ca2+ antagonists (cobalt, EGTA, and verapamil). Dibutyrylcyclic AMP, forskolin, theophylline, and theobromine also increased GnRH-LI concentrations in the medium of cultured placental cells in a dose-related manner, as did prostaglandins E2 and F2 alpha and epinephrine. The effect of epinephrine on GnRH-LI concentrations was mimicked by isoproterenol and reversed by propranolol, suggesting an effect mediated by beta-adrenergic receptors. These results indicate that GnRH-LI release from cultured human placental cells is stimulated by the opening of ionic channels and activation of the adenylate cyclase/cAMP system, and that prostaglandins and epinephrine may be involved in the regulation of GnRH-LI release from human placenta.

Pharmacodynamic evaluation of human cerebral arteries in the genesis of vasospasm.

Experiments were performed on isolated human cerebral arteries to evaluate the role desensitization and tachyphylaxis might play in preventing certain agonists from producing prolonged vasoconstriction after subarachnoid hemorrhage. In addition, the antiproteases leupeptin and pepstatin were studied to ascertain whether these peptides might inhibit contraction as does antithrombin III. The maximal contraction to KCl was used as a standard for comparing the responses elicited by the agonists, the decay of the responses to the agonists over 15 minutes was used as an index of desensitization, and the percentage of decrease in response to a second application of the agonist over the first was a measure of tachyphylaxis. The results showed that desensitization and tachyphylaxis greatly reduced or abolished the contractile responses to norepinephrine, serotonin, angiotensin II, arginine vasopressin, substance P, neuropeptide Y, neurotensin, thrombin, uridine triphosphate, linoleic acid, melittin, and cathepsin D. Moreover, some arteries failed to respond to some of these agonists, and no contractile response was elicited by acetylcholine or bradykinin. In contrast, prostaglandins E2, D2, and F2 alpha, as well as plasmin, produced sustained contractions, without tachyphylaxis, but only prostaglandin E2 and plasmin produced contractions at concentrations of 10(-7) M or less that were comparable to those of KCl. None of the antiprotease peptides inhibited the responses to KCl whereas small concentrations (6 X 10(-8) M) of antithrombin III did. The results support the hypotheses that the phenomenon of desensitization and tachyphylaxis would prevent many diverse agents from acting as spasmogens and that substances like antithrombin III present in the cerebrospinal fluid after hemorrhage could immediately protect patients from cerebral vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Ability of human plasma to inhibit prostaglandin F2 alpha in asthma.

Human plasma has been reported to inhibit the conversion of arachidonic acid into prostaglandin (PG) E2 and PGF2 alpha. In the present study the plasma inhibitory activity was determined in three groups (16 each) of plasma obtained from normal healthy volunteers, treated asthmatics and untreated asthmatic patients. The result showed that plasma from all three groups were equally effective in inhibiting the biosynthesis of PGE2. Plasma of normal volunteers and treated asthmatics also inhibited PGF2 alpha biosynthesis. In contrast the plasma obtained from untreated asthmatics was considerably less active in inhibiting the biosynthesis of PGF2 alpha than plasma from the other two groups.