Relative activity of prostaglandins E1, A1, E2 and A2 on lipolysis, platelet aggregation, smooth muscle and the cardiovascular system

The relative activities of four prostaglandins (PGE₁, PGA₁, PGE₂ and PGA₂) were determined in several biological tests. They were compared as intestinal muscle stimulants on rabbit duodenum and guinea-pig ileum, as inhibitors of adrenaline-induced lipolysis in rat isolated epididymal fat, inhibitors of platelet aggregation in rabbit plasma, as vasodepressor agents in anaesthetized rats and dogs, and on both blood pressure and cardiac output in unanaesthetized dogs. Formation of PGAs by dehydration and introduction of one additional double bond virtually abolished activity in all of these systems except the cardiovascular system. PGE₂ was more active than PGE₁ on isolated rabbit duodenum and as an antilipolytic agent, but less active in the other systems. Only PGE₁ had high potency as an inhibitor of platelet aggregation.     

阿魏酰胍丁胺类似物的设计、合成及Na~+/H~+交换器-1抑制活性

为了寻找新结构类型的Na+/H+交换器-1(NHE-1)抑制剂,以阿魏酸、胍丁胺为先导化合物,设计并合成了9个阿魏酰胍丁胺类似物。其结构经1H NMR、13C NMR和MS确证,其中化合物5f～5i为新化合物。初步的药理实验结果表明,部分目标化合物显示出较好的NHE抑制活性,其中化合物5a、5b和6c对NHE-1的抑制活性明显优于阳性对照药卡立泊来德(cariporide)。     

Protective effect of prostaglandins D2, E1 and I2 against cerebral hypoxia/anoxia in mice

The protective effect of prostaglandins (PGs) against cerebral hypoxia/anoxia was investigated with a variety of experimental models in relation to their CNS depressant effects in mice. Furthermore, the effect of PGs on the changes of cerebral energy metabolites and cyclic nucleotide was examined in hypoxic mice. Mice were given s.c. doses of PGs 30 min before tests. Among the PGs tested, treatment with PGD2, PGE1 and PGI2 Na showed a consistent and dose-dependent protection against cerebral anoxia induced by all models studied: histotoxic anoxia by KCN, hypobaric hypoxia, normobaric hypoxia and decapitation-induced gasping. However, PGA1, PGA2, PGB1, PGB2, PGE2, PGF1 alpha, PGF2 alpha and 6-keto-PGF1 alpha at a dose of 3 mg/kg were without effect against normobaric hypoxia and gasping duration. The three PGs, i.e. PGD2, PGE1 and PGI2 which showed anti-hypoxic effects decreased locomotor activity and potentiated hexobarbital-induced sleep. On the other hand, PGE2, PGA1, PGA2 and PGB2 also caused a decrease in locomotor activity. Similarly, PGE2 and PGA1 caused a potentiation of hexobarbital-induced sleep, but interestingly they did not cause clear-cut increase in cerebral resistance to hypoxia, in contrast with the former three PGs. Thus general depression of CNS function appears not to be responsible for the PGD2-, PGE1- and PGI2-induced increase in cerebral resistance to hypoxia. The levels of Cr-P and ATP were significantly reduced and those of ADP and AMP were markedly elevated in hypoxic brain, resulting in a decrease in a calculated energy charge potential. The lactate level and lactate/pyruvate ratio increased and the glucose level decreased markedly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of aerosols of prostaglandins E1 and E2 as bronchodilators

Summary Aerosols of prostaglandin E₁ (PGE₁) and E₂ (PGE₂) were evaluated as bronchodilators in 32 subjects (6 normals, 15 with bronchial asthma and 11 with chronic bronchitis). PGE₂ caused a significant decrease in pulmonary resistance (mean values 3.2 and 2.6 cm H₂O/l/sec before and after inhalation, respectively). There were no significant changes in pulmonary resistance after PGE₁. Bronchoconstriction occurred in some subjects whose pulmonary resistance had been within normal limits. Static pulmonary compliance did not show any definite change. The frequency dependence of dynamic compliance was measured in 19 subjects; in 3 the results suggested that bronchoconstriction after PGE₁ preferentially affected small airways; in 1 other subject bronchodilatation occurred exclusively in the small airways. Arterial Po₂ decreased in 4 out of 5 patients after inhalation of PGE₁. This was thought to be due to greater unevenness of the ventilation perfusion ratio, since the dynamic pulmonary compliance became more dependent on respiratory frequency even though pulmonary resistance improved in these subjects. The pulse rate did not change significantly, but mean blood pressure decreased in 8 out of 15 subjects. Cough and irrtation of the pharynx were noted in 42 and 62 per cent of subjects during and after the inhalation of PGE₁ and PGe₂, respectively. Five and 23 percent of the subjects complained of headache after inhaling PGE₁ and PGE₂. The results suggest that aerosols of PGE₂ have a bronchodilating action which could be of use in clinical practice, if untoward responses such as irritation of the pharynx, cough and headache could be avoided.Presented in part on April 13, 1972 at the National Meeting of the Japanese Society of Chest Diseases, Hiroshima, Japan.     

Distribution of prostaglandins E1,E2, F1-alpha and F2-alpha in some animal tissues

A survey of the distribution of prostaglandins E₁, E₂, F₁α and F₂α in fourteen tissues from the dog, cat, rat, rabbit, guinea-pig and chicken has been made. One or more of these prostaglandins are present in varying amounts in most tissues with PGE₂ PGF_2α occurring most commonly.     

Effects of prostaglandins E1 and E2 on human, guinea-pig and rat isolated small intestine

1. Prostaglandins E(1) and E(2) contracted the longitudinal muscle of human, guinea-pig and rat isolated ileum.2. The site of action varied with the species. In the rat and in some strips of human tissue prostaglandin appeared to have only a direct action on or in the muscle cells. In the other strips of human tissue and in guinea-pig ileum the prostaglandins seemed to stimulate both the intrinsic cholinergic nerves and the muscle cells.3. In contrast to the longitudinal muscle, the circular muscle of human, guinea-pig and rat isolated ileum was usually inhibited by prostaglandin, apparently by an action directly on the muscle cells.4. Prostaglandins may play a part in the control of intestinal motility.     

Prooxidant and antioxidant activity of vitamin E analogues and troglitazone

The order of antioxidant effectiveness of low concentrations of vitamin E analogues, in preventing cumene hydroperoxide-induced hepatocyte lipid peroxidation and cytotoxicity, was 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC) > troglitazone > Trolox C > alpha-tocopherol > gamma-tocopherol > delta-tocopherol. However, vitamin E analogues, including troglitazone at higher concentrations, induced microsomal lipid peroxidation when oxidized to phenoxyl radicals by peroxidase/H2O2. Ascorbate or GSH was also cooxidized, and GSH cooxidation by vitamin E analogue phenoxyl radicals was also accompanied by extensive oxygen uptake and oxygen activation. When oxidized by nontoxic concentrations of peroxidase/H2O2, vitamin E analogues except PMC also caused hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation. The prooxidant order of vitamin E analogues in catalyzing hepatocyte cytotoxicity, lipid peroxidation, and GSH oxidation was troglitazone > Trolox C > delta-tocopherol > gamma-tocopherol > alpha-tocopherol > PMC. A similar order of effectiveness was found for GSH cooxidation or microsomal lipid peroxidation but not for ascorbate cooxidation. Except for troglitazone, the toxic prooxidant activity of vitamin E analogues was therefore inversely proportional to their antioxidant activity. The high troglitazone prooxidant activity could be a contributing factor to its hepatotoxicity. We have also derived equations for three-parameter quantitative structure-activity relationships (QSARs), which described the correlation between antioxidant and prooxidant activity of vitamin E ananlogues and their lipophilicity (log P), ionization potential (E(HOMO)), and dipole moment.