A.I. Ally

The nutritional regulation of T lymphocyte function.

Prostaglandin (PG) E1 plays a major role in the regulation of thymus development and T lymphocyte function and the evidence for this is reviewed. The production of PGE1 is dependent on nutritional factors with linoleic acid, gamma-linolenic acid, pyridoxine, zinc and vitamin C playing key roles. Inadequate intake of any one of these will lead to inadequate PGE1 formation and defective T lymphocyte function. Megadoses of any one are likely to be only minimally effective in the absence of adequate intakes of the others. By careful attention to diet it should be possible to activate T lymphocyte function in the large number of diseases including rheumatoid arthritis, various auto-immune diseases, multiple sclerosis, and cancer in which such function is defective. It is possible that T lymphocytes may require both endogenous and exogenous PGE1 in order to function adequately. It is therefore of particular interest that many cancer cells and virally infected cells are unable to make PGE1 because they cannot convert linoleic acid to gamma-linolenic acid. The direct provision of gamma-linolenic or dihomo-gammalinolenic acids in these situations is worthy of full investigation.

Thromboxane A2 as a possible natural ligand for benzodiazepine receptors

Receptors for benzodiazepines have recently been found in the brain but the natural ligand which can occupy these receptors is unknown. In a rat vascular preparation diazepam and chloridiazepoxide were found to inhibit pressor responses to noradrenaline and angiotensin but not those to potassium and vasopressin with IC(50) concentrations similar to those reported for displacement of [(3)H]diazepam from brain receptors. Imidazole, an inhibitor of thromboxane A(2) synthesis had similar actions to the benzodiazepines. Interactions between imidazole and the benzodiazepines suggested that the latter may be competitive antagonists of thromboxane A(2). The possibility that thromboxane A(2) may be the natural ligand is supported by recent evidence that brain tissue contains high levels of this substance.

Low prostaglandin concentrations cause cardiac rhythm disturbances. Effect reversed by low levels of copper or chloroquine.

In perfused male rat hearts concentrations of prostaglandins (PGs) E2 and F2alpha in the range 1 pg/ml to 10 ng/ml (2.8 X 10(-12) to 2.8 X 10(-8)M) consistently caused rhythm irregularities. Higher concentrations had no effect themselves and stabilized rhythm in hearts made unstable by lower concentrations. Copper ions (as the sulphate) at 2 X 10(-6)M stabilized hearts made unstable by PGs and when present prior to the PGs prevented PG induced disturbances. Chloroquine also reversed PG-induced rhythm changes.

Quinacrine is a prostaglandin antagonist.

Abstract Quinacrine, an anti-malarial with local anaesthetic properties, because of its fluorescence characteristics and its ability to combine with chromosomes and biological membranes has been widely used as a “probe”. The sites with which it combines in Torpedo marmorata electric organs have many of the characteristics of specific receptors. Using rat vascular and gastric smooth muscle we have shown that quinacrine can competitively antagonise the actions of prostaglandin E2. We suggest that the biological sites to which quinacrine binds can normally be occupied by prostaglandins.

Influence of agents which modulate thromboxane A2 synthesis or action on R3230AC mammary carcinoma

The effects of agents which modulate thromboxane A2 synthesis or action, were tested in the R3230AC transplanted mammary tumour. Three different inhibitors of thromboxane A2 synthesis or action (copper, dipyridamole and diazepam) all caused an increase in tumour growth. Colchicine and melatonin, both stimulators of thromboxane A2 synthesis, inhibited the growth of the tumour significantly.

Prostaglandins E1, E2 and I2: evidence for three distinct actions in vascular smooth muscle.

Abstract In the perfused mesenteric artery of the rat prostaglandins (PGs) E 1 , E 2 and I 2 had distinct actions. PGE 2 potentiated pressor responses to noradrenaline, angiotensin II and potassium ions. PGE 1 potentiated responses to noradrenaline and angiotensin at low concentrations and inhibited them at high concentrations: no concentrations had any effect on potassium responses. PGI 2 inhibited responses to noradrenaline and angiotensin but had no effect on potassium responses. These three distinct actions suggest that the binding sites for the three PGs in this vascular muscle must be distinct.

Adenosine as a natural prostaglandin antagonist in vascular smooth muscle

Adenosine has actions on smooth muscle similar to those of prostaglandin (PG) antagonists. Like some PG antagonists it is a phosphodiesterase inhibitor and seems to interfere with calcium effects. It has agonist/antagonist interactions with theophylline, a PG antagonist. In rat mesenteric vascular smooth muscle adenosine blocked responses to noradrenaline which depend on release of intracellular calcium but not those to potassium ions which depend on calcium entry from extracellular fluid. Partial inhibition of endogenous PG synthesis by indomethacin enhanced the adenosine effect. In preparations in which vascular reactivity had been abolished by indomethacin and then partly restored by 1 or 5 ng/ml PG2, adenosine also inhibited responses to noradrenaline: the curve for the 5 ng/ml PG2 concentration was to the right of and parallel to the 1 ng/ml curve consistent with a competitive interaction between adenosine and PG2. Similar interactions between adenosine and PG2 were shown in human lymphocytes in which activation also depends on calcium release. These findings suggest how calcium-dependent metabolic responses may be controlled and indicate further reasons for caution in the interpretation of cyclic AMP experiments.

Thymic changes in muscular dystrophy and evidence for an abnormality related to prostaglandin synthesis or action.

In Bar Harbor 129 dystrophic mice, thymic development is abnormal. Before weaning, the thymus is slightly smaller than in phenotypically normal littermates; after weaning, however, the lymphoid elements undergo rapid atrophy. The epithelial elements, in contrast, display hyperlasia. Thymectomy has no influence on the course of the disease, and it is possible that the thymic changes are a reflection of a fundamental metabolic abnormality. Thymic lymphoid tissue development seems to require normal levels of PGE1. Levels that are either too high or too low both result in abnormalities. We have investigated the effects of PGE1 in smooth muscle and have demonstrated that while some PGE1 is required for both calcium release and calcium removal, high levels of PGE1 block both processes. We propose that the muscular dystrophies are related to defects in PG synthesis and action. Myotonic dystrophy may be due to PGE11 excess, whereas Duchenne dystrophy may in part be due to PGE1 deficiency.

Effects of propranolol on the responses of the rat stomach strip to prostaglandin E2.

Propranolol is a local anaesthetic, membrane-stabilizing drug as well as a beta blocker. 2 mug/ml is added to many PG bioassay systems in order to inhibit beta adrenergic effects. This concentration inhibited responses of the rat stomach strip to PGE2 concentrations below 5 x 10(-7)M but potentiated responses to higher PGE2 concentrations. In calcium-free buffer only the potentiation was seen. Propranolol may not be a suitable drug for use in PG bioassay systems.

The roles of prostaglandins and calcium accumulation in muscular dystrophy

There is good evidence that abnormal calcium accumulation may be a final common pathway of muscle degeneration in the muscular dystrophies. Prostaglandins are able to promote calcium entry into cells and excess prostaglandin activity coupled with a defect in intracellular calcium release could cause toxic accumulations of calcium in intracellular organelles such as mitochondria. Serotonin stimulates prostaglandin synthesis while tricyclic antidepressants inhibit calcium release from intracellular organelles thus possibly accounting for the models of muscular dystrophy reported using this combination. The prostaglandin/calcium hypothesis can account for the effects of vitamin E, steroids and local anaesthetic-like drugs in muscular dystrophy. Since many drugs already in clinical use for other purposes can be used to control prostaglandin synthesis or action this hypothesis has immediate potential clinical applications.