We propose that intracellular prostaglandins (PGs) are essential for the final expression of the effects of second messengers in most cells. We suggest that the amounts of PGs required are very small (in the picomolar range) and are much lower than those used in most current PG studies. We suggest that while therapeutic levels of inhibitors of PG synthetase may be adequate to block the overflow of PGs from cells, they are in most cases unlikely to reduce intracellular PGs sufficiently to test the role of such PGs. We propose that there is a basal level of PG synthesis unaffected by hormones but that above this level PG synthesis is regulated by the interplay between physiological levels of cortisol, prolactin, growth hormone and thyroid hormones. For the most part prolactin seems to stimulate PG synthesis and cortisol to inhibit it: cortisol has, however, no inhibitory effect on basal PG synthesis. In reducing prolactin-stimulated PG synthesis cortisol is 1000-2000 times more potent than indomethacin on a molar basis. We suggest that the regulation of intracellular PG levels is the mechanism of the so-called "permissive" actions of these hormones. These concepts could prove important in the understanding of many aspects of physiology and pathophysiology including diurnal and seasonal changes in hormone responsiveness. They are also relevant to the use of established drugs and the design of new ones.

Animals↗

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The relationships between cyclic AMP, calcium and prostaglandins as second messengers.

There is considerable dissatisfaction with present second messenger hypotheses involving cyclic nucleotides and calcium. The recent findings that methyl xanthines and adenosine are prostaglandin antagonists casts doubt on much of the evidence in favour of the cyclic AMP hypothesis. There is evidence that allosteric sites may modify the binding of calcium and cyclic nucleotides to key cellular regulators and that a range of substances including steroids, adenosine and prostaglandins may occupy those sites. This concept introduces much needed flexibility into the second messenger concept, allows many experiments to be reinterpreted and has major implications throughout the biomedical sciences.

Adenosine↗

PubMedDate not supplied

Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anaesthetic, anti-arrhythmic, anti-malarial, tricyclic anti-depressant and methyl xanthine compounds. Effects on membranes and on nucleic acid function.

We have recently found that local anaesthetic, anti-malarial, anti-arrhythmic, tricyclic antidepressant and methyl xanthine compounds behave as prostaglandin antagonists at drug concentrations readily attainable in human body fluids. We have also found that various hormones, including prolactin, vasopressin and angiotensin when present in physiological concentrations can be potent stimulators of prostaglandin synthesis. Cortisol has no effect on basal prostaglandin systhesis but in physiological concentrations is able to reverse the effects of other hormones. The drugs are thought to act mainly by interfering with either calcium interactions with membranes, or with cyclic nucleotide synthesis or degradation or with nucleic acid function. We propose that prostaglandins play crucial roles at all three points. The hypothesis leads to new approaches to many aspects of cell regulation, to the functions of many systems, especially the neuromuscular, cardiovascular, renal and respiratory systems. It also has profound implications for drug design and evaluation and for the understanding of many clinical disorders.

Anesthetics, Local↗

PubMedDate not supplied

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.

Animals↗

PubMedDate not supplied

Thromboxane A2: a key regulator of prostaglandin biosynthesis and of interactions between prostaglandins, calcium and cyclic nucleotides.

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Calcium↗

PubMedDate not supplied

The vascular response to zinc varies seasonally: effect of pinealectomy and melatonin.

The effect of physiological concentrations of zinc on the in vitro pressor responses of male Wistar rat mesenteric preparations to norepinephrine was systematically studied over a 2-year period. A marked seasonal variation in the response of the preparations was observed over a range of zinc concentrations from 3.5 X 10(-11) to 3.5 X 10(-6) M. All concentrations of zinc inhibited pressor responses during the winter (November to March), but during the spring months (April to May) zinc became very much less effective and low concentrations of zinc potentiated the response. Inhibition of the pressor response at this time only occurred at zinc concentrations above 3.5 X 10(-7) M. In the summer months. (June to September) the zinc effect shifted back towards the winter situation with lower concentration of zinc potentiating and higher concentrations inhibiting vasoconstriction. Pinealectomy of the rats a week prior to preparation of the mesenteric beds very significantly enchanced pressor responses to norepinephrine in the winter months but had much less effect in the summer. The seasonal variation noted in preparations from control rats was maintained following pinealectomy but the amplitude was reduced. Perfusion of melatonin (4.3 X 10(-10) M through preparations from pinealectomized rats enhanced the inhibitory effect of zinc compared to the response to zinc from similarly perfused preparations from control rats. Thus, the rat mesenteric vascular bed is an in vitro model of seasonal variation in vascular reactivity which is sensitive to physiological concentrations of zinc. The origin of the seasonal rhythmicity remains speculative particularly in view of the fact that the rats were maintained under constant photoperiod. That the pineal may modulate the seasonal effect of zinc is suggested by the shift in response to zinc following pinealectomy. Melatonin reversed the effect of pinealectomy on this preparation implicating it as a possible mediator of normal vascular reactivity to zinc. A possible influence of magnetic radiation in evaluating the occurrence of seasonally varying phenomena in vitro should be considered.

Animals↗