Prostanoids and Drugs

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Genetic and pharmacological analysis of prostanoid receptor function

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Charles Burger, MD, describes the mechanism of action of modern oral prostanoids, and discusses how the latest guidelines address the use of combination therapy in pulmonary arterial hypertension. Charles Burger, MD: Infusion prostanoids are basically replacing what we know to be a suboptimal level of endogenously produced prostacyclin or prostaglandin I2, which has several beneficial effects in the pulmonary circulation.

Some of that effect is acting on prostaglandin receptors. Intermittent claudication IC is a symptom of lower limb ischaemia that results from peripheral arterial disease PAD. It is evident as muscle pain ache, cramp, numbness or sense of fatigue in the leg muscles that occurs during exercise and is relieved by a short period of rest.

The aim of this review was to evaluate the effects of prostanoids in patients with IC. We identified 18 randomised studies with a total of participants, of which four studies compared the effects of PGE1 versus placebo. Overall, there was insufficient high quality evidence to suggest that PGE1 improves walking distances in people with IC. There was also a lack of evidence to determine if PGE1 was more effective than laevadosin, naftidrofuryl or L-arginine.

Prostanoids and Drugs

Evidence on the efficacy of prostacyclin was inconclusive. Results suggest that, compared with PGE1, prostacyclin may be associated with an increased occurrence of side effects including headache, diarrhoea and facial flushing. Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from the administration of prostanoids.

Further well-conducted randomised, double blinded trials with a sufficient number of participants to provide statistical power are required to answer this question. Peripheral arterial disease PAD is a common cause of morbidity in the general population. While numerous studies have established the efficacy of prostanoids in PAD stages III and IV , the question of the role of prostanoids as an alternative or additive treatment in patients suffering from intermittent claudication PAD II has not yet been clearly answered. This is an update of a Cochrane Review first published in It is very likely that prostanoids are also involved in other steps and mechanisms, as nicely described by Prescott in a recent issue of the JCI Candidates for other PG-involved steps have been suggested by in vitro analysis and include the prevention of apoptosis of transformed cells and the stimulation of tumor-associated angiogenesis.

The cardioprotective effects of low doses of aspirin are attributed to its ability to inhibit cumulatively COX-1 in platelets, as outlined in the contribution from Patrono and colleagues in this series Tx biosynthesis increases during pregnancy, a state of hemostatic activation, and suppression of Tx formation in the mice rescues the phenotype In addition to its vasoconstrictor properties, TxA 2 is a potent mitogen of vascular smooth muscle cells.

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Thus, TP antagonism or TP deletion decreases the vascular proliferative response to catheter-induced injury in the mouse, and TP antagonism retards atherogenesis However, differences in the expression of a hypertensive phenotype in mice lacking the EP2 receptor 25 , 26 have highlighted the importance of genetic background and gender in conditioning this response.

Further insights into the role of prostanoids in hemodynamics, reproduction, and renal function afforded by knockout mice are summarized in Table 1. Cloning of members of the prostanoid receptor family has naturally facilitated reassessment of previously developed receptor-active compounds, as well as the development of new drugs.


Using a panel of Chinese hamster ovary cells stably expressing each cloned receptor, Kiriyama et al. This analysis revealed that most of these compounds exhibit no absolute selectivity. For example, as shown in Table 2 , two PGI 2 analogs, iloprost and carbacyclin, indeed bind to IP with good affinities, but they also bind to EP3 with similar or better affinities, and iloprost binds EP1 as well.

The considerable cross-reactivity exhibited by these conventional PG analogs is probably due to the fact that they have not been selected for by specific binding assays, but were screened for by bioassay on native tissues and cells that express more than one type of prostanoid receptor.

Indeed, Okada et al. Recently, a new generation of compounds has been reported, which have been assessed on a complete set of cloned receptors Table 2. As shown, they are highly selective for each receptor. Indeed, these compounds exert pharmacological actions consistent with the phenotypes of mice deficient in the corresponding receptor. Inhibition constants nM of cloned prostanoid receptors for conventional PG analogs and newly developed compounds.

JCI - Genetic and pharmacological analysis of prostanoid receptor function

What, then, is the clinical potential of these selective agonists and antagonists, specifically when compared with selective inhibitors of COX-2 or with traditional NSAIDs, such as aspirin? Low-dose aspirin is effective in the prevention of myocardial infarction and stroke but can still result in gastric toxicity Indeed, when low-dose aspirin is given to individuals who have not previously suffered an event, the number of strokes and myocardial infarctions prevented is almost precisely balanced by the number of major gastrointestinal events caused by the drug.

COX-2 inhibitors, such as rofecoxib and celecoxib, theoretically bypass the consequences of inhibiting COX-1—dependent prostanoids relevant to homeostatic functions, such as hemostasis and gastric cytoprotection. Indeed, at doses that exhibit similar efficacy in the treatment of arthritis, rofecoxib, the most selective compound currently approved for clinical use, results in considerably less gastrotoxicity than the isoform-nonspecific inhibitor naproxen.

However, although COX-2 is typically induced by inflammatory stimuli, its products may also play a protective effect in some settings.

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Thus, COX-2 appears to be the predominant source of PGI 2 formation by the normal vasculature 30 , perhaps due to induction of endothelial expression by physiological rates of shear. In addition to its role as a vasodilator and platelet inhibitor, PGI 2 appears to be important in protecting cardiomyocytes from oxidant stress Likewise, COX-2 products appear to mediate the late phase of cardiac preconditioning Indeed, prostanoids formed during inflammation are not exclusively proinflammatory 6.

Clearly, these observations raise the possibility that compounds acting on specific receptors may offer advantages over upstream inhibitors. In contrast to deletion of COX-2 or, indeed, both COX isozymes, deletion of prostanoid receptors, with the exception of EP4, have not been associated with serious problems during development or in the perinatal period, and the mature animals appear normal under physiological conditions.

A combination of pharmacological and genetic approaches may be needed to elucidate the different effects of receptor antagonism or of COX inhibition. There is now considerable interest in the putative nuclear actions of prostanoids These compounds were first identified in culture media containing PGD 2 , and later studies revealed that dehydration was carried out by slow catalysis of serum albumin in the culture medium. It remains controversial whether PGJ 2 is actually formed in vivo and, if so, to what extent. On the one hand, there is evidence for detection of it or its metabolites based on immunoassays in human urine and in body fluids, such as inflammatory exudates 6.

However, these assays have not been validated by physicochemical methods. Recently, there has been a preliminary report of detecting the PGJ 2 metabolite in human urine However, little information on the assay was provided, and there remains a clear need to determine whether biologically active quantities of PGs of the J series are actually formed in vivo. It has been suggested that cyclopentenone PGs are so reactive that they might largely elude detection in body fluids such as plasma or urine. In any event, the quantities of exogenous PGJ 2 ligands shown to activate PPARs are usually in the 5—10 micromolar range, whereas conventional PGs, acting via membrane receptors, are active in the nanomolar to femtomolar range, consistent with the amounts of these compounds actually formed in vivo.

Thus, given that several polyunsaturated fatty acids can ligate PPARs at concentrations actually found in cells, we believe that the case for these dehydration products to function as physiological mediators remains unproven. Calculations based on bound radioactivity suggest that more than 10 5 proteins are modified, far exceeding the number of nuclear receptors Thus, a broad range of activities — antiproliferative, antiviral, and anti-inflammatory effects, for example — might be anticipated when the synthetic compounds are applied in sufficient concentrations in vitro.

Whether these activities occur in vivo remains a more controversial issue. Less evidence supports a role for other eicosanoids as nuclear ligands. Clarity may be afforded on this issue by comparing the phenotypes of mice lacking biosynthetic enzymes e. admin