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Medical > Therapy > Specific treatments

Prostanoids
Rationale and mechanism of action

 

Prostacyclin is the main product of arachidonic acid in all vascular tissues tested so far. The ability of the vessel wall to synthesize prostacyclin is greatest in the endothelium and progressively decreases from the intima to the adventitia. Prostacyclin is not biologically active after oral ingestion. If administered intravenously, however, it is a powerful vasodilator in all vascular beds. (Dusting et al. 1979). Its short half-lives of about 5 minutes make continuous infusion necessary, but render the drug relatively safe even in critically ill patients, since adverse effects disappear shortly after discontinuation. In addition to its vasodilatory effects, prostacyclin is the most potent endogenous inhibitor of platelet aggregation (Moncada et al. 1979), and also decreases in vitro the proliferation of vascular smooth muscle cell growth (Clapp et al. 2002).

The effects of prostacyclin are mediated by stimulation of adenylate cyclase, which leads to an increase in cyclic adenosine monophosphate (cAMP) in platelets and smooth muscle cells. The rationale for the use of prostacyclin in PAH is the documented dysregulation of the arachidonic acid metabolism in these patients. They exhibit a significant increase in urinary excretion of metabolites thromboxane A2 (Christman et al. 1992), which is both a vasoconstrictor and a potent stimulus for platelet aggregation. By contrast, the release of prostacyclin is depressed. Moreover, prostacyclin synthase expression has been shown to be reduced in the pulmonary arteries of patients with PAH (Tuder et al. 1999). In an animal model of mice transgenic for prostacyclin synthase, protection from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia has been documented (Geraci et al. 1999).

References

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