In general, metabolism leads to a reduction or inactivation of the biological effects of the prostanoid, whilst at the same time facilitating renal clearance.
Metabolism can occur in a number of tissues, particularly in the lung, the liver, and the kidney. The inactivation of prostanoids is rapid and mostly limited to the local site of their release. The lungs occupy a strategic position between the venous and arterial circulation. About 90 per cent of prostanoids escaping the local circulation are removed by a single passage through the lung via enzymatic degradation. Epoprostenol represents an exception of this rule because its pulmonary metabolism is negligible. Epoprostenol and TXA2 are chemically unstable and hydrolyze spontaneously to the stable metabolites 6-keto-PGF 1a and thromboxane B2. The elimination half-life of prostanoids ranges from 30 s to about 5 min (Va.D.e...§n.d...O.!,Gr§dy,.,!99,3,).
Physiological effects Cardiovascular system
A local generation of prostanoids is involved in the control of vascular tone in humans.
PGE2, PGE1, and epoprostenol represent potent vasodilators in almost every vascular bed studied because of a relaxation of vascular smooth muscles in large and small arterial vessels. Both vasodilation and enhancement of thromboresistance by inhibiting the clumping and sticking of platelets and leukocytes to the vascular endothelium result in improved microcirculatory function.
TXA2, which is a strong vasoconstrictor, causes biological effects that are generally the opposite of those produced by vasodilatory prostaglandins ( VaQ.e,,§.Qd O',Gia.dY,
A normal ratio of TXA2 to epoprostenol is important in maintaining the physiological role of platelets and coagulation. TXA 2 most powerfully activates platelet aggregation, whereas epoprostenol represents its natural opponent. In this respect epoprostenol is much more potent than either PGE 1 or PGE2, and its effects last longer.
Epoprostenol and the E series prostaglandins manifest both pro- and anti-inflammatory properties.
When released at the local side of inflammation the vasodilating prostaglandins tend to act as proinflammatory 'modulators' rather than as true inflammatory mediators, since these substances alone are not capable of causing extravasation of plasma. However, prostanoids contribute to the signs and symptoms of inflammation by accentuating the pain and edema initially produced by histamine, serotonin, and bradykinin.
Epoprostenol and the PGEs inhibit macrophage as well as polymorphonuclear leukocyte activation and adhesion to damaged vascular endothelium. In particular, PGE2 decreases T-lymphocyte activation by inhibiting the production of the regulatory cytokine interleukin 2 and also interferes with B-cell functions. Moreover, both epoprostenol and the PGEs inhibit the release of the proinflammatory cytokine, i.e. tumor necrosis factor-a and interleukin 1, from activated mononuclear leukocytes.
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