Physiology and pharmacology of prostaglandins

Prostaglandins (PGs) are products of polyunsaturated acid metabolism, particularly arachidonic acid (AA) released from membrane phospholipids by the action of phospholipase A2 in response to a variety of physical, chemical, and neurohormonal factors. AA is rapidly metabolized to oxygenated products by two distinct enzymatic pathways: cyclooxygenase and lipoxygenase. The intermediate cyclooxygenase products are converted to primary PGs, while the lipoxygenase products are converted to leukotrienes. The generation of various cyclooxygenase products varies from tissue to tissue. Aspirin and related antiinflammatory drugs reduce tissue biosynthesis of all cyclooxygenase products; their therapeutic effects and side effects parallel the inhibition of cyclooxygenase. Exogenous PGs exhibit a broad spectrum of effects. PGs of the E series and PGI2 are generated by the endothelium and the vessel wall to maintain the microcirculation and to counteract the vasoconstrictive and proaggregatory actions of thromboxane A2 (TXA2). Exogenous PGs of the E and I series are potent vasodilators in various vascular beds, and result in decreased systemic blood pressure and reflex stimulation of heart rate. PGEs and PGI2 increase renal blood flow and provoke diuresis and natriuresis, partly by modulating the renin-angiotensin-aldosterone system. PGFs contract the bronchial and gut muscle, while PGEs and PGI2 have opposite effects. PGEs and PGFs, but not PGI2, cause a strong contraction of the uterine muscle, hence their undesirable uterotonic effects. PGEs relax bronchial muscle, whereas PGFs cause bronchoconstriction; their imbalance may contribute to the high bronchial tone in bronchial asthma. PGs of the E and I series and TXA2 are generated by the gastrointestinal mucosa and released into the lumen upon neural or hormonal stimulation; they probably participate in the maintenance of mucosal integrity and microcirculation. Exogenous PGs of the E and I series inhibit gastric acid secretion and stimulate alkaline secretion while increasing mucosal blood flow. All PGs, including those noninhibitory for acid secretion, are cytoprotective against various ulcerogens and necrotizing agents. The classic PGs constitute only a small fraction of biologically active products of AA metabolism, and recent studies on the lipoxygenase products emphasize their biological activity and involvement in a variety of pathological conditions.