The prostaglandins and thromboxanes have major effects on smooth muscle in the vasculature, airways, and gastrointestinal and reproductive tracts. Contraction of smooth muscle is mediated by the release of calcium, while relaxing effects are mediated by the generation of cAMP. Many of the eicosanoids’ contractile effects on smooth muscle can be inhibited by lowering extracellular calcium or by using calcium channel-blocking drugs. Other important targets include platelets and monocytes, kidneys, the central nervous system, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye (the effects on the eye may involve smooth muscle).
A. Smooth Muscle 1. Vascular—TXA2 is a potent vasoconstrictor. It is also a smooth muscle cell mitogen and is the only eicosanoid that has convincingly been shown to have this effect. The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone, which up-regulates smooth muscle cell TP expression. PGF2α is also a vasoconstrictor but is not a smooth muscle mitogen. Another vasoconstrictor is the isoprostane 8-iso-PGF2α, also known as iPF2αIII, which may act via the TP receptor.
Vasodilator prostaglandins, especially PGI2 and PGE2, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, primarily via the IP and EP4 receptors. Vascular PGI2 is synthesized by both smooth muscle and endothelial cells, with the COX-2 isoform in the latter cell type being the major contributor. In the microcirculation, PGE2 is a vasodilator produced by endothelial cells. PGI2 inhibits proliferation of smooth muscle cells, an action that may be particularly relevant in pulmonary hypertension. PGD2 may also function as a vasodilator, in particular as a dominant mediator of flushing induced by the lipid-lowering drug niacin.
2. Gastrointestinal tract—Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle. Longitudinal muscle is contracted by PGE2 (via EP3) and PGF2α (via FP), whereas circular muscle is contracted strongly by PGF2α and weakly by PGI2, and is relaxed by PGE2 (via EP4). Administration of either PGE2 or PGF2α results in colicky cramps (see Clinical Pharmacology of Eicosanoids, below). The leukotrienes also have powerful contractile effects.
TABLE 18–1 Eicosanoid receptors.1 1Splice variants for the eicosanoid receptors are indicated where appropriate. Ca2+i, intracellular calcium; cAMP, cyclic adenosine 3’,5’-monophosphate; PLC, phospholipase C; isoPs, isoprostanes; 15d-PGJ2, 15-deoxy-Δ12,14-PGJ2.
3.
Airways—Respiratory smooth muscle is relaxed by PGE2 and PGI2 and contracted by PGD2, TXA2, and PGF2α. Studies of DP1 and DP2 receptor knockout mice suggest an important role of this prostanoid in asthma, although the DP2 receptor appears more relevant to allergic airway diseases. The cysteinyl leukotrienes are also bronchoconstrictors. They act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine, both in vitro and in vivo. They also stimulate bronchial mucus secretion and cause mucosal edema. Bronchospasm occurs in about 10% of people taking NSAIDs, possibly because of a shift in arachidonate metabolism from COX metabolism to leukotriene formation.
4.