Reproductive—The actions of prostaglandins on reproductive smooth muscle are discussed below under section D, Reproductive Organs.
B. Platelets
Platelet aggregation is markedly affected by eicosanoids. PGI2, a major product of endothelial-derived COX-2, is a potent inhibitor of platelet aggregation. This inhibition occurs via an IP receptor-dependent elevation in Gs activity and cAMP. Dysfunctional genetic variants in the human prostacyclin receptor as well as drug inhibition of COX-2 (reducing prostacyclin signaling and production, respectively) lead to increased platelet activation and aggregation. This has recently been demonstrated to have major implications regarding adverse cardiovascular events, as described below (see Inhibition of Eicosanoid Synthesis). TXA2 is the major product of platelet COX-1, the only COX isoform expressed in mature platelets, with COX-1-derived PGD2 found in lesser amounts. TXA2 is a powerful inducer of platelet aggregation. TXA2 additionally amplifies the effects of other, more potent, platelet agonists such as thrombin. The TP-Gq signaling pathway elevates intracellular Ca2+ and activates protein kinase C, facilitating platelet aggregation and TXA2 biosynthesis. Activation of G12/ G13 induces Rho/Rho-kinase–dependent regulation of myosin light chain phosphorylation leading to platelet shape change. Mutations in the human TP have been associated with mild bleeding disorders. The platelet actions of TXA2 are restrained in vivo by PGI2, which inhibits platelet aggregation by all recognized agonists, and PGD2. Platelet COX-1-derived TXA2 biosynthesis is increased during platelet activation and aggregation and is irreversibly inhibited by chronic administration of aspirin at low doses. Urinary metabolites of TXA2 increase in clinical syndromes of platelet activation, such as diabetes mellitus, and particularly in patients with myocardial infarction and stroke. Macrophage COX-2 appears to contribute roughly 10% of the increment in TXA2 biosynthesis observed in smokers, while the rest is derived from platelet COX-1. A variable contribution, presumably from macrophage COX-2, may be insensitive to the effects of low-dose aspirin. In a single trial comparing lowand high-dose aspirin, no increase in benefit was associated with increased dose; in fact, this study, as well as indirect comparisons across placebo-controlled trials, suggests an inverse dose-response relationship, perhaps reflecting increasing inhibition of PGI2 synthesis at higher doses of aspirin. Low concentrations of PGE2 enhance (via EP3 receptors), whereas higher concentrations inhibit (via IP receptors), platelet aggregation. PGD2 inhibits aggregation via DP1, leading to increased cAMP generation.
C. Kidney
Both the medulla and the cortex of the kidney synthesize prostaglandins, the medulla substantially more than the cortex. COX-1 is expressed mainly in cortical and medullary collecting ducts and mesangial cells, arteriolar endothelium, and epithelial cells of Bowman’s capsule. COX-2 is restricted to the renal medullary interstitial cells, the macula densa, and the cortical thick ascending limb.