Eicosanoid antagonists

Cox-1 is constitutively expressed and responsible for most of the housekeeping functions of eicosanoids, including processes such as calcium metabolism in the bone, and stomach mucous membrane maintenance. It is also responsible for synthesis of thromboxanes in thrombocytes and of prostacyclin (PGI) in endothelial cells, which have antagonistic function in thrombocyte aggregation and activation (see later). 

In a human lung epithelial cell line, in which histamine increased the intracellular calcium concentration and the formation of eicosanoids, this response was antagonized by the histamine Hi receptor antagonist diphenhydramine but unaffected by the H2 receptor antagonist cimetidine. Fenspiride inhibited Hi receptor-induced calcium increase. Histamine also caused a biphasic increase in arachidonic acid release, which was inhibited by fenspiride. This study suggests a further mechanism that would promote antiinflammatory and bronchodilator properties. 

Muller C, Endlich K, Elelwig JJ AT2 antagonist-sensitive potentiation of angiotensin ll-induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature. Br J Pharmacol 124 946-52,1998... 

The major eicosanoids are products of 0)-6 essential fatty acids, and the essentiality of this group of fatty acids relates primarily to their functions as eicosanoids. Both the prostanoids and the leukotrienes (LTs) were discovered as vasoactive substances active on reproductive and pulmonary smooth muscle, respectively. The structures of the more stable prostanoids were determined in the late 1950s and early 1960s by workers at the Karolinksa Institute in Sweden and Unilever Laboratories in the Netherlands. The LTs were known initially as slow-reacting substances of anaphylaxis. Their structures were determined in the early 1980s. The details of the pathways and the enzymes and receptors for these pathways were characterized over the last 35 years. Because eicosanoid overproduction is associated with a number of pathologies, potent enzyme inhibitors and receptor antagonists have been developed that are widely used therapeutically. 

Figure 18-1. Synthesis of eicosanoids and sites of inhibitory effects of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and leukotriene antagonist drugs.

Prostaglandins and other Eicosanoids (ii) Antilipedemic Drugs Hi) Hormone Antagonists... 

The thromboxane receptor antagonist S18SS6 but not aspirin inhibits athero genesis in apo E-deficient mice evidence that eicosanoids other than thromboxane contribute to atherosclerosis. 

---