Leukotrienes physiologic effects

PRIMARY PHYSIOLOGIC EFFECTS OF THE MAJOR CLASSES OF PROSTAGLANDINS, THROMBOXANES, AND LEUKOTRIENES ... 

The physiological effects of the sulphidopeptide leu-kotrienes, including LTC4, are potent contraction of bronchial smooth muscle, contraction of arterial, arteriolar and intestinal smooth muscle, enhanced permeability of post-capillary venules and enhanced bronchial mucus secretion. Because of their potent effects on the airways, leukotrienes have long been regarded as important molecules in the pathogenesis of asthma. Because of this, and the multicellular provenance of leukotrienes many comprehensive reviews have been written on these molecules to which the reader is referred (Ford et al., 1994 Chanarin and Johnston, 1994 Valone et al., 1994). 

The eicosanoids—prostaglandins (PGs), thromboxanes (TXs), prostacyclins (PGIs), and leukotrienes (LTs)—are derived from essential fatty acids and act similarly to hormones (Chapter 30). However, they are synthesized in almost all tissues (unlike hormones, which are synthesized in selected tissues) and are not stored to any significant extent their physiological effects on tissues occur near sites of synthesis rather than at a distance. They function as paracrine messengers and are sometimes referred to as autacoids. 

Fatty acids are saturated and unsaturated carboxylic acids containing between twelve and twenty-four carbon atoms. Fatty acids with even numbers of carbon atoms occur most frequently in nature. The reactions of fatty acids are identical to those of carboxylic acids. They include esterification, production by acid hydrolysis of esters, saponification, and addition at the double bond. Prostaglandins, thromboxanes, and leukotrienes are derivatives of twenty-carbon fatty acids that have a variety of physiological effects. 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

The prostaglandins, thromboxanes, and leukotrienes have been shown to have a variety of effects on virtually every major physiologic system. Studies have indicated that these compounds can influence cardio-... 

This is most effectively achieved by physiological antagonism of bronchial muscle contraction, namely by stimulation of adrenergic bronchodilator mechanisms. Pharmacological antagonism of specific bronchoconstrictors is less effective either because individual mediators are not on their own responsible for a large part of the bronchoconstriction (acetylcholine, adenosine, leukotrienes) or because the mediator is not even secreted during asthma attacks (histamine). 

The acetylenic fatty acids 15-hexadec5moic (15-HDYA) and 17-ODYA have also been explored as modulators of leukotriene (LTB ), an important and clinically relevant inflammatory mediator, and its physiologically active (o-hydroxylated metabolite . Both 15-HDYA and 17-ODYA inactivated the polymorphonuclear leukocytic LTB whole cells and cell lysates . In contrast, the shorter-chain acid, 10-undecynoic acid was much less effective, while the saturated analogs of 15-HDYA and 17-ODYA were inactive. 15-HDYA and 17-ODYA also inactivate pulmonary prostaglandin (o-hydroxylases . 

A,, 8-hydroxyeicosatetraenoic acid, 12-hydroxy-eicosatetraenoic acid, and 12-hydroxystearic acid . The physiological relevance of some of these reactions is of interest but the effects of variability of P450 4F2 have not been demonstrated. Part of the interest lies in the fact that leukotriene... 

Because terhutaline interacts with adrenoceptors and leukotriene with leukotriene receptors, terbutaline cannot be a pharmacologic antagonist of leukotriene. Because the results of adrenoceptor activation oppose the effects of leukotriene receptor activation, terbutaline must be a physiologic antagonist. The answer is (C). 

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