leukotriene-e4 and Hypertension

Leukotrienes are potent inflammatory mediators synthesized locally within the cardiovascular system through the 5-lipoxygenase pathway of arachidonic acid metabolism. The leukotrienes, consisting of dihydroxy leukotriene LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, act by targeting cell surface receptors expressed on inflammatory cells and on structural cells of vessel walls. LTB, induces leukocyte activation and chemotaxis via high- and low-affinity receptor subtypes (BLT1 and BLT2), respectively. Recently, BLT, receptors were found on human vascular smooth muscle cells, inducing their migration and proliferation. Cysteinyl leukotrienes are vasoconstrictors and induce endothelium-dependent vascular responses through the CysLT, and CysLT2 receptor subtypes. There is also pharmacological evidence for the existence of further CysLT receptor subtypes. Taken together, experimental and genetic studies suggest a major role of leukotrienes in atherosclerosis and in its ischemic complications such as acute coronary syndromes and stroke. Furthermore, the effects on vascular smooth muscle cells suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the leukotriene pathway in cardiovascular disease.

Topics: Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm; Arachidonic Acid; Atherosclerosis; Cardiovascular Diseases; Cell Movement; Coronary Restenosis; Disease Models, Animal; Guinea Pigs; Humans; Hypertension; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Mice; Muscle, Smooth, Vascular; Rats; Receptors, Leukotriene; Stroke

Cysteinyl-leukotrienes, i.e. leukotriene (LT) C4, D4 and E4, are inflammatory mediators and potent airway- and vasoconstrictors. Two different cysteinyl-leukotriene receptors have been cloned, CysLT1 and CysLT2. This report reviews recent data on CysLT receptor characterisation as well as studies of modulatory mechanisms involved in cysteinyl-leukotriene-induced responses. On the basis of functional studies in isolated smooth muscle preparations, the existence of an additional receptor for cysteinyl-leukotrienes is suggested. In addition, cysteinyl-leukotriene responses in pulmonary vessels were regulated by the release of modulatory factors, of which cyclooxygenase products dominated in the arteries and nitric oxide was the main modulator in porcine pulmonary veins. Moreover, the interconversion between LTC4 and LTD4 and the metabolism into LTE4 may represent a major modulatory mechanism in the guinea-pig trachea by deciding which CysLT receptor is activated by the cysteinyl-leukotrienes.

Topics: Animals; Bronchoconstriction; Endothelium, Vascular; Guinea Pigs; Humans; Hypertension; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Membrane Proteins; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Prostaglandins; Pulmonary Artery; Pulmonary Veins; Receptors, Leukotriene; Swine; Trachea