leukotriene-d4 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

Topics: Animals; Blood Pressure; Cyclosporine; Drug Interactions; Hypertension; Indomethacin; Kidney; Kidney Diseases; Leukotriene D4; Lipoxygenase; Male; Rats, Sprague-Dawley; Signal Transduction

Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension.. We investigated, in spontaneously hypertensive rats (SHR), the involvement of cysLT in the in-vivo regulation of blood pressure and the in-vitro endothelium-dependent contraction to acetylcholine in isolated aorta.. SHR and Wistar-Kyoto rats (WKY) were orally treated for 3 weeks with either the cysLT biosynthesis inhibitor MK-886 (0.1 mg/ml) or vehicle. After mean arterial blood pressure (MABP) measurement, aortic ring preparations were removed from all groups of animals, and contractions and relaxations were monitored subsequent to stimulation with acetylcholine.. MABP was higher in SHR. Chronic treatment with MK-886 did not alter MABP in either SHR or WKY. In the presence of the N-nitro-L-arginine (L-NA, 100 micromol/l), and on prostaglandin F2alpha (PGF2alpha)-induced tone, acetylcholine evoked concentration-dependent contractions in intact aortic rings from SHR only. Pretreatment with either MK-886 (10 micromol/l), the 5-lipoxygenase (5-LO) inhibitor AA861 (10 micromol/l), or the cysLT1 receptor antagonist MK571 (1 micromol/l) reduced (P < 0.05) acetylcholine-induced contractions in intact aortic rings from SHR only. Acetylcholine-induced contractions were weaker (P < 0.01) in SHR chronically treated with MK-886 than in SHR. In the presence of L-NA, leukotriene (LT) D4 induced greater (P < 0.05) concentration-dependent contractions in aortic rings from SHR than from WKY. MK571 abolished LTD4-evoked contractions.. These data suggested that 5-LO-derived products, through the activation of cysLT1 receptors, could be involved in the endothelium-dependent contraction to acetylcholine in aorta from SHR but not in the regulation of MABP in SHR.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arachidonate 5-Lipoxygenase; Benzoquinones; Biopterins; Blood Pressure; Body Weight; Dinoprost; Endothelium, Vascular; Hypertension; Indoles; Leukotriene D4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Nitroarginine; Propionates; Quinolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Leukotriene; Vasoconstriction

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