Characterization of Cysteinyl Leukotriene Receptors on Human Saphenous Veins: Antagonist Activity of Montelukast and its Metabolites

Abstract

The aims of this study were to determine the cysteinyl leukotriene (CysLT) receptors expressed in the human saphenous vein, to examine contractile response to LTC4 and LTD4, to evaluate antagonist activity of montelukast, a specific CysLT1 receptor antagonist used in asthma, and to characterize the CysLT receptors involved in the contractile response. The analysis by reverse-transcriptase polymerase chain reaction indicated that CysLT1 and CysLT2 receptors are expressed by saphenous veins. In varicose vein rings, the potencies (pD2) of LTC4 and LTD4 were similar: 7.4 +/- 0.2 and 7.4 +/- 0.1, respectively. Pretreatment with acivicin, a gamma-glutamyl transpeptidase (gamma-GT) inhibitor, to prevent potential metabolism of LTC4 to LTD4, did not alter the response to LTC4. In nondistended vein rings from patients undergoing arterial bypass, the LTC4 pD2 was 7.8 +/- 0.1, and pretreatment with S-hexyl-GSH, a potent gamma-GT inhibitor, caused a fourfold rightward shift of the LTC4 concentration-response curve. In varicose and nondistended saphenous vein rings, montelukast (10(-8) and 10(-7) M) exerted a potent activity against LTD4 and LTC4, in the presence or absence of gamma-GT inhibitors. In varicose vein rings, the two active metabolites of montelukast also exerted antagonist activities with potencies similar to montelukast. BAY u9773 (CysLT2 agonist/dual CysLT1/CysLT2 antagonist) did not cause contraction and inhibited the LTC4- and LTD4-induced contractions. In conclusion, human saphenous veins express CysLT1 and CysLT2 receptors, but only CysLT1 receptors are implicated in the contraction.

Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics

“…Study demonstrated that human saphenous veins were sensitive to LTC 4 and LTD 4 , and these ligands were equipotent in producing a marked constriction, which was unaltered by inhibitors of nitric oxide. However, lower concentrations of LTC 4 and LTD 4 induced relaxations in human saphenous veins that were dependent on nitric oxide and prostanoid release [119] . Moreover, human artery smooth muscle cells have been shown to increase intracellular calcium by LTC 4 , which was not inhibited by CysLT 1 receptor antagonist but inhibited by a calcium channel blocker, ni cardipine, which is known to be a vasorelaxant [120] .…”

The role of small airway disease in asthma

“…This is in line with other observations [42] and calls upon strategies to control mast cell-induced or mast cell-associated inflammation. The majority of mast cells express leukotriene C4-synthase, a key enzyme in leukotriene synthesis [44], while the affinity and the number of cysteinyl leukotriene receptors are actually higher within peripheral than in central airways [45]. The majority of mast cells express leukotriene C4-synthase, a key enzyme in leukotriene synthesis [44], while the affinity and the number of cysteinyl leukotriene receptors are actually higher within peripheral than in central airways [45].…”

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…RT-PCR has allowed the demonstration that human saphenous veins express both a functional CysLT 1 R, which mediates contractile effects of cysteinyl LTs, but also a CysLT 2 R, which, on the contrary, does not seem to be implicated in contraction (Mechiche et al, 2004) and whose functional role remains to be determined (Allen et al, 1992). Human pulmonary veins also express both receptors and although activation of the former induced the release of a contractile factor only partially blocked by CysLT 1 R antagonists, the activation of the CysLT 2 R released nitric oxide (NO) (Ortiz et al, 1995).…”