Endothelin analogs which distinguish vasoconstrictor and vasodilator ETB receptors

Natarajan, Sesha; Hunt, John T.; Festin, Stephen; Serafino, Randy; Zhang, Rongan; Moreland, Suzanne

doi:10.1016/s0024-3205(95)00070-4

Cited by 5 publications

(7 citation statements)

References 18 publications

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“…In addition, using the synthetic agonists and antagonists RES 701-1, BMS 184696, and BQ 788, the existence of two ET B receptor subtypes was postulated (Natarajan et al 1995;Gellai et al 1996;Schroder et al 1998), namely, ET B1 receptors on the endothelium mediating vasodilation and vasoconstrictor ET B2 receptors located on vascular smooth muscle cells.…”

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confidence: 99%

“…Pharmacological studies aimed at defining the role of vasoconstrictor ET B receptors are highly controversial, and studies from different groups lead to contradictory results even for identical organ systems (Takase et al 1995; Sharifi and Schiffrin 1996; Touyz et al 1995; Mickley et al 1997; Rizzoni et al 1997; Adner et al 1998). In addition, using the synthetic agonists and antagonists RES 701-1, BMS 184696, and BQ 788, the existence of two ET B receptor subtypes was postulated (Natarajan et al 1995; Gellai et al 1996; Schroder et al 1998), namely, ET B1 receptors on the endothelium mediating vasodilation and vasoconstrictor ET B2 receptors located on vascular smooth muscle cells.…”

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confidence: 99%

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Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Wendel

Kummer

Knels

et al. 2005

J Histochem Cytochem.

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S U M M A R YThe endothelin/endothelin-receptor system is a key player in the regulation of vascular tone in mammals. We raised and characterized an antiserum against rat ET B receptor and investigated the distribution of ET B receptors in different vascular beds during postnatal development (day 0 through day 28) and in the adult rat. We report the tissuespecific and age-dependent presence of vasoconstrictor ET B receptors. At the time of birth, vascular smooth muscle cells from all tissues examined did not exhibit ET B receptor immunoreactivity. The occurrence of ET B receptor immunoreactivity in the postnatal development was time dependent and started in small coronary and meningeal arteries at day 5, followed by small mesenteric arteries as well as brachial artery and vein at day 14. At day 21, ET B receptors were present in the media of muscular segments of pulmonary artery, large coronary arteries, and intracerebral arterioles. At day 28, ET B receptor immunoreactivity was evident in interlobular renal arteries, vas afferens, and efferens. Large renal arteries, mesenteric artery, and elastic segments of pulmonary arteries, as well as coronary and mesenteric veins, did not exhibit ET B receptor immunoreactivity. These data demonstrate the age-dependent and tissue-specific presence of ET B receptors, mainly on arterial smooth muscle cells in the vascular system of the rat. E ndothelin -1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide (Yanagisawa et al. 1989). It takes part in the regulation of vascular tone after birth (for review see Perreault and Coceani 2003) and is implicated in the pathophysiology of cardiovascular, renal, and pulmonary diseases (Saito et al. 1990;Watanabe et al. 1990;Larriviere and Lebel 2003;Michel et al. 2003).ET-1 exerts its biological effects through two distinct ET-receptor subtypes, ET A and ET B . ET A receptors on smooth muscle cells exclusively mediate vasoconstriction, whereas ET B receptors can mediate both vasodilation as well as vasoconstriction, depending on their location on endothelial cells and vascular smooth muscle, respectively. While the role of the ET A receptor subtype in mediating vasoconstriction is beyond debate, the existence of ET B receptors on vascular smooth muscle cells in distinct vascular beds is still controversial, and systematic histological investigations on the distribution pattern of vascular ET receptors are missing. Recently, colocalization of ET A and ET B receptors on arterial smooth muscle cells in the coronary circulation (Wendel-Wellner et al. 2002) and small pulmonary arteries of adult rats were demonstrated (Soma et al. 1999).Pharmacological studies aimed at defining the role of vasoconstrictor ET B receptors are highly controversial, and studies from different groups lead to contradictory results even for identical organ systems (Takase et al.

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confidence: 99%

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confidence: 99%

Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Wendel

Kummer

Knels

et al. 2005

J Histochem Cytochem.

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“…The ETB functional assays were performed as previously described. 28 In Vivo Rat Pressor Studies. This study was performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…The activity of ET B receptors can be observed in vitro by contracting Wistar rat isolated aorta with phenylephrine and then relaxing that contraction with ET B -selective peptide sarafotoxin s6c. 28 Compound 20 blocked the relaxations in a concentration dependent manner (ET B K B ) 0.64 ( 0.1 µM).…”

Section: Structure-activity Relationshipsmentioning

confidence: 95%

Biphenylsulfonamide Endothelin Antagonists: Structure−Activity Relationships of a Series of Mono- and Disubstituted Analogues and Pharmacology of the Orally Active Endothelin Antagonist 2‘-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4‘-(2-methylpropyl)[1,1‘-biphenyl]-2-sulfonamide (BMS-187308)

Murugesan

et al. 1998

J. Med. Chem.

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Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

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“…There are three endothelin isoforms (ET‐1, ‐2 and ‐3) encoded by three distinct, independently expressed genes. Endothelin receptors are present on many cell types and there are at least two receptor subtypes, ET‐A receptors (ET‐RA) and ET‐B receptors (ET‐RB) 2, 3, which are both seven‐transmembrane domain G protein‐coupled receptors 4, 5. Endothelins have many roles, including regulation of cell growth 1, 6, differentiation 7, inflammation 8, and angiogenesis 9.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors

2002

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Endothelins (ET‐1, ET‐2 and ET‐3) are 21‐amino acid vasoactive peptides that bind to G‐protein‐linked transmembrane receptors, ET‐RA and ET‐RB. As well as modulating vasoconstriction, endothelins regulate growth in several cell types and may also affect differentiation, inflammation and angiogenesis. Both macrophages and endothelins are found in areas of hypoxia in solid tumors and ET‐2 expression may be modulated by hypoxia in some tumors. As the peptide structure of mature endothelins is similar to that of CXC chemokines, we asked if endothelins contribute to control of macrophage distribution in tumors. We found that ET‐2 is a chemoattractant for macrophages and THP‐1 monocytic cells, but not for freshly isolated monocytes. The chemotactic response to ET‐2 shows a typical bell‐shaped response curve. Experiments with endothelin receptor antagonists showed that migration to ET‐2 is mediated via the ET‐RB receptor. Moreover, monocytes do not express ET‐RB. Chemotaxis towards ET‐2 is via the MAPK pathway: p44 and p42 are phosphorylated when THP‐1 cells are stimulated with ET‐2, and the MAPKK inhibitor PD98059 stops chemotaxis. As with ‘classical’ chemokines, migration toET‐2 is also inhibited by hypoxia and by pertussis toxin. As well as its chemotactic properties, ET‐2 leads to activation of macrophages. In human breast tumors that express ET‐2, endothelins and ET‐RB expressing macrophages often co‐localized. While shorter than ‘classical’ chemokines, ET‐2 shares a similar peptide sequence with chemokines and may signal via a similar receptor and MAPK‐mediated pathway. Furthermore, ET‐2 expression by tumors may modulate the behavior of macrophages such that activated cells accumulate in areas of hypoxia.

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Endothelin analogs which distinguish vasoconstrictor and vasodilator ETB receptors

Cited by 5 publications

References 18 publications

Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Biphenylsulfonamide Endothelin Antagonists: Structure−Activity Relationships of a Series of Mono- and Disubstituted Analogues and Pharmacology of the Orally Active Endothelin Antagonist 2‘-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4‘-(2-methylpropyl)[1,1‘-biphenyl]-2-sulfonamide (BMS-187308)

Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors

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Endothelin analogs which distinguish vasoconstrictor and vasodilator ETB receptors

Cited by 5 publications

References 18 publications

Muscular ETBReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Muscular ETBReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Biphenylsulfonamide Endothelin Antagonists: Structure−Activity Relationships of a Series of Mono- and Disubstituted Analogues and Pharmacology of the Orally Active Endothelin Antagonist 2‘-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4‘-(2-methylpropyl)[1,1‘-biphenyl]-2-sulfonamide (BMS-187308)

Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors

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Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature

Muscular ET_BReceptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature