Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor

Ihara, Masaki; Noguchi, Kazuhito; Saeki, Toshihiko; Fukuroda, Takahiro; Tsuchida, Sonoko; Kimura, Sachiyo; Fukami, Tatsuki; Ishikawa, Kiyofumi; Nishikibe, Masaru; Yano, Mitsuo

doi:10.1016/0024-3205(92)90331-i

Cited by 862 publications

(321 citation statements)

References 21 publications

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“…receptors are thought to be located on the vascular smooth muscle, and their mechanism of action is unknown (1 [2][3][4][5][6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

1994

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ABSTRACT. The physiologic role of endothelin-1 (ET-1) and its receptors in regulating fetal pulmonary vascular tone is unknown. We therefore investigated the role of ET-1 and its receptors in the regulation of fetal pulmonary vascular tone using BQ 123 (an ET, receptor antagonist) and 4 Ala ET-1 (an ETb receptor agonist). In six fetal sheep in utero, we found that injections of ET-1 (250 ng/ kg fetal weight) into the left pulmonary artery increased left pulmonary blood flow (21.0 f 17.5 to 74.7 f 32.9 mL/ kg/min, p < 0.05) and decreased left pulmonary vascular resistance (6.02 f 7.00 to 0.84 f 0.48 mm Hg/kg/min/mL, p c 0.05). BQ 123 (5 mg) increased pulmonary blood flow (24.6 f 28.7 to 47.7 f 27.4 mL/kg/min, p < 0.05) and 1 1, 18). We have previously shown that BQ 123 is a selective ET, antagonist in newborn lambs and inhibits ET-I-induced pulmonary vasoconstriction (8). In contrast to BQ 123,4 Ala ET-1 is a selective ETh agonist that induces pulmonary vasodilation during U44619-induced pulmonary hypertension ( 18).This study had two main objectives. The first was to investigate the role of ET-I and its receptors in the regulation of pulmonary vascular tone in near-term, chronically instrumented fetal sheep in tttero by studying the effects of a selective ET-I receptor antagonist and agonist. The second objective was to investigate the mechanism of the ET-I effect on the pulmonary circulation. For the first objective, we studied the effects of injections of ET-1 and 4 Ala ET-I into the left pulmonary artery and inferior vena cava and infusions of BQ 123 into the left pulmonary artery on fetal pulmonary vascular tone. For the second objective, we compared the hemodynamic effects of exogenous ET-1 before and during the infusion of glibenclamide (an ATP-dependent potassium channel blocker). MATERIALS AND METHODSSztrgical preparation. Fetal surgery was performed as previously described (19). Briefly, a total of six Western fetal sheep were studied at 135.8 k 6.1 d gestational age (term 145 d). The ewe was anesthetized with an epidural injection of 4 mL of I % tetracaine hydrochloride. Polyvinyl catheters were inserted into the maternal pedal vein and artery after local infiltration with 2% lidocaine hydrochloride.With use of aseptic techniques, the uterus was exposed through a midline incision. Through a small uterine incision the hind limb was exposed, and polyvinyl catheters were inserted into the fetal wdal vein and artery and their tips advanced to the descend- Polyvinyl catheters were then inserted into the internal thoracic

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“…receptors are thought to be located on the vascular smooth muscle, and their mechanism of action is unknown (1 [2][3][4][5][6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

1994

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“…It has been demonstrated that not only ETA but also ETB receptors can mediate vaso-or bronchoconstriction [4][5][6]. Furthermore, the importance of ETB receptors in pathological situations may be reflected by enhanced receptor densities as recently described for the aorta of spontaneously hypertensive rats [9], the basilar artery of rabbits after subarachnoidal hemorrhage [11] and for the rabbit carotid artery after balloon denudation [29].…”

Section: Discussionmentioning

confidence: 90%

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

Breu¹,

Clozel²,

Burri³

et al. 1996

FEBS Letters

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“…Thus, inhibition of MAPK may be a novel therapeutic target for the treatment of CVD. (Ihara et al, 1992) was shown to be an ET A receptor antagonist. A potent ET A receptor antagonist, cyclic pentapeptide BQ123, was subsequently derived from this substance (Ihara et al, 1992;Spatola & Crozet, 1996).…”

Section: The Role Of Mapk In Vascular Endothelin Receptor Upregulationmentioning

confidence: 99%

“…(Ihara et al, 1992) was shown to be an ET A receptor antagonist. A potent ET A receptor antagonist, cyclic pentapeptide BQ123, was subsequently derived from this substance (Ihara et al, 1992;Spatola & Crozet, 1996). Further extensive structure-activity relationship analysis of the carboxyl terminal of the endothelin peptide led to peptide antagonists that had affinity for both ET A and ET B receptors, such as PD142893 (Warner et al, 1993).…”

Section: The Role Of Mapk In Vascular Endothelin Receptor Upregulationmentioning

confidence: 99%

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

Xu¹,

Sun²,

Edvinsson³

2010

Pharmacology & Therapeutics

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Cardiovascular disease remains as the leading cause of death in the developed world.However, there is limited knowledge about how cardiovascular risk factors actually cause vascular disease. Traditional cardiovascular risk factors include increased circulating levels of low-density lipoproteins, cigarette smoking and hypertension (both strongly related to arterial wall injury), inflammation and atherosclerosis.

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Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor

Cited by 862 publications

References 21 publications

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

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Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor

Cited by 862 publications

References 21 publications

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

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In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor