Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

Donoso, M. Verónica; Faúndez, H; Rosa, Gigliola; Fournier, Alain; Edvinsson, Lars; Huidobro‐Toro, J. Pablo

doi:10.1016/s0196-9781(96)00188-x

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…In line with competitive antagonism, it reduced the sensitivity and responses to ET‐1, ET‐2 and ET‐3. Yet, preventive effects of BQ123 were more marked for ET‐3 and ET‐1 than for ET‐2, in contrast to earlier reports where preventive effects were more marked for ET‐3 and ET‐2 than for ET‐1 (Donoso et al ., 1996). In addition, the relaxing effects of BQ123 were larger than predicted in the case of ET‐2 and ET‐3, but smaller than predicted for ET‐1.…”

Section: Discussioncontrasting

confidence: 99%

Agonist‐dependent modulation of arterial endothelin_A receptor function

Compeer¹,

Meens²,

Hackeng

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEEndothelin-1 (ET-1) causes long-lasting vasoconstrictions. These can be prevented by ETA receptor antagonists but are only poorly reversed by these drugs. We tested the hypothesis that endothelin ETA receptors are susceptible to allosteric modulation by endogenous agonists and exogenous ligands. EXPERIMENTAL APPROACHRat isolated mesenteric resistance arteries were pretreated with capsaicin and studied in wire myographs, in the presence of L-NAME and indomethacin to concentrate on arterial smooth muscle responses. KEY RESULTSEndothelins caused contractions with equal maximum but differing potency (ET-1 = ET-2 > ET-3). ET-11-15 neither mimicked nor antagonized these effects in the absence and presence of ET16-21. 4 Ala ET-1 (ETB agonist) and BQ788 (ETB antagonist) were without effects. BQ123 (peptide ETA antagonist) reduced the sensitivity and relaxed the contractile responses to endothelins. Both effects depended on the agonist (pKB: ET-3 = ET-1 > ET-2; % relaxation: ET-3 = ET-2 > ET-1). Also, with PD156707 (non-peptide ETA antagonist) agonist-dependence and a discrepancy between preventive and inhibitory effects were observed. The latter was even more marked with bulky analogues of BQ123 and PD156707. CONCLUSIONS AND IMPLICATIONSThese findings indicate allosteric modulation of arterial smooth muscle ETA receptor function by endogenous agonists and by exogenous endothelin receptor antagonists. This may have consequences for the diagnosis and pharmacotherapy of diseases involving endothelins. Abbreviations 4 Ala

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Section: Discussioncontrasting

confidence: 99%

Agonist‐dependent modulation of arterial endothelin_A receptor function

Compeer¹,

Meens²,

Hackeng

et al. 2012

British J Pharmacology

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“…1C and E). In contrast to earlier reports, where BQ123 inhibited ET-2-induced contractions more effectively than ET-1-induced contractions in a preparation of either rings of the superior mesenteric artery or the perfused mesenteric arterial bed (Donoso et al, 1996), the effect of the antagonist was observed to be more pronounced against ET-1 (11 fold reduction of sensitivity) than against ET-2 (2 fold) in our preparation using 2nd order mesenteric artery side branches and a different pharmacological study protocol. As a consequence, the apparent affinity of BQ123 was 30 times higher against ET-1 (pK B : 7.1 ± 0.2) than against ET-2 (pK B : 5.6 ± 0.4).…”

Section: Effects Of An Et a -Antagonistcontrasting

confidence: 99%

Endothelin-1 and -2: Two amino acids matter

et al. 2012

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“…Perfusion of the arterial bed was performed using a peristaltic pump at a flow of 2 ml min −1 . The mesenteric bed was excised from the intestines and placed in a dish specially designed to collect the perfusates (Donoso et al ., 1996). A pressure transducer was placed close to the entrance of the artery; the transducer was connected to a Grass polygraph.…”

Section: Methodsmentioning

confidence: 99%

P2Y₁ and P2Y₂ receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed

Buvinic

Briones

Huidobro‐Toro

2002

British J Pharmacology

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1 To assess the role of nucleotide receptors in endothelial-smooth muscle signalling, changes in perfusion pressure of the rat arterial mesenteric bed, the luminal output of nitric oxide (NO) and guanosine 3',5' cyclic monophosphate (cGMP) accumulation were measured after the perfusion of nucleotides. 2 The rank order of potency of ATP and analogues in causing relaxation of precontracted mesenteries was: 2-MeSADP=2-MeSATP4ADP4ATP=UDP=UTP4adenosine. The vasodilatation was coupled to a concentration ± dependent rise in NO and cGMP production. MRS 2179 selectively blocked the 2-MeSATP-induced vasodilatation, the NO surge and the cGMP accumulation, but not the UTP or ATP vasorelaxation. 3 mRNA encoding for P2Y 1 , P2Y 2 and P2Y 6 receptors, but not the P2Y 4 receptor, was detected in intact mesenteries by RT ± PCR. After endothelium removal, only P2Y 6 mRNA was found. 4 Endothelium removal or blockade of NO synthase obliterated the nucleotides-induced dilatation, the NO rise and cGMP accumulation. Furthermore, 2-MeSATP, ATP, UTP and UDP contracted endothelium-denuded mesenteries, revealing additional muscular P2Y and P2X receptors. 5 Blockade of soluble guanylyl cyclase reduced the 2-MeSATP and UTP-induced vasodilatation and the accumulation of cGMP without interfering with NO production. 6 Blockade of phosphodiesterases with IBMX increased 15 ± 20 fold the 2-MeSATP and UTPinduced rise in cGMP; sildena®l only doubled the cGMP accumulation. A linear correlation between the rise in NO and cGMP was found. 7 Endothelial P2Y 1 and P2Y 2 receptors coupled to the NO/cGMP cascade suggest that extracellular nucleotides are involved in endothelial-smooth muscle signalling. Additional muscular P2Y and P2X receptors highlight the physiology of nucleotides in vascular regulation.

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Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

Cited by 11 publications

References 40 publications

Agonist‐dependent modulation of arterial endothelin_A receptor function

Agonist‐dependent modulation of arterial endothelin_A receptor function

Endothelin-1 and -2: Two amino acids matter

P2Y₁ and P2Y₂ receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed

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Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

Cited by 11 publications

References 40 publications

Agonist‐dependent modulation of arterial endothelinA receptor function

Agonist‐dependent modulation of arterial endothelinA receptor function

Endothelin-1 and -2: Two amino acids matter

P2Y1 and P2Y2 receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed

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Product

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About

Agonist‐dependent modulation of arterial endothelin_A receptor function

Agonist‐dependent modulation of arterial endothelin_A receptor function

P2Y₁ and P2Y₂ receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed