There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic...
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There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.
ET-1 is the most potent vasoconstrictor known to date, causing vasoconstriction when bound to the ETA receptor. Inhibitors of the binding of ET-I to the ETA receptor would be of immense value as potential therapeutic ...
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ET-1 is the most potent vasoconstrictor known to date, causing vasoconstriction when bound to the ETA receptor. Inhibitors of the binding of ET-I to the ETA receptor would be of immense value as potential therapeutic agents in the treatment of cardiovascular disorders such as angina and hypertension. We present here the rational design of such an inhibitor, which is arrived at on the basis of a model of theET-1/ ETA receptor complex proposed by us. The model is found to be consistent with binding and mutagenesis studies of ET-I as well as of BQ123, a known, potent ETA-selective antagonist which competes with ET-1 for receptor binding. BQ123 is a peptidic antagonist which is constrained to adopt a definite conformation on account of its cyclic nature, The noncyclic peptide antagonist designed by us also has a unique conformation because it contains two dehydro-Alanine (Delta Ala) residues which, on account of their planarity, cause the peptide backbone to bend in a specific and predictable manner. The folding rules for peptides containing Delta Ala were derived in our earlier studies. Energy minimization and modelling of the complex of the designed peptide with the ETA receptor indicate that the antagonist is ETA-selective and the binding is more stable and more specific as compared to that of BQ123.
An imbalance between proliferation and apoptosis is an important causal factor for disorders involving abnormal cell accumulation. The role and mechanism of how G protein-coupled receptors are linked to apoptosis are ...
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An imbalance between proliferation and apoptosis is an important causal factor for disorders involving abnormal cell accumulation. The role and mechanism of how G protein-coupled receptors are linked to apoptosis are poorly understood. Endothelin-1 (ET-1), a 21-amino acid peptide that binds to G protein-coupled receptors with mitogenic and vasoconstricting activities, suppressed apoptosis of human prostatic smooth muscle cells induced by paclitaxel treatment or serum withdrawal. Serum withdrawal or paclitaxel (1-10 mu M) treatment for 48 h resulted in DNA fragmentation, a characteristic of apoptosis. The addition of ET-1 attenuated DNA fragmentation. The attenuating effect of ET-1 on DNA fragmentation was not affected by wortmannin, bisindolylmaleimide I, tyrphostin AG490, or AG1478. However, PD98059, an inhibitor for the extracellular signal-regulated kinase (ERK) kinase, induced apoptosis, potentiated the effect of serum withdrawal on inducing apoptosis, and blocked the antiapoptotic effect of ET-1. The ERK1/2 activity in these cells decreased rapidly after paclitaxel treatment or serum withdrawal, but was maintained at a 2-fold higher level in the presence of ET-1 for at least 4 h. These results suggest that the ERK1/2 pathway is activated by ET-1, and blocking this pathway abolishes the antiapoptotic effect of ET-1.
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