Structure–desensitization relationships of angiotensin analogues in the rat isolated uterus

Moore, Graham J.; Franklin, K. J.; Nystrom, Diana M.; Goghari, Mahesh H.

doi:10.1139/y85-159

Cited by 28 publications

(18 citation statements)

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“…All of these agonists required extracellular calcium for their contractile effects in the porcine coronary preparation and were not affected by tetrodotoxin. The response to A11 (but not other agonists) showed rapid bchyphylaxis, as is well recognized for this peptide (Moore et al 1985). However, by spacing the dose interval by more than 50 min, the second and subsequent responses to A11 proved to be reproducible for experiments Basting as long as 8 h (not shown).…”

Section: Properties Of Agonist-induced Contractions In the Porcine Comentioning

confidence: 53%

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

Laniyonu

Saifeddine²,

Yang³

et al. 1994

Can. J. Physiol. Pharmacol.

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LANIYBNU, A.A., SAIFEDDINE, M., YAIVG, S.-G., and WBLLENBBRG, M.D. 1994. Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists. Can. J. Physiol. Pharrnacol. 72: 1075-1885. In a porcine coronary artery helical strip preparation, the tyrosine kinase inhibitors genistein and tyrphostin (AG82) attenuated the contractile actions of angiotensin 11, arginine vasopressin, epidermal growth factor -urogastrone, noradrenaline, and prostaglandin F,,, under conditions where contractions due to acetylcholine and KC1 were not affected. Both genistein and typhostin also caused a selective inhibition of angiotensin 11 action in rat aorta helical strips, without affecting KCI-mediated contractions. The HC, , values for the inhibition of contraction in the porcine coronary artery were in the range of 2-5 pM for genistein and 8 -15 pM for tyrphostin. Comparable IC, values were observed for the inhibitory effects of genistein on angiotensin 11 and prostaglandin FZu action in the rat aorta, whereas much higher tyrphostin concentrations (BCSo r 40 pM) were required to block angiotensin III action in this preparation. Angiotensin 11 caused an elevation of phosphotyrosyl protein (antiphosphotyrosine Western blot) in the porcine coronary artery, which was reversed by genistein. In addition, porcine coronary artery derived membrane and cytosolic fractions exhibited sarcoma vims related tyrosine kinase activity, which was inhibited by both genistein and tyrphostin. Our data (i) document the selective inhibition by genistein and tyrphostin of the contractile action of some, but by no means all, G-protein-linked vascular agonists in porcine and rat arterial preparations, (ii) establish the presence of sarcoma vims related tyrosine kinase activity in the porcine coronary artery, and (iii) demonstrate angiotensin II mediated increases in phosphstyrosyl protein content in porcine coronary artery tissue. These data support the hypothesis that selected G-protein-linked contractile vascular agonists may act in part via the stimulation of nonreceptor tyrosine kinases. The data also indicate the complex actions of the tyrosine kinase inhibitors, even for the same agonist acting in vascular preparations obtained from different species.

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Section: Properties Of Agonist-induced Contractions In the Porcine Comentioning

confidence: 53%

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

Laniyonu

Saifeddine²,

Yang³

et al. 1994

Can. J. Physiol. Pharmacol.

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“…Also differing from desensitization, tachyphylaxis induction depends on the aromatic ring at position 4 of ANG II, but some apparently conflicting aspects need to be analyzed. The phenolic hydroxyl of Tyr 4 is vital to elicit in vitro tachyphylaxis, a property that is lost with [Phe 4 ]-ANG II (185,262). However, paradoxically, this ANG II analog is able to trigger tachyphylaxis in vivo (286), a condition that was not described for wild-type ANG II.…”

Section: Desensitization and Tachyphylaxismentioning

confidence: 99%

The Angiotensin II AT₁Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure

Oliveira¹,

Costa-Neto²,

Nakaie³

et al. 2007

Physiological Reviews

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The most prevalent physiological effects of ANG II, the main product of the renin-angiotensin system, are mediated by the AT1 receptor, a rhodopsin-like AGPCR. Numerous studies of the cardiovascular effects of synthetic peptide analogs allowed a detailed mapping of ANG II's structural requirements for receptor binding and activation, which were complemented by site-directed mutagenesis studies on the AT1 receptor to investigate the role of its structure in ligand binding, signal transduction, phosphorylation, binding to arrestins, internalization, desensitization, tachyphylaxis, and other properties. The knowledge of the high-resolution structure of rhodopsin allowed homology modeling of the AT1 receptor. The models thus built and mutagenesis data indicate that physiological (agonist binding) or constitutive (mutated receptor) activation may involve different degrees of expansion of the receptor's central cavity. Residues in ANG II structure seem to control these conformational changes and to dictate the type of cytosolic event elicited during the activation. 1) Agonist aromatic residues (Phe8 and Tyr4) favor the coupling to G protein, and 2) absence of these residues can favor a mechanism leading directly to receptor internalization via phosphorylation by specific kinases of the receptor's COOH-terminal Ser and Thr residues, arrestin binding, and clathrin-dependent coated-pit vesicles. On the other hand, the NH2-terminal residues of the agonists ANG II and [Sar1]-ANG II were found to bind by two distinct modes to the AT1 receptor extracellular site flanked by the COOH-terminal segments of the EC-3 loop and the NH2-terminal domain. Since the [Sar1]-ligand is the most potent molecule to trigger tachyphylaxis in AT1 receptors, it was suggested that its corresponding binding mode might be associated with this special condition of receptors.

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“…The antagonistic activity of AII, characterized by slow receptor desensitization rates, can be obtained with an amino acid replacement. This antagonistic behavior is highly dependent on the nature of the amino acid in position 8 [21] and by aliphatic amino acids this peptide (Ile, Ala and Thr). AII competitive antagonists are also obtained by modifying the hydroxyl group of the Tyr 4 residue [22].…”

Section: Introductionmentioning

confidence: 99%

Biological and conformational evaluation of angiotensin II lactam bridge containing analogues

Oliveira

Fázio

Silva

et al. 2011

Regulatory Peptides

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Angiotensin II (AII) is the active octapeptide product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. In an attempt to establish the AII-receptor-bound conformation of this octapeptide, we designed conformationally constrained analogues by scanning the entire AII sequence with an i-(i+2) and i-(i+3) lactam bridge consisting of an Asp-(Xaa)(n)-Lys scaffold. Most analogues presented low agonistic activity when compared to AII in the different bioassays tested. The exceptions are cyclo(0-1a) [Asp(0), endo-(Lys(1a))]-AII (1) and [Asp(0), endo-(Lys(1a))]-AII (2), both of which showed activity similar to AII. Based on peptide 1 and the analogue cyclo(3-5)[Sar(1), Asp(3), Lys(5)]-AII characterized by Matsoukas et al., we analyzed the agonistic and antagonistic activities, respectively, through a new monocyclic peptide series synthesized by using the following combinations of residues as bridgehead elements for the lactam bond formation: D- or L-Asp combined with D- or L-Lys or L-Glu combined with L-Orn. Six analogues showed an approximately 20% increase in biological activity when compared with peptide (1) and were equipotent to AII. In contrast, six analogues presented antagonistic activity. These results suggest that the position of the lactam bridge is more important than the bridge length or chirality for recognition of and binding to the angiotensin II AT1-receptor.

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Structure–desensitization relationships of angiotensin analogues in the rat isolated uterus

Cited by 28 publications

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Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

The Angiotensin II AT₁Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure

Biological and conformational evaluation of angiotensin II lactam bridge containing analogues

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Structure–desensitization relationships of angiotensin analogues in the rat isolated uterus

Cited by 28 publications

References 0 publications

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

Tyrosine kinase inhibitors and the contractile action of G-protein-linked vascular agonists

The Angiotensin II AT1Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure

Biological and conformational evaluation of angiotensin II lactam bridge containing analogues

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The Angiotensin II AT₁Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure