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Differential Agonistic Activities of Angiotensin Peptide Analogs
Author(s) -
Speth Robert C,
Sturchler Emmanuel,
McDonald Patricia
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.765.9
Subject(s) - chemistry , sarcosine , angiotensin ii , arginine , agonist , alanine , calcium , medicine , endocrinology , renin–angiotensin system , amino acid , potency , pharmacology , biochemistry , glycine , in vitro , receptor , biology , organic chemistry , blood pressure
Biased agonism of angiotensin (Ang) peptides may differentiate beneficial from pathophysiological actions of the renin‐angiotensin system. To assess the potential for biased agonism a series of Ang peptides modified at the amino terminal, or carboxy terminal (with Isoleucine 8 ), or with D amino acid substitutions were evaluated for their ability to increase cytoplasmic calcium levels, or to alter cellular impedence using the CellKey system to measure agonism, and also to cause desensitization. The most potent analogs for increasing cytoplasmic calcium were 71 to 2 times more potent (EC 50 values) in the calcium assay relative to the CellKey assay in the order N‐Methylaspartate 1 Ang II, Gly 1 Ang II, D‐Arginine 1 Ang III, Sarcosine 0 , Sarcosine 1 Ang II, D‐Alanine 1 Ang II, and Ang II. Less potent Ang peptides had potency ratios of calcium activation to CellKey activation of ~ 1 to 0.07. Isoleucine (Ile) 8 substituted Ang II analogs had extremely weak ability to increase cytoplasmic calcium and moderately weak ability to alter impedence in the CellKey assay with potency ratios of 0.06 to 0.24. The ability of these Ang peptides to cause loss of responsiveness to a subsequent challenge with Ang II in the CellKey assay largely paralleled their potency, with N‐Methylaspartate 1 Ang II, Gly 1 Ang II,, Sarcosine 0 , Sarcosine 1 Ang II,, and Ang II being most potent at causing desensitization (EC 50 values ~ 1 nM). D‐Arginine 1 Ang III, D‐Alanine 1 Ang II, D‐Aspartate 1 Ang II L‐beta Aspartate 1 Ang II had lower potencies to cause desensitization, ~ 3 to 20 fold less potent. Interestingly two of the Ile 8 substituted Ang peptides; D‐Alanine 1 , Ile 8 Ang II and D‐beta Aspartate 1 , Ile 8 Ang II displayed abilities to desensitize the response to Ang II with 24 and 47 nM potencies. Since the CellKey system measures an integrated cellular response resulting from both G protein as well as beta‐arrestin signaling, these data are consistent with possible differential agonism of these Ang peptide analogs. These data are consistent with previously noted biased agonistic effects of Ile 8 containing analogs of Ang II. Since the most well characterized biased agonist for Ang II receptors, Sarcosine 1 , Ile 4 , Ile 8 Ang II has a micromolar EC 50 , D‐Alanine 1 , Ile 8 Ang II and D‐beta Aspartate 1 , Ile 8 Ang II might represent more efficacious beta arrestin biased agonists. Support or Funding Information R.C. Speth: NIH HL‐113905; Cardiovascular Neuroscience Research Fund, Nova Southeastern University; President's Faculty Research Development Grant, Nova Southeastern University.