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Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors
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  • Igor Souza-Silva,
  • Cristiane de Paula,
  • Lucas Bolais-Ramos,
  • Anderson Santos,
  • Filipe da Silva,
  • Vívian de Oliveira,
  • Isabella da Rocha,
  • Maísa Antunes,
  • Lídia Cordeiro,
  • Vanessa Teixeira,
  • Sérgio Ricardo Scalzo Júnior,
  • Flavio Amaral,
  • Jarbas Resende,
  • Marco Antônio Fontes,
  • Gustavo Menezes,
  • Silvia Guatimosim,
  • Robson Santos,
  • Thiago Verano-Braga
Igor Souza-Silva
Federal University of Minas Gerais
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Cristiane de Paula
Federal University of Minas Gerais
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Lucas Bolais-Ramos
Federal University of Minas Gerais
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Anderson Santos
Federal University of Minas Gerais
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Filipe da Silva
Federal University of Minas Gerais
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Vívian de Oliveira
Federal University of Minas Gerais
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Isabella da Rocha
Federal University of Minas Gerais
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Maísa Antunes
Federal University of Minas Gerais
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Lídia Cordeiro
Federal University of Minas Gerais
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Vanessa Teixeira
Federal University of Minas Gerais
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Sérgio Ricardo Scalzo Júnior
Federal University of Minas Gerais
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Flavio Amaral
Federal University of Minas Gerais
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Jarbas Resende
Federal University of Minas Gerais
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Marco Antônio Fontes
Federal University of Minas Gerais
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Gustavo Menezes
Federal University of Minas Gerais
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Silvia Guatimosim
Federal University of Minas Gerais
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Robson Santos
Federal University of Minas Gerais
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Thiago Verano-Braga
Federal University of Minas Gerais
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Abstract

Background and purpose: Bradykinin [BK-(1-9)] is an endogenous nonapeptide involved in multiple physiological and pathological processes. A long-held belief is that peptide fragments of BK-(1-9) are biologically inactive. Here, we have tested the biological activities of BK-(1-9) and two major peptide fragments in human and animal systems. Experimental Approach: Levels of BK peptides in male Wistar rat plasma were quantified by mass spectrometric methods. Nitric oxide was quantified in human, mouse and rat cells, and loaded with DAF-FM. We used aortic rings from adult male Wistar rats to test vascular reactivity. Changes in blood pressure and heart rate were measured in conscious adult male Wistar rats. Key results: Plasma levels of BK-(1-7) and BK-(1-5) in rats were increased following infusion of BK-(1-9). All tested peptides induced NO production in all cell types tested. However, unlike BK-(1-9), NO production elicited by BK-(1-7) or BK-(1-5) was not inhibited by B1 or B2 receptor antagonists. BK-(1-7) or BK-(1-5) also induced concentration-dependent vasorelaxation of aortic rings, without involving B1 or B2 receptors. In vivo, either intravenous or intra-arterial administration of BK-(1-7) or BK-(1-5) induced similar hypotension response. Conclusions and implications: BK-(1-7) and BK-(1-5) are endogenous peptides present in plasma. They are formed, at least partially, through the BK-(1-9) proteolysis. BK-related peptide fragments show biological activity, not mediated by B1 or B2 receptors. These BK-fragments could constitute new, active components of the kallikrein-kinin system.

Peer review status:IN REVISION

23 Jan 2021Submitted to British Journal of Pharmacology
25 Jan 2021Assigned to Editor
25 Jan 2021Submission Checks Completed
29 Jan 2021Reviewer(s) Assigned
22 Feb 2021Review(s) Completed, Editorial Evaluation Pending
26 Feb 2021Editorial Decision: Revise Minor