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Kinin Receptors and ACE Inhibitors: An Interrelationship

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Renin Angiotensin System and Cardiovascular Disease

Part of the book series: Contemporary Cardiology ((CONCARD))

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Abstract

The beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due in part to augmenting the actions of bradykinin (BK) and Lys-BK on their receptors (R). They inhibit kinin inactivation and thereby stimulate the release of mediators such as prostaglandins, nitric oxide (NO), and others. In addition to inhibiting an enzyme, ACE inhibitors affect BK Rs as allosteric effectors in cultured cells, such as human endothelial cells. ACE inhibitors can potentiate BK and ACE-resistant BK analog’s actions on B2 Rs. They elevate arachidonic acid and NO release as indirect allosteric enhancers acting on a heterodimer formed by human ACE and B2 R. This has been shown by co-immunoprecipitation, immunohistochemistry and fluorescence resonance energy transfer (FRET). After carboxypeptidase N or M removes the C-terminal Arg of kinins, the resulting des-Arg9-BK and des-Arg10-Lys1-BK are inactive on B2 Rs, but are agonists of B1 Rs. Activation of this R leads to prolonged release of NO, synthesized by iNOS. ACE inhibitors are also agonists of the B1 R at a Zn-binding sequence of this heptahelical G protein-coupled R. The site of activation is different from that of the orthosteric peptide ligands; it is on the extracellular loop 2 at residues 195–199. Thus, ACE inhibitors act as direct allosteric agonists. B1 Rs are present mainly in endothelial and other cells after an inflammatory process or induced by cytokines, which also bring about iNOS expression. While constitutively expressed eNOS activation via B2 R results in a short burst of NO, the longer lasting NO release initiated by peptide or ACE inhibitor ligands of the B1R may help to alleviate some detrimental effects in the failing heart.

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Authors and Affiliations

  1. Departments of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA

    Ervin G. Erdös MD, Fulong Tan PhD & Randal A. Skidgel PhD

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  1. Ervin G. Erdös MD
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  2. Fulong Tan PhD
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  3. Randal A. Skidgel PhD
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Correspondence to Ervin G. Erdös MD .

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  1. Department of Pharmacology, University of Puerto Rico, San Juan, 00936, U.S.A.

    Walmor C. DeMello

  2. Ochsner Clinic Foundation, Jefferson Highway 1514 , New Orleans, 70121, U.S.A.

    Edward D. Frohlich

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC

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Erdös, E.G., Tan, F., Skidgel, R.A. (2009). Kinin Receptors and ACE Inhibitors: An Interrelationship. In: DeMello, W., Frohlich, E. (eds) Renin Angiotensin System and Cardiovascular Disease. Contemporary Cardiology. Humana Press. https://doi.org/10.1007/978-1-60761-186-8_11

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  • DOI: https://doi.org/10.1007/978-1-60761-186-8_11

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