Hypotensive Peptides: Bradykinin, Kallidin, and Eledoisin

doi:10.1016/S1054-3589(08)60097-6

Advances in Pharmacology

Volume 4, 1966, Pages 1-90

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This chapter discusses the hypotensive peptides. It deals with hypotensive peptides and with eiizynies which liberate them. Two groups of peptides are included: one belongs to kinins, the bradykinin-kallidin-type peptides, the other consists of eledoisin and its derivatives. The cardiovascular effect is but one of the coninion features between these groups. Although eledoisin-type peptides have riot yet been found in the mammalian body, these inaterials have been tested frequently on experimental animals and clinical subjects. The precursor of bradykinin and kallidin occurs in abundance in blood plasma. The progress made toward the understanding of the structure, action, and fate of kinins and eledoisin is quite impressive, especially if one considers the number of vasoactive substances which have appeared under various names in the literature since the turn of the century but never have been characterized.

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An exploration of bioactive peptides: My collaboration with Ervin G. Erdös
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Citation Excerpt :
Briefly, the concept was that the rapid enzymatic metabolism of kinins determines their transient effects. For this reason, bradykinin or kallidin would never be useful medications, but if they have a significant role in certain physiological or pathological conditions, agents that directly block their effects or inhibit their enzymatic degradation could be very important (14). This concept would lead to the development of ACE inhibitors, highly effective drugs for lowering blood pressure and decreasing oxygen demand by the heart.
This paper provides a brief historical sketch of the science of biologically active peptides. It also offers the story of how Ervin G. Erdös, a pioneer in the study of metabolism of various peptides, influenced me through collaborations that span many years. I worked in Dr. Erdös's research laboratories in Oklahoma City, Dallas, and Chicago, and we shared research interests through visits across the Atlantic between the former Yugoslavia and the United States. Among other findings, we discovered angiotensin-converting enzyme in the retina, which opened up a new research direction for many scientists interested in serious ocular diseases. This tribute to my mentor paints a portrait of a man who, in addition to his dedication to science and his seminal discoveries about the metabolism of peptides, took the time to invest in training many young scientists. His fine personal qualities explain why all of those who worked with him hold him in such high regard.
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Kidney function is regulated by a complex interplay between circulating and locally produced chemicals known as vasoactive substances. These substances affect the tone of the renal vasculature, leading to either vasodilation or vasoconstriction; and consequently affect renal blood flow and/or glomerular filtration rate. They belong to a chemically heterogeneous group and include proteins, peptides, lipids, and nucleosides. This chapter summarizes the role of these vasoactive substances in the maintenance of normal renal function and also highlights their role in disease states including acute kidney injury, chronic kidney disease, and hypertension.
Non-enzymatic proteins from snake venoms: A gold mine of pharmacological tools and drug leads
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Citation Excerpt :
This factor explained why “natural” bradykinin was more potent than the synthetic one. BPF potentiated bradykinin in several pharmacological tests, possibly by inhibiting its blood destruction (Ferreira, 1966; Ferreira and Vane, 1967a; Erdös, 1966). This hypothesis, made at Prof. J. R. Vane's laboratory in London, led us to realize that the major site of inactivation of circulating bradykinin was in the pulmonary vascular bed (Ferreira and Vane, 1967b) and, similarly to the conversion of angiotensin-I, was inhibited by BPF.
Non-enzymatic proteins from snake venoms play important roles in the immobilization of prey, and include some large and well-recognized families of toxins. The study of such proteins has expanded not only our understanding of venom toxicity, but also the knowledge of normal and disease states in human physiology. In many cases their characterization has led to the development of powerful research tools, diagnostic techniques, and pharmaceutical drugs. They have further yielded basic understanding of protein structure–function relationships. Therefore a number of studies on these non-enzymatic proteins had major impact on several life science and medical fields. They have led to life-saving therapeutics, the Nobel prize, and development of molecular scalpels for elucidation of ion channel function, vasoconstriction, complement system activity, platelet aggregation, blood coagulation, signal transduction, and blood pressure regulation. Here, we identify research papers that have had significant impact on the life sciences. We discuss how these findings have changed the course of science, and have also included the personal recollections of the original authors of these studies. We expect that this review will provide impetus for even further exciting research on novel toxins yet to be discovered.
Vasoactive Substances As Mediators of Renal Injury
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Kidney function is regulated by a complex interplay between circulating and locally produced chemicals known as vasoactive substances. These substances affect the tone of the renal vasculature, leading to either vasodilation or vasoconstriction; and consequently affect renal blood flow and/or glomerular filtration rate. They belong to a chemically heterogeneous group and include proteins, peptides, lipids, and nucleosides. This chapter summarizes the role of these vasoactive substances in the maintenance of normal renal function and also highlights their role in disease states including acute kidney injury, chronic kidney disease, and hypertension.
Peptides and the enzymes that release or inactivate them: A short history of my life and work entwined
2004, Comprehensive Biochemistry
Ervin Erdös was born in the 1920s in Budapest, Hungary. He worked at the Institute of Pathophysiology in the late 1940s and his job was to do bioassays using isolated strips of guinea pig ileum. He measured isotonic contractions in response to added stimulating agents. Many of his discoveries were made in Werle's laboratory based on just paper chromatography, bioassays in vitro, and measurements of blood pressure in laboratory animals. The enzymatic metabolism of oxytocin or methylation of histamine and many other subjects were among them. Werle and Ervin Erdös published a paper in 1954 that described an oxytocic material in human urine that contracted smooth-muscle preparations. In 1954, Ervin Erdös studied the in vitro hydrolysis of local anesthetics such as procaine by a plasma enzyme, which was called then “pseudocholinesterase.”
B2-kinnergic action of linear and cyclic tryptophan<sup>6</sup>- and tyrosine<sup>6</sup>-kallidin
1996, Life Sciences
This study was undertaken to determine the importance of the central aromatic moiety in the kallidin and cyclokallidin molecules, using the relaxation of the isolated duodenum of the rat. Replacement in kallidin of the central phenylalanine by tryptophan increased the potency from an EC₅₀ of 3 × 10⁻¹⁰M to 2 × 10⁻¹²M. Replacement by tyrosine decreased the potency to an EC₅₀ of 8 × 10⁻⁸M. In cyclo-kallidin (EC₅₀: 10⁻⁸M) the potencies were decreased: cyclo-Trp^o -kallidin showed an EC₅₀ of 10⁻⁶M and cyclo-Tyr⁶-kallidin of 3 × 10⁻⁷M. The relaxation of the rat duodenum by linear and cyclic kinins was potentiated by the bradykinin potentiating peptide BPP_5a and antagonized by the B2 antagonist HOE-140. At a concentration of 10⁻⁹M, HOE-140 significantly decreased the potencies of bradykinin and cyclo-kallidin, but not of the B1 agonist desArg⁹ -bradykinin.

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^*: Some of the studies described here were supported in part by Grants HE 04592 and NB 05196 from the National Institutes of Health, U.S.P.H.S. and by a Wellcome Research Travel Grant from the Wellcome Trust, London.

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Hypotensive Peptides: Bradykinin, Kallidin, and Eledoisin*

Publisher Summary

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Life Sciences

Gastroenterology

Gastroenterology

J. Biol. Chem.

Brit. J. Pharmacol.

Nature

Tohoku J. Exptl. Med.

Compt. Rend. Soc. Biol.

Federation Proc.

J. Physiol. (London)

Brit. J. Pharmacol.

Brit. J. Pharmacol.

J. Physiol. (London)

Brit. J. Pharmacol.

Nature

Brit. J. Pharmacol.

Comp. Biochem. Physiol.

Z. Naturforsch.

Z. Naturforsch.

Biochem. J.

Circulation Res.

Ann. N.Y. Acad. Sci.

Nature

Nature

J. Physiol. (London)

Nature

J. Physiol. (London)

J. Physiol. (London)

J. Physiol. (London)

Biochem. Pharmacol.

Arch. Klin. Chir.

Proc. Soc. Exptl. Biol. Med.

Ann. N.Y. Acad. Sci.

J. Am. Med. Assoc.

Compt. Rend. Soc. Biol.

J. Physiol. (London)

Clin. Sci.

Boll. Soc. Ital. Biol. Sper.

Thromb. Diath. Haemorrhag.

Ann. N.Y. Acad. Sci.

Nature

J. Physiol. (London)

Am. J. Physiol.

Am. J. Physiol.

J. Physiol. (London)

Hypotensive Peptides: Bradykinin, Kallidin, and Eledoisin^*