Elsevier

Regulatory Peptides

Volume 79, Issues 2–3, 5 February 1999, Pages 71-81
Regulatory Peptides

Invited review
Bradykinin and its receptors in non-mammalian vertebrates

https://doi.org/10.1016/S0167-0115(98)00160-8Get rights and content

Abstract

The generation of bradykinin (BK) in blood by the action of the kallikrein–kinin system has been studied intensively in mammals but the system has received relatively little attention in non-mammalian vertebrates. The plasma of crocodilians and Testudines (turtles and tortoises) contains all the components of the kallikrein–kinin system found in mammals (prekallikrein activator, prekallikrein, kininogen, and kininases) and activation results in generation of [Thr6]-BK. Plasma of birds and snakes probably lacks a prekallikrein activator analogous to mammalian Factor XII but treatment with exogenous proteases (pig pancreatic kallikrein and/or trypsin) generates [Thr6, Leu8]-BK (chicken), [Ala1, Thr6]-BK (python) and [Val1, Thr6]-BK (colubrid snakes). The skins of certain frogs, particularly of the genus Rana, contain very high concentrations of BK-related peptides but their pathway of biosynthesis involves the action of cellular endoproteinase(s) cleaving at the site of single arginyl residues rather than by the action of the kallikrein–kinin system. Evidence for a prekallikrein activator in fish plasma is lacking but treatment with exogenous proteases generates [Arg0, Trp5, Leu8]-BK (trout and cod), [Trp5]-BK (bowfin and gar), [Met1, Met5]-BK (sturgeon). The cardiovascular actions and effects upon gastrointestinal smooth muscle of these peptides in their species of origin differ markedly. For example, intra-arterial injections of the native BK peptides into unanesthetized fish produce transient hypertension in the cod, complex depressor and pressor responses in the trout and bowfin and hypotension in the sturgeon. Pharmacological studies in snakes and fish and with the recombinantally expressed chicken BK receptor have demonstrated that the BK receptors in the tissues of non-mammalian vertebrates have appreciably different ligand binding properties from the well-characterized mammalian B1 and B2 receptors.

Introduction

The kallikrein–kinin system in mammals involves the sequential action of several well-characterized proteolytic enzymes and has been the subject of several recent reviews 1, 2, 3, 4, 5. In brief, activation of Factor XII (Hageman factor) in blood at the site of tissue injury or in vitro by contact with a charged surface results in the activation of plasma prekallikrein and subsequent generation of bradykinin (BK) by the cleavage of high molecular mass kininogen. BK is rapidly degraded, primarily in the pulmonary circulation, by the action of carboxypeptidase N (kininase I), angiotensin-converting enzyme (kininase II) and endopeptidase 24.11. In the human, alternative splicing of the primary transcript of the kininogen gene gives rise to a second mRNA that directs the synthesis of low molecular mass kininogen [6]. This protein is a substrate for glandular or tissue kallikrein, a serine-protease that is localized predominantly in kidney, pancreas and pituitary, generating lysyl-bradykinin ([Lys0]-BK), also known as kallidin 7, 8. [Lys0]-BK is rapidly converted to BK in the circulation by the action of aminopeptidases. In the rat, putative duplications of the kininogen gene has led to expression of two T-kininogens which function as acute phase reactants in this species [3]. BK may be produced from kininogens in vitro by incubation of heat-denatured plasma with trypsin and [Lys0]-BK may be produced by incubation with porcine pancreatic kallikrein [9]. The generation and degradation of BK and kallidin are illustrated schematically in Fig. 1.

In mammals, generation of BK and/or [Lys0]-BK results in vasodilatation arising from decreased arteriolar resistance, increased vascular permeability, bronchoconstriction, contraction of gastrointestinal and uterine smooth muscle, stimulation of renal electrolyte secretion, activation of primary afferent sensory neurons, release of cytokines and possible mitogenic effects (reviewed in 1, 4, 10, 11). The actions of BK are mediated through interaction with two well-characterized receptors, termed B1 and B2, that are differentiated pharmacologically by the rank orders of potencies of selected agonists and antagonists (reviewed in 12, 13, 14, 15). B2 receptors are preferentially activated by BK and kallidin and are specifically antagonized by Hoe 140 (D-Arg-[Hyp3-Thi5-D-Tic7-Oic8]-BK) [16]whereas des-Arg9-BK and des-Arg10-kallidin are selective B1 receptor agonists and [Leu8]-des-Arg9-BK is a selective antagonist 17, 18]. The primary structure of the B2 receptor has been deduced from the nucleotide sequences of cloned cDNAs and/or genomic fragments from the human, rat, mouse, guinea pig and rabbit and the corresponding sequence of the B1 receptor from the human, mouse and rabbit (reviewed in 19, 20, 21). The amino acid sequence of the human B1 receptor is 36% identical to the amino acid sequence of the human B2 receptor indicating that the receptors are probably homologous.

In mammals, intravenously or intra-arterially administered BK produces a rapidly reversible fall in blood pressure arising from arteriolar vasodilatation with resulting decrease in peripheral resistance. This response is mediated primarily through B2 receptors and involves release of nitric oxide and prostaglandins 21, 22. The ability of BK and its analogues to contract isolated longitudinal smooth muscle from the guinea-pig ileum and cat ileum –` classical' bioassays used in the original characterization of the peptide – are mediated through interaction with B2 receptors [17]. In the rat, however, contraction of the longitudinal muscle of the ileum is mediated through the B1 receptor [23]and BK causes a biphasic relaxation followed by contraction of the isolated rat duodenum [24]and stomach fundus [25]. The inability of B1 and B2 receptor antagonists to inhibit responses in certain mammalian smooth muscle preparations e.g. guinea-pig and sheep trachea [26]has led to the hypothesis that these tissues contain a novel B3 receptor. However, the availability of cloned mammalian BK receptors for pharmacological studies has made it apparent that there are appreciable differences in properties between the same receptor sub-type from different species. For example, the cloned mouse B2 receptor, transfected into Chinese hamster ovary cells, has a 60-fold higher affinity for the antagonist [D-Arg0, Hyp3, D-Phe7]-BK (NPC 567) than its cloned human homologue [27].

Despite intensive study of the kallikrein–kinin system in mammals, the system in non-mammalian vertebrates has received very little attention [28]. This article focuses upon the diversity of primary structure of BK-related peptides generated in the plasma of species ranging from birds to a sturgeon. The biological properties of these peptides in their species of origin are reviewed with emphasis on cardiovascular and gastrointestinal actions. The pharmacological properties of the BK receptors in the tissues of non-mammalian vertebrates are compared with those of the mammalian B1 and B2 receptors.

Section snippets

Ornithokinin

Early work from several laboratories showed that treatment of the plasma of certain birds e.g. chicken Gallus domesticus [29], pigeon Columba livia domestica [30]and duck Anas platyrhynchos [31]with pig pancreatic kallikrein and/or trypsin generated peptide material with a BK-like ability to contract the rat uterus and produce vasodilatation in the perfused dog hind-leg. This factor, termed ornithokinin, was rapidly degraded in plasma and was not produced in avian blood by incubation with a

Reptiles

Treatment of plasma from the crocodilians, the alligator Alligator mississipiensis 32, 33and the spectacled caiman Caiman sclerops [31]and from the chelonians, the turtles Pseudemys scripta, Chelydra sepentina and Terrapene ornata [33]with glass beads in the presence of a kininase inhibitor generated material with the BK-like ability to contract the isolated rat uterus and to decrease the perfusion pressure in the dog hind-limb. These data led to the hypothesis that the blood of these reptiles

BK-related peptides from frog skin

The skin of amphibians has proved to be a remarkably rich store-house of regulatory peptides including kinins [44]. The occurrence of BK-related peptides in extracts of the skins of a wide range of frogs from Africa [45], America [46], Australia, Papua New Guinea [47]and Europe [48]has been investigated by Erspamer and coworkers using standard smooth muscle and blood pressure bioassays. The skin of certain Ranid frogs contain very high concentrations of BK with an amino acid sequence identical

Dipnoi

The lungfishes occupy a particularly important position in vertebrate phylogeny. Although phylogenetic relationships among the Sarcopterygii, particularly the evolutionary relationships between the coelacanths, lungfishes and tetrapods, continues to be a matter of controversy, paleontological 67, 68, morphological 69, 70and molecular 71, 72analyses generally favor the hypothesis that lungfish and tetrapods are sister groups. Trypsin treatment of heat-denatured plasma from the African lungfish

BK-related peptides from teleosts

Evidence is accumulating for the existence of a kallikrein–kinin system in the blood of teleost fish. Using chromogenic substrates, Lipke and Olson [74]showed that gill and kidney of the rainbow trout Oncorhynchus mykiss contained kallikrein activity and kininogen and kininases were detected in trout plasma. More recently, a serine proteinase with kallikrein-like substrate specificity has been purified from the pyloric caeca of the black sea bass Centropristis striata [75]. Incubation of

BK-related peptides from phylogenetically ancient fish

The ray-finned fishes (Actinopterygii) may be divided into the `higher actinopterygians', which comprise the Ginglymodi (gars), Halecomorphi (bowfin) and Teleostei (teleosts) and are collectively referred to as the Neopterygii, and the `lower actinopterygians', which comprise only two extant lineages, the Polypteriformes (bichirs and reedfish) and the Acipenseriformes (sturgeons and paddlefish) [82]. The bowfin Amia calva occupies a particularly important position in phylogeny as the sole

Acknowledgements

The work in the author's laboratory is supported by grants from the National Science Foundation (IBN 9806997 and INT9732434).

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