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Cardiovascular Research 2002 54(3):485-491; doi:10.1016/S0008-6363(02)00284-5
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Copyright © 2002, European Society of Cardiology

Kinins, the long march—A personal view

Ervin G Erdös*

University of Illinois College of Medicine at Chicago, Department of Pharmacology (MC 868) 835 S. Wolcott Ave., Room E403 MSA, Chicago, IL 60612-7344, USA

egerdos{at}uic.edu

* Tel.: +1-312-996-9146; fax: +1-312-996-1648

Received 4 February 2002; accepted 6 February 2002

"Science betokens the most complete renunciation of the pleasure-principle of which our minds are capable."1 Sigmund Freud.

"Oh boy, was he wrong!"2

When asked to write a review article for Cardiovascular Research, I was not sure what the aim of such an endeavor should be. To make a complete list of reports on kinins and kallikreins by now could overload even the hard drive of a computer. A review article on hypotensive peptides in 1966 cited over 600 references and another one in 1968 on bradykinin alone listed 897 ones [1]. Should this brief review be very selective in quoting contributions or a jeremiad of all the near and not-so-near misses made in research? Then I realized that the stated aim of this series of articles is to reflect on how some major research findings were made—in my case, in the field of peptides and peptidases—or maybe how some of them just happened, since the persons who made the initial fundamental discoveries are not with us anymore. Braun-Menendez, Page, Frey, Werle, Rocha e Silva, Beraldo, Erspamer, von Euler and the others cannot look back to reveal more on the beginnings of their explorations.

Briefly, as requested by the editor, this is a personal story of how studying peptide excretion in human urine [2] led much later to show, beyond peptidase inhibition, the other ways of how angiotensin I converting enzyme (ACE) inhibitors can act [3,4]. The components of the complex kallikrein–kinin–kininase system share some properties with those of the renin–angiotensin (Ang)-ACE system. The earliest common feature in the two cascades was the very negative reception, a gut reaction, that greeted the discoverers and the discoveries. (I.H. Page, personal communication, E. Werle, personal communication). Innovative discoveries frequently face strenuous efforts to attribute the findings to some presumed, assumed, or felt missteps in the logic of the discoverers* thoughts.

The kallikrein–kinin cascade is a complex one. Prokallikrein of plasma or tissue, after it is activated, releases from kininogen bradykinin (BK) or Lys–BK (Fig. 1; [5]). The two peptides act on their B2 receptor. They are metabolized by ACE or kininase II by the release of C-terminal Phe–Arg or by carboxypeptidases N or M, which cleave off C-terminal Arg only (Fig. 2; [6]). The resulting des-Arg–kinin then acts on a receptor different from B2, called B1 [5–8]. The two receptors are both G protein-coupled, seven transmembrane, heptahelical receptors on plasma membrane, but otherwise, they differ [8–10]. While B2 is ubiquitous, B1 is mainly expressed after induction by endotoxin, cytokines, ischemia and other noxious stimuli [5,8]. It should be noted here that a single investigator, T.L. Goodfriend, was involved in finding the receptors both, for Ang II first, then for BK [11,12].


Figure 1
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  		Fig. 1. Release of kinins from kininogen by kallikreins. Ser-X, extended sequence in the light chain of kininogen. (Modified from Ref. [5]).

 

Figure 2
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  		Fig. 2 Cleavage sites of Lys–bradykinin (kallidin) and bradykinin. Conversion from ligand to B2 receptor to agonist of B1 receptor. KI, kininase I; KII, kininase II; NEP, neutral endopeptidase 24.11, neprilysin; CPN, carboxypeptidase N; CPM, carboxypeptidase M; ACE, angiotensin I converting enzyme; CATA, cathepsin A, deamidase, lysosomal protective protein. (Modified from Ref. [5]).

 
Our contributions fortunately were sometimes aided by serendipity. I started out by finding an agent in human urine that was hypotensive and contracted smooth muscles. With the over-optimism of youth, I called it ‘substance Z,’ possibly for no other reason than that future discoveries should not follow it, at least not in alphabetical order [2]. This material was nothing less than a mixture of BK and Lys–BK, kallidin, found out later after the sequence of BK and Lys–BK and their synthesis were established [6,13].

Following that, I had been studying cholinesterases when synthetic BK and Lys–BK, so-called hypotensive peptides, became available [13,14]. Thus, applying what I had learned about acetylcholine, I figured that enzymatic metabolism of kinins may be more important than their gross hypotensive effects after external applications. The concept was summarized in 1966 in a review article [15].

"For the pharmacologist the status of kinins somewhat resembles that of acetylcholine or histamine. Bradykinin may never become a therapeutically important agent. Nevertheless, if kinins play a significant role in some physiological or pathological conditions, agents which block their effect or inhibit their enzymatic metabolism would be of prime importance."

We found initially that human blood and tissues indeed contained enzymes that converted Lys–BK to BK and inactivated BK either by releasing the N-terminal Arg1 [16,17] or by hydrolyzing the C-terminal Phe8–Arg9 bond (Fig. 1). The aminopeptidase that cleaved BK at the Arg1–Pro2 bond was extracted first from red blood cells [16], later from kidney [18], then from other tissues [5]. Lys–BK was also converted to BK at Lys1–Arg2-bond by another aminopeptidase [16,19] present in plasma and tissues [20]. However, the major kininase in human plasma, first expected to be an aminopeptidase, released Arg9 instead of Arg1 of BK and thus acted as a carboxypeptidase, named carboxypeptidase N [17]. This enzyme was described later as life-sustaining and an inactivator of anaphylatoxins [21]. It is a tetramer of two large regulatory subunits (83 kDa) and two low molecular weight (50 kDa) active subunits [22]. When its presence in urine was sought [23,24], a lower molecular weight carboxypeptidase that cleaved C-terminal Lys or Arg, different from carboxypeptidase N, was discovered there and in the kidney. This kininase turned out to be, unlike carboxypeptidase N, membrane-bound in many tissues on plasma membrane but released into body fluids [22–25]. It also cleaves basic C-terminal amino acids but Arg more favorably than Lys, which is the opposite of how carboxypeptidase N acts [24–27].

Looking further for another carboxypeptidase-type kininase, we found, to our surprise, in a renal so-called microsomal fraction [28] and in human plasma [29] a kininase that cleaved off a dipeptide instead of a single amino acid from BK. Not overly inspiringly, we called carboxypeptidase-type enzymes kininase I, then the other one that released the dipeptide, kininase II. We know now that this terminology represents two groups of enzymes, which cleave either at Phe8–Arg9 or Pro7–Phe8 bond of BK [22]. The metallocarboxypeptidases N and M and a serine carboxypeptidase, cathepsin A or deamidase, form the first group, while ACE and neprilysin (neutral aminopeptidase 24.11) belong to the second group ([22]; Fig. 2).

Another enzyme, abundantly present in the kidney, which cleaves des-Arg9 BK and Ang II at the Pro7–Phe8 bond is the prolylcarboxypeptidase (lysosomal carboxypeptidase or angiotensinase C; [30,31]. At the time of its discovery, prolylcarboxypeptidase was thought to inactivate Ang II by converting it to Ang 1–7, and to cleave the inactive derivative of BK, des-Arg9-BK, further by hydrolyzing the same Pro–Phe-OH. We now know it is the other way around. Ang 1–7 is an active derivative of Ang II [32] and kinins converted by carboxypeptidase N or M to des-Arg9-BK or des-Arg9–Lys1-BK act on the B1 receptor [8]. Thus, topsy-turvy, prolylcarboxypeptidase can release a receptor agonist of the renin–angiotensin system and inactivate one in the kallikrein–kinin system. These human carboxypeptidases have been purified, sequenced, cloned and obtained as recombinant proteins, including the active subunits of carboxypeptidase N [22,33].

Kininase II generated most interest after its identity with ACE was shown [34,35]. At first, an idea that a single protein inactivates a hypotensive peptide and releases a hypertensive one by liberating a C-terminal dipeptide Phe8–Arg9 of BK or His9–Leu10 of Ang I, was not well accepted partly because BK hydrolysis was much less Cl— sensitive than Ang I cleavage [36]. BK has a much lower Km than Ang I, hence BK has a much higher specificity constant (kcat/Km) than Ang I. In addition to cleaving C-terminal unprotected dipeptides, ACE hydrolyzes C-terminal protected dipeptides and even N-terminal tripeptides, as in LHRH [22]. ACE cleaves in vitro the heptapeptide Met5–enkephalin–Arg6–Phe7 fastest mainly by its N-domain active center [37]. Also finding that ACE in lung has high sialic acid content compared, for example, to renal ACE, suggested the lung as the origin of the plasma enzyme [22].

The volume of research in kinins increased exponentially with time, partially owing to the clinical application of ACE inhibitors [38–40], and to the manifold direct and mostly indirect effects of BK and Lys–BK or kallidin [5]. These include release of NO, endothelium derived hyperpolarizing factor (EDHF), norepinephrine, prostaglandins, substance P, cytokines and tissue plasminogen activator. All of these are, in addition to the direct spasmogenic or algogenic actions of kinins, the consequence of the initial activation of a BK receptor, frequently the B2 one [5,6,9,11].

ACE (kininase II) inhibitors are administered to many millions of patients suffering, for example, from high blood pressure, congestive heart failure, or diabetic nephropathy, and are given to ameliorate the consequences of myocardial infarction [38–40]. Some beneficial and even some side effects of the inhibitors are attributed to the potentiation of the action of BK on its receptor, by preventing its inactivation [5,41]. A report of recent ACE inhibitor studies involving large numbers of patients [39] also concluded that some aspects of the very successful therapeutic applications of ACE inhibitors were still waiting for an explanation [42]. They certainly cannot be attributed only to a lowering of blood pressure. The idea that the ACE inhibitors can contribute more to therapy than just blocking peptide hydrolysis comes in part from some very simple experiments done on pieces of the guinea pig ileum. Here, ‘kininase,’ that is, kinin inactivating enzyme inhibitors, enhanced the contractions induced by BK but so did other compounds which did not block kininases, as reviewed already in 1970 [43]. This ancient pharmacological assay method measures the isotonic contractions of isolated ileal smooth muscles by BK. Adding ACE inhibitors to the tissue bath at the peak of contraction caused by BK immediately elevated it much higher [44]. Already in 1978, an initial report on captopril emphasized that captopril blocked the inactivation of BK and thereby potentiated the isotonic contraction caused by the peptide [45]. With clear hindsight, sharpened by the decades passed, it is easy to conclude that there must have been more to that than just blocking BK hydrolysis. Captopril sensitized the muscle to BK after 2 min of preincubation of the inhibitor in the tissue bath prior to adding BK. Captopril concentrations beyond the one needed to inhibit ACE still enhanced the effect of BK, elevating the contraction further. The isolated guinea pig ileal preparations broke down BK slowly (12–16 min), but ACE inhibitors were immediately effective [44]. It is unlikely that the potentiators, the ACE inhibitors, protected BK against inactivation in seconds or could simply release BK from an adsorption site on ACE in the vicinity of the receptor. This is also improbable, because after an exposure to an ACE inhibitor, the guinea pig ileum stays sensitized to BK even after repeated washing [44]. We reached a similar conclusion in experiments with the guinea pig atrial preparation where BK was inotropic, but tachyphylactic and ACE inhibitors restored the sensitivity to BK in the preparation [46].

Other investigators concluded, based on using cells, blood vessel or isolated perfused heart, that ACE inhibitors augmented the responses to BK via the B2 receptor independent of blocking its enzymatic degradation, and offered various explanations [47–51]. As a gold standard to show the involvement of the B2 receptors of BK, a B2 receptor antagonist, HOE 140 or another one, is used to block activities [41].

To deal with these issues further at a cellular and subcellular level required a rather intimate knowledge of the structure of ACE [52] and the BK receptors [8–10], fortunately provided by a number of laboratories. To follow up the events triggered by the activation of the B2 receptor and affected by ACE inhibitors, we have studied cultured cells, for example, Chinese hamster ovary (CHO) cells transfected with the cDNA of human ACE and B2 BK receptor or only with the enzyme or B2 and used endothelial cells that constitutively express both proteins [3,4]. In these experiments, the parameters measured included the release of labeled arachidonic acid, 1,4,5-inositoltrisphosphate and [Ca2+]i elevation. The results with these agents were taken as an indication of prostaglandin and NO synthesis by the cells, after signal transduction was initiated by BK B2 receptor through G{alpha}1 or G{alpha}q proteins.

Pretreating cells with ACE inhibitors, slowly cleaved substrates or antibodies to ACE, potentiated BK effects on the B2 receptor, even when a partially or fully ACE resistant BK analogue was the ligand, provided the cells expressed both ACE and B2 receptor. ACE inhibitors, after the first application of BK desensitized the receptor, resensitized the B2 receptor to the BK present in the medium, without adding more peptide (Fig. 3; [3,4,46,51,53,54]). This resensitization of the receptor was abolished when calcium reentry in the cells was blocked. Thus, ACE inhibitors induced indirectly an opening of calcium channels [54].


Figure 3
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  		Fig. 3 Bradykinin desensitizes the B2 receptor; ACE inhibitor resensitizes it. Bradykinin (BK; 100 nM) raises [Ca2+]i level and desensitizes human B2 receptor to second dose of BK in CHO cells expressing B2 receptor and WT-ACE. Ramiprilat (RAM, 1 µM) resensitizes the receptor to BK present in the medium. (A) simultaneous measurements in one hundred CHO-AB cells. (B) tracing showing calculated mean value from A. (From Ref. [4] with permission).

 
ACE is a type I transmembrane enzyme [52,55–57], has two active, N- and C-domains bound to plasma membrane by an anchor peptide, and has a short cytosolic portion. The two active centers, although both have a high degree of homology around the active site, contain Zn cofactor, but they differ in Cl– sensitivity and cleave some substrates preferentially [58–60]. We wanted to determine which portions of ACE are necessary for a crosstalk with the receptor. To follow that, a variety of mutants and chimeric proteins were engineered [4,61]. Maintaining the N-terminal amino acids, but deleting most of the active N-domain and retaining the C-domain active center, the transmembrane anchor and the cytosolic peptide of ACE did not change the potentiation of BK effects by ACE inhibitors, but altered some of the enzymatic characteristics of ACE. Deleting most of the cytosolic portion of ACE, including three out of the potential five sites of phosphorylation, again did not affect the activation of BK receptor by ACE inhibitors. Then, a chimeric ACE was constructed where the transmembrane anchor peptide, together with the cytosolic C-terminal end, were replaced with a glycosylphosphatidylinositol (GPI) anchor (GPI-ACE). In GPI-ACE expressing cells, the B2 receptor was still activated by agonists, but ACE inhibitors did not resensitize the receptor. When the cells were treated with filipin to deplete cholesterol, this process returned the sensitivity to inhibitors. In immunocytochemistry, GPI-ACE had a patchy, uneven dispersal on the plasma membrane, which was restored to normal distribution by filipin. Thus, ACE inhibitors did not induce crosstalk as long as GPI-ACE was sequestered in cholesterol-rich membrane domains [4], possibly in a lipid raft.

These experiments supported the notion that ACE inhibitors do not act directly on B2 receptor but induce a cross-talk between ACE and the B2 receptor; the resulting allosteric modification of the receptor conformation enhances the activity of the peptide ligands and resensitizes the receptor after it has been desensitized by the agonist. In all of these experiments, both BK and its partially or fully ACE-resistant peptide analogues were used with the same results [4,53,62].

The primary activation of the receptor by a peptide ligand and the response of the receptor, resensitized by ACE inhibitor following desensitization by agonist, do not initiate the same type of signal transduction pathway. Protein kinase C and phosphatase inhibitors distinguished the signaling by the receptor, activated first by BK, from BK acting on the resensitized receptor. Treatment of cells with calphostin, staurosporine, calyculin or okadaic acid did not affect [Ca2+]i elevation by BK. Protein kinase C (the first two compounds) or phosphatase inhibitors (the latter two), however, abolished the resensitization of the B2 receptor by enalaprilat or ramiprilat to BK [62,63]. The experiments differentiated the primary activation of the receptor by BK from potentiation and activation of the resensitized receptor after ACE inhibitor treatment.

The significance of BK or Lys–BK rests on the consequences of B2 receptor activation liberating important mediators of vascular tone, fibrinolysis and pain [5–7,64]. The classic scheme of activation includes a cascade starting with plasma or tissue kallikrein activation followed by release of a kinin from kininogen. A process presumed to be of such importance should have a backup system, a shortcut to receptor activation, besides by a peptide ligand. Kallikreins, indeed, in addition to releasing peptide agonists, directly activate the receptor. Porcine and human recombinant tissue kallikrein and human plasma kallikrein mobilize [Ca2+]i and release [3H]arachidonic acid from cultured cells stably transfected to express human BK B2 receptor [Chinese hamster ovary (CHO/B2), Madin-Darby canine kidney (MDCK/B2), human embryonic kidney (HEK/B2)] and from endothelial cells used as control [65]. As with BK, the actions of kallikreins were blocked by the B2 antagonist, HOE 140, and kallikreins were inactive on cells lacking the B2 receptor. Kallikrein and BK desensitized the receptor only homologously; there was no cross-desensitization. Furthermore, other proteases, such as human cathepsin G and trypsin, also activated the receptor. Human tissue kallikrein competitively decreased the [3H]BK binding to the receptor with a low KD (3 nM). Thus, kallikreins and some other proteases activate human BK B2 receptor directly, independent of BK release. The BK B2 receptor may belong to a newly detected group of serine protease-activated receptors [65].

The B1 receptor has also been cloned [8,10]. It is constitutively expressed in some cells, in others it is induced by endotoxin, cytokines or transfection. Its most effective ligand is des-Arg10–kallidin (des-Arg10–Lys1-BK), which is more potent than des-Arg9-BK, active in several orders of magnitude lower concentration [8]. Lys–BK is released from low molecular weight plasma kininogen by tissue kallikrein, after it is enzymatically activated from its inactive prokallikrein zymogen form [5]. However, the N-terminal Lys of Lys–BK is easily removed by an aminopeptidase present in blood, kidney and elsewhere [16–19]. To activate the B1 receptor in low concentration, the C-terminal Arg10 of kallidin (Lys–BK) has to be split off by plasma carboxypeptidase N or tissue carboxypeptidase M [6,22]. Consequently, the only potent ligand of B1, Lys1–des-Arg10-BK, is the product of three sequential enzymatic reactions, provided the peptide escapes inactivation by an ubiquitous aminopeptidase [16–18]. This enzyme cleaves Lys1, converts the peptide to des-Arg9BK, and thereby renders it up to 1000 times less active [8] on B1 receptor. Even if carboxypeptidase M [23–27], which cleaves C-terminal Arg of BK and Lys–BK [66], can be induced by endotoxin in tissues simultaneously with the B1 receptor, very likely other effective exogenous and endogenous agonists to activate B1 will be found in the future. Thus, the induced B1 receptor is still a ‘semi-orphan’ receptor waiting for additional, maybe more stable, agonists.

After spending decades to detect and characterize enzymes that cleave active peptides and proteins, slowly it dawned on us to look for shortcuts in the complex enzymatic release, activation and inactivation steps in cells and tissues. Paradoxically, studies of the very complicated signal transduction systems which follow receptor activation, guide towards an appreciation of shunting of the preceding intricate steps in the extracellular milieu and plasma membrane. At least, it appears so in the kallikrein–kinin–kininase inhibitor complexes.

Inhibitors used as therapeutic agents, besides inhibiting enzymes that cleave functionally related and unrelated peptides, may enhance the actions of peptide ligands on their receptors by inducing a crosstalk, a protein-to-protein interaction, a heterodimer enzyme-receptor formation, a sort of transactivation of the receptor to the ligand. And hopefully, finding ‘new’ enzymes, receptors and inhibitors will signal the development of improved therapeutic agents.

Time for primary review days


   Acknowledgements
 
Some of the studies described here were supported by NIH, NHLBI HL36473 and HL58118. I am grateful for the very skilled editorial assistance of Ms. Sara Bahnmaier.


   Notes
 
1 Cited from: F. Stern, Einstein's German World, Princeton University Press, 1999, p. 67. Back

2 E.G. Erdös, unpublished. Back


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