Cardiovascular Research 54 (2002) 485–491
www.elsevier.com / locate / cardiores
Editorial
Kinins, the long march—A personal view
¨ *
Ervin G. Erdos
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
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
*Tel.: 11-312-996-9146; fax: 11-312-996-1648.
¨
E-mail address: [email protected] (E.G. Erdos).
1
Cited from: F. Stern, Einstein’s German World, Princeton University
Press, 1999, p. 67.
2
¨ unpublished.
E.G. Erdos,
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 B 2 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 B 2 , called B 1 [5–8]. The two receptors are both G
protein-coupled, seven transmembrane, heptahelical receptors on plasma membrane, but otherwise, they differ [8–
10]. While B 2 is ubiquitous, B 1 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].
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].
0008-6363 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 02 )00284-5
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¨ / Cardiovascular Research 54 (2002) 485 – 491
E.G. Erdos
Fig. 1.. Release of kinins from kininogen by kallikreins. Ser-X, extended sequence in the light chain of kininogen. (Modified from Ref. [5]).
‘‘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 Arg 1
[16,17] or by hydrolyzing the C-terminal Phe 8 –Arg 9 bond
(Fig. 1). The aminopeptidase that cleaved BK at the
Arg 1 –Pro 2 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 Lys 1 –Arg 2 -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
Arg 9 instead of Arg 1 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 Phe 8 –Arg 9 or Pro 7 –Phe 8 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,
Fig. 2. Cleavage sites of Lys–bradykinin (kallidin) and bradykinin. Conversion from ligand to B 2 receptor to agonist of B 1 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]).
¨ / Cardiovascular Research 54 (2002) 485 – 491
E.G. Erdos
which cleaves des-Arg 9 BK and Ang II at the Pro 7 –Phe 8
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-Arg 9 -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-Arg 9 -BK or des-Arg 9 –Lys 1 -BK act on the B 1 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
Phe 8 –Arg 9 of BK or His 9 –Leu 10 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 Cterminal protected dipeptides and even N-terminal tripeptides, as in LHRH [22]. ACE cleaves in vitro the
heptapeptide Met 5 –enkephalin–Arg 6 –Phe 7 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 B 2
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
487
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 B 2 receptor
independent of blocking its enzymatic degradation, and
offered various explanations [47–51]. As a gold standard
to show the involvement of the B 2 receptors of BK, a B 2
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 B 2
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 B 2
BK receptor or only with the enzyme or B 2 and used
endothelial cells that constitutively express both proteins
[3,4]. In these experiments, the parameters measured
included the release of labeled arachidonic acid, 1,4,5inositoltrisphosphate and [Ca 21 ] i elevation. The results
488
¨ / Cardiovascular Research 54 (2002) 485 – 491
E.G. Erdos
with these agents were taken as an indication of prostaglandin and NO synthesis by the cells, after signal
transduction was initiated by BK B 2 receptor through Ga 1
or Ga q proteins.
Pretreating cells with ACE inhibitors, slowly cleaved
substrates or antibodies to ACE, potentiated BK effects on
the B 2 receptor, even when a partially or fully ACE
resistant BK analogue was the ligand, provided the cells
expressed both ACE and B 2 receptor. ACE inhibitors, after
the first application of BK desensitized the receptor,
resensitized the B 2 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].
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.
Fig. 3. Bradykinin desensitizes the B 2 receptor; ACE inhibitor resensitizes it. Bradykinin (BK; 100 nM) raises [Ca 21 ] i level and desensitizes
human B 2 receptor to second dose of BK in CHO cells expressing B 2
receptor and WT-ACE. Ramiprilat (RAM, 1 mM) 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).
The two active centers, although both have a high degree
of homology around the active site, contain Zn cofactor,
but they differ in Cl 2 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 (GPIACE). In GPI-ACE expressing cells, the B 2 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, GPIACE 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 B 2 receptor but induce a
cross-talk between ACE and the B 2 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 [Ca 21 ] i elevation by BK. Protein kinase C
(the first two compounds) or phosphatase inhibitors (the
latter two), however, abolished the resensitization of the B 2
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 B 2 receptor activation liberating important
mediators of vascular tone, fibrinolysis and pain [5–7,64].
¨ / Cardiovascular Research 54 (2002) 485 – 491
E.G. Erdos
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 [Ca 21 ] i and release [ 3 H]arachidonic acid from
cultured cells stably transfected to express human BK B 2
receptor [Chinese hamster ovary (CHO / B 2 ), Madin-Darby
canine kidney (MDCK / B 2 ), human embryonic kidney
(HEK / B 2 )] and from endothelial cells used as control
[65]. As with BK, the actions of kallikreins were blocked
by the B 2 antagonist, HOE 140, and kallikreins were
inactive on cells lacking the B 2 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 [ 3 H]BK binding to the receptor with a low KD (3 nM).
Thus, kallikreins and some other proteases activate human
BK B 2 receptor directly, independent of BK release. The
BK B 2 receptor may belong to a newly detected group of
serine protease-activated receptors [65].
The B 1 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-Arg 10 –kallidin (des-Arg 10 –Lys 1 BK), which is more potent than des-Arg 9 -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 B 1 receptor in low
concentration, the C-terminal Arg 10 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 B 1 , Lys 1 –des-Arg 10 -BK, is the product of three
sequential enzymatic reactions, provided the peptide escapes inactivation by an ubiquitous aminopeptidase [16–
18]. This enzyme cleaves Lys 1 , converts the peptide to
des-Arg 9 BK, and thereby renders it up to 1000 times less
active [8] on B 1 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 B 1 receptor, very likely other effective
exogenous and endogenous agonists to activate B 1 will be
found in the future. Thus, the induced B 1 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
489
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.
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.
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