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Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B₁ receptor?

¹Centre de Recherche en Cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, Centre de Recherche du Pavillon l'Hôtel-Dieu de Québec, Canada G1R 2J6; ²Institut de Pharmacologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada J1H 5N4; ³Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada H3C 3J7; and ⁴Institute of Pharmacology, University of Ferrara, Ferrara, 44100, Italy

Submitted 23 December 2002 ; accepted in final form 17 March 2003

	ABSTRACT

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It has been recently claimed that the human B₁ receptors for kinins bind angiotensin-converting enzyme (ACE) inhibitors via a potential zinc-binding domain and are pharmacologically stimulated by these drugs. We verified whether ACE inhibitors stimulate B₁ receptors in vitro. The isolated rabbit aorta or mouse stomach responded by negligible contractions to the application of captopril, enalaprilat, or zofenoprilat. The human isolated umbilical vein also failed to respond to enalaprilat. All of these preparations were responsive to the B₁ receptor agonists des-Arg⁹-bradykinin (BK) or Lys-des-Arg⁹-BK. Furthermore, enalaprilat applied continuously had no significant interaction with the effects of Lys-des-Arg⁹-BK on the rabbit aorta. Enalaprilat failed to stimulate [³H]arachidonate release, translocate the receptors (confocal microscopy), or stimulate ERK1/2 phosphorylation (immunoblot) in HEK-293 cells stably expressing the rabbit B₁ receptor conjugated to yellow fluorescent protein. The phospho-ERK1/2 content of arterial smooth muscle cells of human or rabbit origin was increased by treatment with Lys-des-Arg⁹-BK but not with enalaprilat. ACE inhibitors do not act as bona fide agonists of the kinin B₁ receptors.

enalaprilat; angiotensin II; des-Arg⁹-bradykinin

	Materials and Methods

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Drugs. Enalaprilat (Vasotec IV) was manufactured by Merck. Zofenoprilat and B-9858 were gifts from Menarini Ricerche (Florence, Italy) and Laboratoires Fournier (Daix, France), respectively. Des-Arg⁹-BK was purchased from Bachem Bioscience (King of Prussia, PA), human recombinant interleukin-1 (IL-1) was from R&D Systems (Minneapolis, MN), and the remaining drugs were from Sigma (St. Louis, MO).

Contractility studies. Exploratory studies were conducted to compare direct contractile effects of the B₁ receptor agonist des-Arg⁹-BK to that of selected ACE inhibitors in two smooth muscle bioassays: the isolated rabbit aorta and mouse stomach. Murine tissues were obtained either from C57B1/6 mice or from a described mouse strain in which the B₂ receptor gene had been inactivated (4); they were prepared as described (1). Rabbit aortic rings (New Zealand White, 1.5–2 kg, Charles River, St. Constant, Canada) were suspended under a tension of 2 g in 5-ml tissue baths containing oxygenated (95% O₂-5% CO₂) and warmed (37°C) Krebs solution as described (9).

Kinins contract the isolated human umbilical vein via preformed B₂ receptors responsive to BK and via inducible B₁ receptors responsive to both des-Arg⁹-BK and Lys-des-Arg⁹-BK (6, 13, 20). Further contractility studies in the rabbit aorta and human umbilical vein preparations (conducted as described, see Ref. 13) were based on the construction of cumulative concentration-response curves for the high-affinity B₁ receptor agonist Lys-des-Arg⁹-BK. Two cumulative concentration-response curves were constructed at 3 and 6 h from the beginning of the incubation of the preparations with ample washings between the interventions. This protocol accounts for the fact that the maximal response to this kinin increases as a function of the postisolation incubation time in these preparations, a behavior specific for agonists of B₁ receptors and attributed to the postisolation formation of these receptors (9, 19, 20). The stimulant drug was always Lys-des-Arg⁹-BK for the first curve and this kinin or enalaprilat for the second one. Some rabbit tissues stimulated with the kinin twice were continuously treated with either ZnCl₂ (100 nM) or enalaprilat (1 µM) to monitor any effect on the sensitivity, maximal effect, or sensitization process. Some rabbit tissues acutely stimulated with enalapril at 6 h had been also treated with ZnCl₂. Contractility results were expressed in grams of tension.

It was verified in separate preparations of isolated rabbit aortas with intact endothelium that the ACE inhibitor enalaprilat could reduce the apparent contractile potency of ANG I, largely attributed to the in situ conversion of this peptide into ANG II (21). To do so, cumulative concentration-effect curves for either ANG I or ANG II were established twice at 1 and 5 h postmounting; enalaprilat (1 µM) was applied 30 min before the construction of the second curve.

Cellular systems. The derivation of a HEK-293 cell line stably expressing B₁R-YFP and its properties have been described elsewhere (18). These cells were used in a phospholipase A₂ assay (24-well plates) and confocal microscopy (35-mm petri dishes), precisely as described (18), and also in a ERK1/2 phosphorylation assay (see ERK1/2 phosphorylation assay). Primary cultures of vascular smooth muscle cells from the rabbit aorta and human umbilical artery were obtained as described (2, 19).

ERK1/2 phosphorylation assay. To extend the investigation of cellular responses mediated by B₁ receptors, we tested the presence of phospho-ERK1/2 in resting or drug-treated cells (untransfected HEK-293 cells, HEK-293 cells stably expressing B₁R-YFP or primary cultures of smooth muscle cells from the rabbit aorta or human umbilical artery). These kinases are known to be activated by the peptide agonist of the B₁ receptors des-Arg⁹-BK in cellular systems (15). Confluent 75-cm² HEK-293 cell flasks were cultured overnight with medium containing a reduced fetal bovine serum concentration (0.5%) to minimize the background phosphorylation of the tested kinases. Rabbit aortic smooth muscle cells express kinin B₁ receptors in a regulated manner and in higher abundance following treatment with IL-1 (19). Human umbilical artery smooth muscle cells were also shown to express the messenger RNA coding for the kinin B₁ receptor in a regulated manner (stimulation by IL-1 treatment) (2). Accordingly, the human cells bind the selective B₁ receptor radioligand [³H]Lys-des-Arg⁹-BK in a more intense manner if pretreated with IL-1 (T. Sabourin and F. Marceau, unpublished observations). Smooth muscle cells of either origin (75 cm² flasks) were starved in fetal bovine serum (0.5%) 36 h before kinase assay and treated with recombinant IL-1 (5 ng/ml) 4 h before use to maximize the receptor abundance. The cells were treated with the stimulants agonist Lys-des-Arg⁹-BK (10 nM) or enalaprilat (1 µM; both applied 30 min before extraction in HEK-293 cells or 10 min in muscle cells), the B₁ receptor antagonists Lys-[Leu⁸]des-Arg⁹-BK (1 µM) or B-9858 (Lys-Lys-[Hyp³,Igl⁵,D-Igl⁷,Oic⁸]des-Arg⁹-BK; see Ref. 10; 10 nM; antagonists applied 40 min before extraction in HEK-293 cells or 10 min in muscle cells), or combinations of these drugs. Total cell extracts applicable to immunoblots were then prepared as outlined elsewhere (7). Transferred proteins were revealed using two types of antibodies for each sample: phospho-ERK1/2 (monoclonal, dilution 1/1,000, New England Biolabs) and total ERK1/2 (to show comparable loading; polyclonal, dilution 1/1,000, New England Biolabs). Staining was revealed using the appropriate peroxidase-conjugated secondary antibodies (1/16,000 for each).

	RESULTS

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Contractility studies. The isolated aorta from the rabbit or isolated stomach from the mouse, either from control or B₂ receptor gene knockout animals, responded by negligible contractions to the application of captopril (10^-7–10^-5 M), enalaprilat (10^-5 M), or zofenoprilat (10^-5 M) (Table 1). All these preparations were responsive to the B₁ receptor agonist des-Arg⁹-BK.

In another series of experiments, no direct activation of B₁ receptors by enalaprilat (1 nM-1 µM, applied at 6 h) was recorded in tissues previously proven to respond to the alternate B₁ receptor agonist Lys-des-Arg⁹-BK (Fig. 1). Furthermore, enalaprilat applied continuously had no significant interaction with the effects of Lys-des-Arg⁹-BK (Fig. 1). Because hypothetical loading of B₁ receptors with ZnCl₂ has been suggested to favor the stimulant action of ACE inhibitors, we have continuously treated some tissues with this salt (100 nM). Zinc preloading is not permissive for a direct action of enalaprilat nor does it modify the contractile effect of Lys-des-Arg⁹-BK (Fig. 1).

View larger version (25K): [in this window] [in a new window]   Fig. 1. Enalaprilat fails to contract the isolated rabbit aorta [incubated in vitro for 6 h (B) to induce a large population of B1 receptors] and fails to influence the concentration-effect relationship of the B1 receptor agonist Lys-des-Arg9-bradykinin (BK) [no significant inhibition, potentiation, or modification of the maximum effect increase from the time point 3 h (A) to 6 h]. Some tissues had been preloaded with ZnCl2 to facilitate the hypothetical interaction of the angiotensin-converting enzyme (ACE) inhibitor with the B1 receptor. Values are means ± SE of the number of replicates (n).

Other sets of isolated rabbit aortas have been stimulated with ANG I or ANG II twice, the second time in the presence of enalaprilat (1 µM; Fig. 2). The drug produced a 15.8-fold shift to the right of the concentration-effect curve (loss of apparent potency) for ANG I but exerted negligible effects on the response to ANG II.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Effect of enalaprilat (1 µM) on contractile response to ANG I and ANG II in the isolated rabbit aorta. Concentration-effect curves were constructed twice for either peptide: in absence (1 h) and presence (5 h) of enalaprilat. Values are means ± SE of 5 determinations and expressed as a percentage of the maximal response for each curve. Maximal effects in absolute force units (g) were similar at 1 and 5 h.

As observed with the isolated rabbit aorta, the isolated umbilical vein incubated for 6 h failed to respond by significant contractions to enalaprilat (1 nM-1 µM) (Fig. 3). The human preparation responded to Lys-des-Arg⁹-BK, but the change of contractile response to this B₁ receptor agonist as a function of time (from 3 to 6 h postmounting) was less important than for the rabbit aorta (compare Fig. 3 with Fig. 1).

View larger version (17K): [in this window] [in a new window]   Fig. 3. Enalaprilat fails to contract isolated human umbilical vein (incubated in vitro for 6 h). Presentation as in Fig. 1. Values are means ± SE of the number of replicates (n).

Cellular system expressing B₁ receptors. Enalaprilat (1–1,000 nM) failed to stimulate [³H]arachidonate release in a phospholipase A₂ assay based on HEK-293 cells stably expressing B₁R-YFP (Fig. 4). In the same series of experiments, Lys-des-Arg⁹-BK was highly active in this respect (Fig. 4). Untransfected HEK-293 cells are unresponsive to this peptide in this assay (18).

View larger version (18K): [in this window] [in a new window]   Fig. 4. [3H]Arachidonate released by HEK-293 cells stably expressing B1R-yellow fluorescent protein (YFP) and exposed to enalaprilat or Lys-des-Arg9-BK for 30 min. Results are expressed as means ± SE (n = 15–18). Set of values were statistically heterogeneous (Kruskall-Wallis test, P < 10-4). Mann-Whitney U test was applied to compare agonist-stimulated cells with their appropriate controls (*P < 0.01).

Confocal fluorescence microscopy reveals that B₁R-YFP is expressed essentially as an evenly distributed membrane protein (Fig. 5, see Ref. 18). Enalaprilat (1 µM, 30 min) failed to modify the cellular distribution of B₁R-YFP, whereas Lys-des-Arg⁹-BK (10 nM, 30 min) concentrated fluorescent receptors in structures that remained close to the membrane surface (previously proposed to be cholesterol-rich caveolaerelated rafts) (18).

View larger version (85K): [in this window] [in a new window]   Fig. 5. Subcellular localization of B1R-YFP fusion protein in stably transfected HEK-293 cells maintained in the complete culture medium and treated with cycloheximide (71 µM) and the indicated concentration of the agonist Lys-des-Arg9-BK or enalaprilat for 30 min. All photomicrographs represent rectangular fields with small sides of 16.6 µm. Selected confocal planes are halfway to the thickness of most cells. Representative results of several microscopic fields in 2 separate days of experiments.

ERK1/2 was phosphorylated in HEK-293 cells stimulated with Lys-des-Arg⁹-BK (10 nM) if they expressed B₁R-YFP but not in untransfected cells (Fig. 6, top). The response was further shown to be dependent on B₁ receptor signaling as it was abrogated by the antagonist B-9858. Enalaprilat (1 µM) failed to stimulate ERK1/2 phosphorylation in either type of HEK-293 cells (Fig. 6). Similarly, ERK1/2 was phosphorylated in response to Lys-des-Arg⁹-BK in smooth muscle cells derived from either the rabbit aorta or human umbilical artery (Fig. 6, bottom). This response was abrogated by the antagonist Lys-[Leu⁸]des-Arg⁹-BK. The phospho-ERK1/2 content of enalaprilat-treated smooth muscle cells was not different from that of control cells.

View larger version (40K): [in this window] [in a new window]   Fig. 6. ERK1/2 phosphorylation mediated by B1 receptors. Untransfected HEK-293 cells, HEK-293 cells stably expressing B1R-YFP (top), or IL-1 pretreated smooth muscle cells from either the human umbilical artery or rabbit aorta (bottom) were treated with Lysdes-Arg9-BK (10 nM), enalaprilat (1 µM), an antagonist [either B-9858 10 nM or Lys-[Leu8]des-Arg9-BK (1g µM)], or a combinations of the antagonist with the tested stimulants. The same total cell extracts were immunoblotted for phospho-ERK1/2 and total ERK1/2 (to assess comparable loading of tracks). Representative results of 2 experiments.

	DISCUSSION

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We failed to reproduce the claim of Ignjatovic et al. (8): it cannot be generally supported that ACE inhibitors directly activate B₁ receptor signaling in tissue-based or cellular bioassays in the present experiments, including in systems based on the human form of the receptor. Especially the ACE inhibitors failed to contract the smooth muscle preparations responsive to the conventional peptide agonists (Table 1, Figs. 1 and 3). The B₁ receptor seems to be constitutively expressed in the mouse stomach preparation (1); neither ACE inhibitors nor des-Arg⁹-BK were more active in the stomach isolated from B₂ receptor knockout mice, in which a certain compensatory upregulation of B₁ receptors has been proposed to apply to the cardiovascular and renal systems (5). Enalaprilat also failed to influence the potency, maximal effect, or sensitization behavior of the response to Lys-des-Arg⁹-BK in the rabbit aorta (Fig. 1). The isolated human umbilical vein is an established bioassay for the human form of the B₁ receptor, and it did not respond to enalaprilat (Fig. 3). Moreover, preloading the rabbit or mouse tissues with zinc, a procedure inspired by Ignjatovic et al. (8), also failed to reveal an effect of enalaprilat, captopril, or zofenoprilat (Table 1, Fig. 1). As reported with the early ACE inhibitor teprotide (21), enalaprilat reduced the apparent potency of ANG I without affecting that of ANG II in the rabbit aorta contractility assay, providing a positive control for the presence of ACE in the preparation and for the activity of the drug.

One of the cellular systems that we exploit here, HEK-293 cells expressing recombinant B₁R-YFP, allowed the testing of ACE inhibitors effects on three additional functional end points different from contractility (Figs. 4, 5, 6). Enalaprilat failed to stimulate phospholipase A₂ activity, ERK1/2 phosphorylation, or receptor translocation, whereas the peptide agonist Lys-des-Arg⁹-BK was active in all cases. Arterial smooth muscle cells of rabbit or human origin express wild-type B₁ receptors at a more physiological density; these cellular systems respond to Lys-des-Arg⁹-BK, but not to enalaprilat, as judged by the phosphorylation of ERK1/2 (Fig. 6). Different transduction mechanisms, largely unexplored for the B₁ receptor, may link GPCRs to these noncontractile cell responses.

Despite of our discrepant results, we give credit to Ignjatovic et al. (8) for pointing out a plausible and well-conserved metal binding site in a B₁ receptor extracellular domain that may assume other roles, such as the formation of heterodimers with other molecular partners that remain to be identified, an enzymatic function, or the direct binding of other kallikrein-kinin system components. It is not clear whether B₁ receptor-mediated signaling has been observed in the cellular systems previously described (8). One possibility is that a low endogenous level of kinins is produced in the systems, either because the cells synthesize components of the kallikrein-kinin system or have taken up some from the culture media. This type of artifact is probably involved in the pharmacological actions of human tissue kallikrein in systems that express the rabbit BK B₂ receptors (7).

Whether B₁ receptors are automatically involved in the therapeutic effects of ACE inhibitors is not supported by the present experiments. The des-Arg⁹-kinins that are optimal B₁ receptor agonists are low-affinity substrates for ACE; when this enzyme is blocked, there is clinical evidence that the individual efficacy of alternate degradation pathways predicts the probability of angioedema, a severe ACE inhibitor-associated side effect (14). Therefore, B₁ receptors may be associated with the inflammatory side effects of ACE inhibitors.

In summary, ACE inhibitors do not stimulate cell or tissue responses that are stimulated with the conventional peptide agonists at the natural or recombinant B₁ receptors.

	ACKNOWLEDGMENTS

 
This study was supported by the Canadian Institutes of Health Research Grants MOP-14077 (to F. Marceau and A. Adam) and MA-4032 (to D. Regoli). J.-P. Fortin is the recipient of a Studentship from the Fonds de la recherche en Santé du Québec.

	FOOTNOTES

 

Address for reprint requests and other correspondence: F. Marceau, 11 Cote-du-Palais, Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, Canada G1R 2J6 (E-mail: Francois.marceau{at}crhdq.ulaval.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) All Versions of this Article: 285/1/H277    most recent 01124.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Fortin, J.-P. Articles by Marceau, F. Search for Related Content PubMed PubMed Citation Articles by Fortin, J.-P. Articles by Marceau, F.