ACE Activity is Modulated by Kinin B2 Receptor (original) (raw)
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Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B1 receptor?
American journal of physiology. Heart and circulatory physiology, 2003
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....
Journal of Biological Chemistry, 2000
To investigate further the relationship of angiotensin I-converting enzyme (ACE) inhibitors to activation of the B 2 bradykinin (BK) receptor, we transfected Chinese hamster ovary cells to stably express the human receptor and either wild-type ACE (WT-ACE), an ACE construct with most of the cytosolic portion deleted (Cytdel-ACE), or ACE with a glycosylphosphatidylinositol (GPI) anchor replacing the transmembrane and cytosolic domains (GPI-ACE). BK or its ACE-resistant analogue were the agonists. All activities (arachidonic acid release and calcium mobilization) were blocked by the B 2 antagonist HOE 140. B 2 was desensitized by repeated administration of BK but resensitized to agonist by ACE inhibitors in the cells expressing both B 2 and either WT-ACE or Cyt-del-ACE. In GPI-ACE expressing cells, the B 2 receptor was still activated by the agonists, but ACE inhibitors did not resensitize. Pretreatment with filipin returned the sensitivity to inhibitors. In immunocytochemistry, GPI-ACE showed patchy, uneven distribution on the plasma membrane that was restored by filipin. Thus, ACE inhibitors were inactive as long as GPI-ACE was sequestered in cholesterol-rich membrane domains. WT-ACE and B 2 receptor in Chinese hamster ovary cells co-immunoprecipitated with antibody to receptor, suggesting an interaction on the cell membrane. ACE inhibitors augment BK effects on receptors indirectly only when enzyme and receptor molecules are sterically close, possibly forming a heterodimer.
2000
Elmarakby, Ahmed A., Peter Morsing, and David M. Pollock. Enalapril attenuates endothelin-1-induced hypertension via increased kinin survival. Recent studies have shown that angiotensin-converting enzyme (ACE) inhibitors attenuate endothelin-1 (ET-1)-induced hypertension, but the mechanisms for this effect have not been clarified. Initial experiments were conducted to contrast the effect of the ACE inhibitor enalapril, the combined ACE-neutral endopeptidase inhibitor omapatrilat, and the angiotensin II receptor antagonist candesartan on the hypertensive and renal response to ET-1 in anesthetized Sprague-Dawley rats. Acute intravenous infusion of ET-1 (10 pmol⅐kg Ϫ1 ⅐min Ϫ1 ) for 60 min significantly increased mean arterial pressure (MAP) from 125 Ϯ 8to145Ϯ 8 mmHg (P Ͻ 0.05) and significantly decreased glomerular filtration rate (GFR) from 0.31 Ϯ 0.09 to 0.13 Ϯ 0.05 ml⅐min Ϫ1 ⅐100 g kidney wt Ϫ1 . Pretreatment with enalapril (10 mg/kg iv) before ET-1 infusion inhibited the increase in MAP (121 Ϯ 4 vs. 126 Ϯ 4 mmHg) before and during ET-1 infusion, respectively (P Ͻ 0.05) without blocking the effect of ET-1 on GFR. In contrast, neither omapatrilat (30 mg/kg) nor candesartan (10 mg/kg) had any effect on ET-1-induced increases in MAP or decreases in GFR. To determine whether the effect of enalapril was due to the decrease in angiotensin II or increase in kinin formation, rats were given (1 mg/kg iv), a selective B2 receptor antagonist, with or without enalapril before ET-1 infusion. REF-000359 completely blocked the effect of enalapril on ET-1 infusion (MAP was 117 Ϯ 5 vs. 135 Ϯ 5 mmHg before and during ET-1 infusion, respectively, P Ͻ 0.05). REF-000359 alone had no effect on the response to ET-1 infusion (MAP was 117 Ϯ 4 vs. 144 Ϯ 4 mmHg before and during ET-1 infusion, respectively, P Ͻ 0.05). REF-000359 with or without enalapril had no significant effect on the ability of ET-1 infusion to decrease GFR. These findings support the hypothesis that decreased catabolism of bradykinin and its subsequent vasodilator activity oppose the actions of ET-1 to increase MAP. endothelin; angiotensin-converting enzyme inhibitors; bradykinin receptors; blood pressure; glomerular filtration rate ENDOTHELIN-1 (ET-1) has been described as the most powerful vasoconstrictor yet discovered and produces
Hypertension, 1998
We used the isolated N-and C-domains of the angiotensin I-converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1-7 derivative of angiotensin (Ang) II and inhibition by 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE). Ang-(1-7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC 50 of C-ACE with 100 mol/L Ang I substrate was 1.2 mol/L and the K i was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38-to 47-times lower concentration than by N-ACE; IC 50 values with C-ACE were 0.5 and 0.04 mol/L. Furthermore, we investigated how Ang-(1-7) acts via bradykinin and the involvement of its B 2 receptor. Ang-(1-7) was ineffective directly on the human bradykinin B 2 receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1-7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 mol/L), acting on the B 2 receptor when the cells were cotransfected with cDNAs of both B 2 receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1-7) can potentiate the actions of a ligand of the B 2 receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1-7). (Hypertension. 1998;31:912-917.)
Human ACE and bradykinin B2 receptors form a complex at the plasma membrane
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2006
To investigate how angiotensin I-converting enzyme (ACE) inhibitors enhance the actions of bradykinin (BK) on B2 receptors independent of blocking BK inactivation, we expressed human somatic ACE and B2 receptors in CHO cells. Bradykinin and its ACE-resistant analog were the receptor agonists. B2 fused with green fluorescent protein (GFP) and ACE were coprecipitated with antisera to GFP or ACE shown in Western blots. Immunohistochemistry of fixed cells localized ACE by red color and B2-GFP by green. Yellow on plasma membranes of coexpressing cells also indicated enzyme-receptor complex formation. Using ACE-fused cyan fluorescent protein donor and B2-fused yellow fluorescent protein (YFP) acceptor, we registered fluorescence resonance energy transfer (FRET) by the enhanced fluorescence of donor on acceptor photobleaching, establishing close (within 10 nm) positions of B2 receptors and ACE. Bradykinin stimulation cointernalized ACE and B2 receptors. We expressed ACE fused to N terminus...
Circulation Research, 2001
Using B 2 kinin receptor gene knockout mice (B 2 Ϫ/Ϫ), we tested the hypothesis that (l) lack of B 2 receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT 1-ant), whereas lack of B 2 receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B 2 Ϫ/Ϫ and 129/SvEvTac mice (wild-type control, B 2 ϩ/ϩ). An ACEi (ramipril, 2.5 mg/kg/d) or AT 1-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B 2 ϩ/ϩ and B 2 Ϫ/Ϫ mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B 2 Ϫ/Ϫ mice (respective values for B 2 ϩ/ϩ versus B 2 Ϫ/Ϫ mice: overall increase in ejection fraction, 64Ϯ10% versus 21Ϯ5% [PϽ0.01]; increase in CO, 69Ϯ17% versus 23Ϯ9% [PϽ0.01]; overall decrease in LVDd, Ϫ24Ϯ3% versus Ϫ7Ϯ4% [PϽ0.01]; and decrease in LV mass, Ϫ38Ϯ3% versus Ϫ6Ϯ6% [PϽ0.01]). AT 1-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B 2 Ϫ/Ϫ mice (respective values for B 2 ϩ/ϩ versus B 2 Ϫ/Ϫ mice: overall increase in ejection fraction, 46Ϯ10% versus 25Ϯ9% [PϽ0.01]; increase in CO, 44Ϯ14% versus 15Ϯ5% [PϽ0.01]; overall decrease in LVDd, Ϫ14Ϯ4% versus Ϫ6Ϯ3% [PϽ0.01]; and decrease in LV mass, Ϫ33Ϯ4 versus Ϫ16Ϯ7% [PϽ0.01]). The effect of ACEi or AT 1-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B 2 Ϫ/Ϫ mice. We concluded that (1) lack of B 2 kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B 2 receptor play an important role in the cardioprotective effect of ACEi and AT 1-ant.
Hypertension, 2016
The renin-angiotensin system and the kallikrein-kinin system contribute to fluid homeostasis and blood pressure regulation. The renin-angiotensin system is composed of 2 arms with opposing functions. The pressor arm, represented by the angiotensin type 1 receptor (AT 1 R), angiotensin-converting enzyme (ACE), and angiotensin II, is responsible for the vasoconstrictive, proliferative, fibrotic, and hypertensive effects of the renin-angiotensin system. In contrast, the second arm exerts depressor and cardiovascular protective effects through angiotensin-(1-7) (Ang-(1-7)), the Ang-(1-7)-specific receptor Mas that transduces the main physiological actions of Ang-(1-7), and ACE2 that catalyzes the generation of Ang-(1-7) from angiotensin II. 1-3 Bradykinin, generated by the kallikrein-kinin system, exerts cardioprotective, vasodilatory, and depressor properties through B2 receptor (B2 R) stimulation. 4,5 Several studies showed the existence of a cross talk between the renin-angiotensin system and kallikrein-kinin system. 6,7 For instance, kallikrein not only catalyzes the generation of kinin from kininogen, but also acts as a prorenin-activating enzyme leading to an increase in angiotensin II. 6 In addition , ACE not only generates the vasopressor angiotensin II but also responsible for the proteolytic degradation of bradykinin. 6,7 Not only was a cross talk between both systems reported at the enzymatic level, but also between the components of these systems. For example, Ang-(1-7) exerts kinin-like effects and Abstract-Bradykinin B 2 receptor (B 2 R) and angiotensin-(1-7) Mas receptor (MasR)-mediated effects are physiologically interconnected. The molecular basis for such cross talk is unknown. It is hypothesized that the cross talk occurs at the receptor level. We investigated B2R-MasR heteromerization and the functional consequences of such interaction. B2 R fused to the cyan fluorescent protein and MasR fused to the yellow fluorescent protein were transiently coexpressed in human embryonic kidney293T cells. Fluorescence resonance energy transfer analysis showed that B 2 R and MasR formed a constitutive heteromer, which was not modified by their agonists. B 2 R or MasR antagonists decreased fluorescence resonance energy transfer efficiency, suggesting that the antagonist promoted heteromer dissociation. B 2 R-MasR heteromerization induced an 8-fold increase in the MasR ligand-binding affinity. On agonist stimulation, the heteromer was internalized into early endosomes with a slower sequestration rate from the plasma membrane, compared with single receptors. B 2 R-MasR heteromerization induced a greater increase in arachidonic acid release and extracellular signal-regulated kinase phosphorylation after angiotensin-(1-7) stimulation, and this effect was blocked by the B2 R antagonist. Concerning serine/ threonine kinase Akt activity, a significant bradykinin-promoted activation was detected in B2 R-MasR but not in B2 R-expressing cells. Angiotensin-(1-7) and bradykinin elicited antiproliferative effects only in cells expressing B2 R-MasR heteromers, but not in cells expressing each receptor alone. Proximity ligation assay confirmed B2 R-MasR interaction in human glomerular endothelial cells supporting the interaction between both receptors in vivo. Our findings provide an explanation for the cross talk between bradykinin B2 R and angiotensin-(1-7) MasR-mediated effects. B2R-MasR heteromerization induces functional changes in the receptor that may lead to long-lasting protective properties. (Hypertension. 2016;68:00-00.
Kinin B1 receptors and the cardiovascular system: regulation of expression and function
Cardiovascular Research, 2000
Kinins are important peptide mediators of a diverse range of physiological and pathological functions of the cardiovascular system. The kinin peptides exert their effects by selective activation of two distinct G-protein coupled receptors termed B and B. The principal kinin 1 2 peptides involved in the acute regulation of cardiovascular function during normal physiology are bradykinin (BK) and Lys-BK which 9 9 produce their effects via activation of B receptors. The B receptor is activated by the des-Arg kinin metabolites namely des-Arg BK 2 1 9 and Lys-des-Arg BK, the synthesis of which are increased during inflammation. The B receptor, which is not constitutively expressed, is 1 induced in various pathologies relating to inflammation. Recent investigations into the molecular mechanisms of B receptor induction 1 and their distribution and function in the cardiovascular system have shown that following an inflammatory stimulus the B receptor is 1 induced and may play an important role in modulation of cardiovascular function. This review summarises recent studies on B receptor 1 expression and function in the cardiovascular system and discusses the role of these receptors in regulation of circulatory homeostasis and their potential as therapeutic targets.
Cardiovascular Phenotypes of Kinin B2 Receptor- and Tissue Kallikrein-Deficient Mice
Hypertension, 2002
To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B2 receptor-deficient (B2-/-) and tissue kallikrein-deficient (TK-/-) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B2-/-, TK-/-, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dt(max)) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B2-/- mice compared with TK-/- and WT mice. In addition, B2-/- mice, but not TK-/- mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2-/- mice were significantly more sensitive than were TK-/- mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B2-/- mice and smaller in TK-/- mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK-/- and B2-/- mice could be underlain by tissue kallikrein kinin-independent effect and/or kinin B1 receptor activation.