Coronary Vasomotor Response to the Selective B1-Kinin-Receptor Agonist Des-Arg9-Bradykinin in Humans

Aptecar, Eduardo; Lecorvoisier, Philippe; Teiger, Emmanuel; Garot, Philippe; Dupouy, Patrick; Sediame, Saı̈d; Vermès, Emmanuelle; Loisance, D; Hittinger, Luc; Dubois‐Randé, Jean‐Luc; Montagne, Olivier

doi:10.1016/j.healun.2005.08.020

Cited by 12 publications

(10 citation statements)

References 29 publications

(43 reference statements)

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“…Similar target profiles were predicted for 1 and 2 that occasionally overlapped the predictions for amprenavir. In contrast with all publicly available prediction models, the top consensus SPiDER prediction for 1 and 2 was the bradykinin B 1 receptor, a G protein-coupled receptor involved in the mechanisms of inflammatory pain (45) and coronary vasomotor function (46). Being confidently predicted and practically exclusive to our approach, we tested compounds 1 and 2 for antagonistic activity toward the B 1 receptor.…”

Section: Resultsmentioning

confidence: 99%

Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus

Reker

Rodrigues

Schneider

2014

Proc. Natl. Acad. Sci. U.S.A.

210

165

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De novo molecular design and in silico prediction of polypharmacological profiles are emerging research topics that will profoundly affect the future of drug discovery and chemical biology. The goal is to identify the macromolecular targets of new chemical agents. Although several computational tools for predicting such targets are publicly available, none of these methods was explicitly designed to predict target engagement by de novo-designed molecules. Here we present the development and practical application of a unique technique, self-organizing map-based prediction of drug equivalence relationships (SPiDER), that merges the concepts of self-organizing maps, consensus scoring, and statistical analysis to successfully identify targets for both known drugs and computer-generated molecular scaffolds. We discovered a potential off-target liability of fenofibraterelated compounds, and in a comprehensive prospective application, we identified a multitarget-modulating profile of de novo designed molecules. These results demonstrate that SPiDER may be used to identify innovative compounds in chemical biology and in the early stages of drug discovery, and help investigate the potential side effects of drugs and their repurposing options.drug design | target prediction | polypharmacology | machine learning | chemical similarity C omputer-assisted de novo molecular design has evolved as a popular source of ideas to combat the perceived lack of new chemical entities (NCEs) in chemical biology and drug discovery (1). We demonstrate that automated de novo design delivers readily synthesizable NCEs with desirable activity profiles. Although receptor-based design operates on a model of a macromolecular binding site, ligand-based methods are either explicitly or implicitly based on the chemical similarity principle (2) without requiring a receptor model (3). Instead, the latter typically uses some measure of chemical or pharmacophore feature similarity to a reference ligand as a fitness function, which aims to generate NCEs as template mimetics via scaffold hopping (4-8). We report the development, implementation, and successful prospective application of an innovative computational technique for the target profiling of de novo-designed molecules. The approach combines the concepts of self-organizing maps (SOMs) (9) for macromolecular target prediction (10), consensus scoring (11), and a statistical evaluation that provides confidence estimates for the predictions.Predicting polypharmacological activities is a topic relevant to chemical biology and drug discovery, not only to take advantage of inherent drug promiscuity but also to decrease lead compound attrition caused by unfavorable off-target modulation

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Section: Resultsmentioning

confidence: 99%

Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus

Reker

Rodrigues

Schneider

2014

Proc. Natl. Acad. Sci. U.S.A.

210

165

View full text Add to dashboard Cite

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“…In a previous study examining the effects of B 1 kinin receptor agonism in the coronary circulation in vivo in man, Aptecar and colleagues demonstrated a reduction in epicardial coronary artery diameter, despite the absence of a change in coronary blood flow following administration of des-Arg 9 -bradykinin, both in healthy patients and heart transplant recipients [29]. These unexpected and conflicting results are likely to reflect differences in the study design as well as the B 1 kinin receptor agonist used [29].…”

Section: Discussionmentioning

confidence: 99%

Vasomotor and fibrinolytic responses to kinin receptor agonists in the atherosclerotic human lower limb

et al. 2011

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Upregulation of vascular B(1) kinin receptor expression has been reported in human atheroma, but its role remains unclear. We examined vasomotor and fibrinolytic responses to selective B(1) and B(2) kinin receptor agonism in the human femoral circulation and correlated responses with femoral arterial plaque load. Femoral arterial cross-sectional area, blood flow and plaque volume were determined using intravascular ultrasound and Doppler during selective arterial infusion of Lys-des-Arg(9)-bradykinin (B(1) agonist), bradykinin (B(2) agonist) and sodium nitroprusside in eleven patients undergoing diagnostic coronary angiography. Net release of tissue plasminogen activator was determined across the femoral vascular bed. Mean femoral arterial plaque load was 8.1 (±0.9) mm(3)/mm of vessel. Bradykinin and sodium nitroprusside caused dose-dependent increases in femoral blood flow (p < 0.05 and p < 0.005, respectively). Bradykinin caused a dose-dependent increase in net tissue plasminogen activator release (p < 0.05), which was augmented by angiotensin-converting enzyme inhibition (p < 0.05). There were no correlations between plaque load and bradykinin-mediated vasodilation or tissue plasminogen activator release. Lys-des-Arg(9)-bradykinin had no effect on blood flow or tissue plasminogen activator release. The vasomotor and fibrinolytic actions of bradykinin in the femoral circulation are mediated solely by the B(2) kinin receptor, irrespective of the presence of atheroma. In keeping with previous data, bradykinin-mediated tissue plasminogen activator release was augmented in the presence of angiotensin-converting enzyme inhibition consistent with its putative vascular protective effect.

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“…10 Des-Arg9-BK decreases epicardial diameters in heart transplant patients. 11 In isolated pig coronary arteries, we found that B1 receptors mediate strong, endothelium-independent coronary constriction in endotoxin-damaged arteries, but has no response in normal coronary arteries. 8 Furthermore, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds by coupling to cyclooxygenases-2 and activation of thromboxane-prostanoid receptors.…”

Section: Discussionmentioning

confidence: 71%

“…25 Various mediators, including cytokines, endotoxin, angiotensin II, and endothelin-1, induce transcriptional upregulation of kinin B1 receptors in vascular smooth muscle cells and subsequently increase vasoconstriction in cardiopulmonary vascular beds. 8,10,11 B1 receptors have been shown to mediate strong contractile response to B1 receptor agonist des-Arg9-BK in pulmonary arteries in neonatal group B streptococcal sepsis in piglets and likely participate in the increase of pulmonary vascular resistance. 10 Des-Arg9-BK decreases epicardial diameters in heart transplant patients.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH. With this same reasoning, B1 receptor antagonists may have therapeutic potential for treating PAH by reducing inflammation, inhibiting smooth muscle contraction, attenuating vascular and cardiac remodeling, and improving cardiac function.…”

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confidence: 99%

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Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

et al. 2015

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P ulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increases in pulmonary arterial pressure. This increasing pressure is associated with perivascular inflammation, excessive pulmonary vascular proliferation, remodeling, and vasoconstriction. Ultimately, PAH can cause right heart failure and death.1-3 Despite new treatment options, PAH patients still face high mortality rates. [1][2][3] Therefore, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. [1][2][3] Kinins are proinflammatory peptides that exert a variety of biological actions via stimulation of 2 pharmacologically distinct receptor subtypes, B1 and B2. 4,5 The former are normally weakly expressed, but can be upregulated in the presence of cytokines and endotoxins or during tissue injury, whereas the latter are expressed constitutively. 4,5 One important difference between the 2 subtypes is that the B2 is internalized rapidly and desensitizes, whereas kinin B1 receptor-induced responses are more persistent and suggesting the lack of the internalization of the B1 receptorligand complex.4-6 Thus, kinin B1 receptors represent a novel therapeutic target for chronic inflammatory diseases. 4-6Kinin B1 receptors are involved in diverse pathological processes, including inflammation, smooth muscle contraction, increased vascular permeability, edema, pain, cytokine and chemokine release, cell proliferation, and vascular and myocardial remodeling. [4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH. With this same reasoning, B1 receptor antagonists may have therapeutic potential for treating PAH by reducing inflammation, inhibiting smooth muscle contraction, attenuating vascular and cardiac remodeling, and improving cardiac function.The small molecule BI113823 is a newly developed, orally active, nonpeptide B1 receptor antagonist that exerts a potent anti-inflammatory effect with a favorable cardiovascular profile. 7,9 This study examined the effects of kinin B1 receptor blockade with BI113823 in a well-established experimental model of monocrotaline-induced PAH and vascular remodeling in left pneumonectomized rats. 12Abstract-This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg). The rats were then randomly assigned to receive treatment with vehicle or with BI113823 (a selective B1 receptor antagonist, 30 mg/kg, twice per day) via oral gavage from the day of monocrotaline injection to day 28. By day 28, BI113823-treated rats had s...

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Coronary Vasomotor Response to the Selective B1-Kinin-Receptor Agonist Des-Arg9-Bradykinin in Humans

Cited by 12 publications

References 29 publications

Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus

Identifying the macromolecular targets of de novo-designed chemical entities through self-organizing map consensus

Vasomotor and fibrinolytic responses to kinin receptor agonists in the atherosclerotic human lower limb

Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

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