Effects of a Novel Bradykinin B1 Receptor Antagonist and Angiotensin II Receptor Blockade on Experimental Myocardial Infarction in Rats

Wu, Dongmei; Lin, Xinchun; Bernloehr, Christian; Hildebrandt, Tobias; Doods, Henri

doi:10.1371/journal.pone.0051151

Cited by 15 publications

(9 citation statements)

References 36 publications

(54 reference statements)

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“…Treatment with kinin B 1 receptor antagonist improved cardiac function after myocardial infarction, as evidenced by attenuation of elevated LV end diastolic pressure [28]. On the other hand, it was shown that tissue kallikrein, through the kinin B 2 receptor and NO formation, improves cardiac function, apoptosis, and inflammation, and limits LV remodeling after ischemic injury [29], [30].…”

Section: Discussionmentioning

confidence: 99%

Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

et al. 2014

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Sympathetic hyperactivity induces adverse effects in myocardial. Recent studies have shown that exercise training induces cardioprotection against sympathetic overload; however, relevant mechanisms of this issue remain unclear. We analyzed whether exercise can prevent pathological hypertrophy induced by sympathetic hyperactivity with modulation of the kallikrein-kinin and angiogenesis pathways. Male Wistar rats were assigned to non-trained group that received vehicle; non-trained isoproterenol treated group (Iso, 0.3 mg kg−1 day−1); and trained group (Iso+Exe) which was subjected to sympathetic hyperactivity with isoproterenol. The Iso rats showed hypertrophy and myocardial dysfunction with reduced force development and relaxation of muscle. The isoproterenol induced severe fibrosis, apoptosis and reduced myocardial capillary. Interestingly, exercise blunted hypertrophy, myocardial dysfunction, fibrosis, apoptosis and capillary decreases. The sympathetic hyperactivity was associated with high abundance of ANF mRNA and β-MHC mRNA, which was significantly attenuated by exercise. The tissue kallikrein was augmented in the Iso+Exe group, and kinin B1 receptor mRNA was increased in the Iso group. Moreover, exercise induced an increase of kinin B2 receptor mRNA in myocardial. The myocardial content of eNOS, VEGF, VEGF receptor 2, pAkt and Bcl-2 were increased in the Iso+Exe group. Likewise, increased expression of pro-apoptotic Bad in the Iso rats was prevented by prior exercise. Our results represent the first demonstration that exercise can modulate kallikrein-kinin and angiogenesis pathways in the myocardial on sympathetic hyperactivity. These findings suggest that kallikrein-kinin and angiogenesis may have a key role in protecting the heart.

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Section: Discussionmentioning

confidence: 99%

Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

et al. 2014

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“…7,27 It exhibits high affinity (Ki) for both human and rat B1 receptors (5.3 and 13.3 nmol/L, respectively), whereas has no affinity for the B2 receptors (IC50>10.000 nmol/L). 27 BI 113823 does not influence blood pressure in conscious rats.…”

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.…”

Section: -6mentioning

confidence: 99%

“…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.…”

Section: -6mentioning

confidence: 99%

“…[4][5][6] Kinin 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.…”

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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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Snake venom‐derived bradykinin‐potentiating peptides: A promising therapy forCOVID‐19?

Gouda¹,

Mégarbane

2020

Drug Development Research

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The severe acute respiratory syndrome coronavirus‐2 (SARS‐COV‐2), a novel coronavirus responsible for the recent infectious pandemic, is known to downregulate angiotensin‐converting enzyme‐2 (ACE2). Most current investigations focused on SARS‐COV‐2‐related effects on the renin–angiotensin system and especially the resultant increase in angiotensin II, neglecting its effects on the kinin–kallikrein system. SARS‐COV‐2‐induced ACE2 inhibition leads to the augmentation of bradykinin 1‐receptor effects, as ACE2 inactivates des‐Arg9‐bradykinin, a bradykinin metabolite. SARS‐COV‐2 also decreases bradykinin 2‐receptor effects as it affects bradykinin synthesis by inhibiting cathepsin L, a kininogenase present at the site of infection and involved in bradykinin production. The physiologies of both the renin–angiotensin and kinin–kallikrein system are functionally related suggesting that any intervention aiming to treat SARS‐COV‐2‐infected patients by triggering one system but ignoring the other may not be adequately effective. Interestingly, the snake‐derived bradykinin‐potentiating peptide (BPP‐10c) acts on both systems. BPP‐10c strongly decreases angiotensin II by inhibiting ACE, increasing bradykinin‐related effects on the bradykinin 2‐receptor and increasing nitric oxide‐mediated effects. Based on a narrative review of the literature, we suggest that BPP‐10c could be an optimally effective option to consider when aiming at developing an anti‐SARS‐COV‐2 drug.

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Effects of a Novel Bradykinin B1 Receptor Antagonist and Angiotensin II Receptor Blockade on Experimental Myocardial Infarction in Rats

Cited by 15 publications

References 36 publications

Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

Exercise Training Can Prevent Cardiac Hypertrophy Induced by Sympathetic Hyperactivity with Modulation of Kallikrein-Kinin Pathway and Angiogenesis

Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

Snake venom‐derived bradykinin‐potentiating peptides: A promising therapy forCOVID‐19?

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