Des-Arg9-bradykinin causes kinin B1 receptor mediated endothelium-independent contractions in endotoxin-treated porcine coronary arteries

More, Amar S.; Kim, Hye Min; Khang, Gilson; Hildebrandt, Tobias; Bernlöhr, Christian; Doods, Henri; Vanhoutte, Paul M.; Wu, Dongmei

doi:10.1016/j.phrs.2014.09.001

Cited by 16 publications

(16 citation statements)

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“…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%

“…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. 8,10 Kinin production increases during inflammation and inflammatory cells are sources of tissue kallikrein.…”

Section: Discussionmentioning

confidence: 99%

“…8 Furthermore, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds by coupling to cyclooxygenases-2 and activation of thromboxane-prostanoid receptors. 8,10 Kinin production increases during inflammation and inflammatory cells are sources of tissue kallikrein. 26 Therefore, it is logical to presume that the local kinin production during inflammation can have pathological significance in the pulmonary vascular tone and leading to PAH.…”

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.…”

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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