Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

Abstract

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...

Challenges and opportunities in treating inflammation associated with pulmonary hypertension

“…The targeting of several inflammatory pathways and the resulting modulation of chronic PAH, based on such successful targeting (35 –37), all support the notion that inflammation plays an important role in the pathobiology of hypoxia-induced PAH. An important aspect of chronic hypoxic PAH models is that the PAH is reversible upon withdrawal of the hypoxic stimulus.…”

Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms

“…39 Recent evidence suggest that novel orally active, selective non-peptide B1R antagonists are effective in the treatment of various in vivo models of inflammation and insulin resistance. 40–42 It has been postulated that the kinin receptor signaling pathway may act as a molecular link between changes in hemodynamic forces and the activation of inflammatory pathways. 39 Our data clearly show the beneficial effect of central B1R blockade in reducing inflammation and preventing the development of hypertension.…”

Hypertension Editors’ Picks

“…Here, the Editors have assembled 17 full-length articles related to PAH, which were published in our Journal in 2014 and 2015. Potentially important signaling pathways highlighted include microRNAs, 1,2 myocardin-related transcription factor A, 3 kinins, 4 estradiol, 5 leukotrienes, 6 tumor necrosis factor-α, 7 nuclear factor-κB, 8 oxidative stress, 9,10 TWIK-2 potassium channels, 11 and transient receptor potential channels. 12 Two articles 13,14 focus on possible adverse impacts of the sympathetic nervous system activation known to accompany PAH.…”