Identification of a Novel Vasoconstrictor Peptide Specific for the Systemic Circulation

Wenzel, Daniela; Koch, Manuel; Matthey, Michaela; Heinemann, Jan C.; Fleischmann, Bernd K.

doi:10.1161/hypertensionaha.111.188367

Cited by 8 publications

(5 citation statements)

References 24 publications

(23 reference statements)

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“…2+ imaging experiments Single-cell Ca 2+ imaging experiments were performed as described earlier (28). MTSMCs grown on a coverslip were loaded for 30 min with the ratiometric dye fura-2 AM (10 mM) in physiological salt solution (PSS).…”

Section: Single-cell Camentioning

confidence: 99%

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

et al. 2017

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Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of G q protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein AQ4 )-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptoractivating medications results in desensitization. We therefore hypothesized that pharmacological G q inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of G q , was effective in silencing G q signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective G q inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of G q proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

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Section: Single-cell Camentioning

confidence: 99%

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

et al. 2017

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“…Isometric force measurements of vascular rings were performed in a wire myograph as recently described (10–12). For that purpose, murine PAs and aortas (AOs) were isolated and the connective tissue removed.…”

Section: Methodsmentioning

confidence: 99%

The β ₂ agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via a adrenoceptor antagonism

et al. 2018

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Pulmonary hypertension is a severe, incurable disease with a poor prognosis. Although treatment regimens have improved during the last 2 decades, current pharmacologic strategies are limited and focus on the modulation of only a few pathways related to endothelin, NO, and prostacyclin signaling. Therefore, the identification of novel molecular targets is urgently needed. We found that the β adrenoceptor (AR) agonists terbutaline (TER) and salbutamol induced a dose-dependent vasorelaxation in large pulmonary arteries but not aortas of mouse. This effect was found to be independent of β ARs and the endothelium but was determined by the type of the preconstrictor. Vasodilation by β AR agonists occurred after pretreatment of pulmonary arteries with phenylephrine and serotonin, both agonists of α ARs, but was absent after preconstriction with the thromboxane analog U46619. These data indicated α-adrenolytic activity of β AR agonists, which was confirmed by a right shift of the phenylephrine dose-response curve by TER. This effect was physiologically relevant because TER also relaxed small intrapulmonary arteries in lung slices and diminished pulmonary arterial pressure in an isolated perfused lung model under normoxia and hypoxia. Finally, TER applied as an aerosol also selectively decreased pulmonary arterial pressure without effects on systemic blood pressure and heart rate in mouse in vivo. Thus, β AR agonists display α-adrenolytic activity in pulmonary arteries ex vivo and in vivo, and may provide a novel option to reduce pulmonary arterial pressure in pulmonary hypertension.-Neumann, V., Knies, R., Seidinger, A., Simon, A., Lorenz, K., Matthey, M., Breuer, J., Wenzel, D. The β agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via α adrenoceptor antagonism.

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“…Isometric force measurements were performed as described previously 31,32 . In detail, mouse tracheas were isolated and in some tracheas the epithelium was mechanically removed.…”

Section: Isometric Force Measurements Of Murine Tracheamentioning

confidence: 99%

The endocannabinoid anandamide is an airway relaxant in health and disease

et al. 2022

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Chronic obstructive airway diseases are a global medical burden that is expected to increase in the near future. However, the underlying mechanistic processes are poorly understood so far. Herein, we show that the endocannabinoid anandamide (AEA) induces prominent airway relaxation in vitro and in vivo. In contrast to 2-arachidonlyglycerol-induced airway relaxation, this is mediated by fatty acid amide hydrolase (FAAH)-dependent metabolites. In particular, we identify mouse and also human epithelial and airway smooth muscle cells as source of AEA-induced prostaglandin E2 production and cAMP as direct mediator of AEA-dependent airway relaxation. Mass spectrometry experiments demonstrate reduced levels of endocannabinoid-like compounds in lungs of ovalbumin-sensitized mice indicating a pathophysiological relevance of endocannabinoid signalling in obstructive airway disease. Importantly, AEA inhalation protects against airway hyper-reactivity after ovalbumin sensitization. Thus, this work highlights the AEA/FAAH axis as a critical regulator of airway tone that could provide therapeutic targets for airway relaxation.

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Identification of a Novel Vasoconstrictor Peptide Specific for the Systemic Circulation

Cited by 8 publications

References 24 publications

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

The β ₂ agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via a adrenoceptor antagonism

The endocannabinoid anandamide is an airway relaxant in health and disease

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Identification of a Novel Vasoconstrictor Peptide Specific for the Systemic Circulation

Cited by 8 publications

References 24 publications

Targeted inhibition of G q signaling induces airway relaxation in mouse models of asthma

Targeted inhibition of G q signaling induces airway relaxation in mouse models of asthma

The β 2 agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via a adrenoceptor antagonism

The endocannabinoid anandamide is an airway relaxant in health and disease

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Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

Targeted inhibition of G _q signaling induces airway relaxation in mouse models of asthma

The β ₂ agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via a adrenoceptor antagonism