Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor

Leuchte, Hanno; Prechtl, Christoph; Callegari, Jens; Meis, Tobias; Haziraj, Shani; Bevec, Dorian; Behr, Jüergen

doi:10.1152/ajplung.00317.2014

Cited by 14 publications

(11 citation statements)

References 34 publications

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“…Interestingly, the NEP/ACE mixed inhibitors we tested were less effective than the more selective NEP inhibitors, despite some having excellent biochemical potency on the NEP target in vitro. Besides enkephalins, NEP and ACE are each capable of hydrolysis of a number of peptide hormones—some of which have prosecretory activities such as VIP and substance P ( Skidgel and Erdos, 2004 ; Leuchte et al, 2015 ). Perhaps mixed inhibition of these enzymes produces a different profile of stabilized peptides that dampens the effect of selective NEP inhibition in this model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea

Griggs

Prinsen

Oliva

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over 4 hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil–treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy.

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Section: Discussionmentioning

confidence: 99%

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea

Griggs

Prinsen

Oliva

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Nonetheless, TP may play other roles in smooth muscle in terms of actin polymerization (and thus tissue stiffening) (156,157). Furthermore, interactions of TP with other GPCRs could be relevant to understanding whether specific constricting (263,310) or dilating agents (420,476,510) (such as BTRs) may be more potent under certain conditions.…”

Section: L1117 Smooth Muscle and Beyondmentioning

confidence: 99%

Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

Prakash

2016

American Journal of Physiology-Lung Cellular and Molecular Phys

114

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Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease.

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“…It is difficult to explain this discrepancy between studies in animal and human beings, as it may not necessarily be reproducible in COPD patients. In murine models, lung remodeling and airway hyperreactivity increased when VIP levels were low, suggesting a therapeutic effect of exogenous VIP [26,48] . In human epithelial cell lines VIP protected against hypoxia-induced tissue damage and increased experimental wound repair through cAMP-dependent regulatory signaling [24,25] .…”

Section: Discussionmentioning

confidence: 99%

Vasoactive intestinal peptide for diagnosing exacerbation in chronic obstructive pulmonary disease

Mandal

Roth²,

Costa³

et al. 2015

Pneumologie

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levels were significantly higher at AE-COPD (130.25 pg/ml, ) as compared to stable COPD (40.07 pg/ml, 95% CI 37.13-43.96, p < 0.001). The association of increased serum VIP with AE-COPD remained significant after propensity score matching (p < 0.001). Analysis of the Youden index indicated the optimal serum VIP cutoff value as 56.6 pg/ml. The probability of AE-COPD was very low if serum VIP was ≤ 35 pg/ml (sensitivity >90%) and very high if serum VIP was ≥ 88 pg/ml (specificity >90%). Serum VIP levels presented a robust performance to diagnose AE-COPD (AUC 0.849, 95% CI 0.779-0.899). Conclusions: Increased serum VIP levels are associated with AE-COPD.

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Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor

Cited by 14 publications

References 34 publications

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea

Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

Vasoactive intestinal peptide for diagnosing exacerbation in chronic obstructive pulmonary disease

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