What question did this study set out to answer?

To compare the cardiovascular and neuromodulatory activities of endothelin-1, -2, -3 and their respective proendothelins, and to evaluate their processing mechanisms using the enzyme inhibitors phosphoramidon and thiorphan.

September 1, 1993British Journal of PharmacologyOpen Access

Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

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Population

Anaesthetized, ganglion-blocked rats and electrically stimulated rat vas deferens

Comparison

Endothelin-1, -2, -3 and big-endothelin-1, -2… vs Responses without protease inhibitors

Design

Preclinical

Authors

GMGiovan Giuseppe MatteraAlfasigma (Italy)AEAnthony EglezosStarpharma (Australia)ARAnna Rita RenzettiAzienda Ospedaliera Citta' della Salute e della Scienza di Torino

Discussion

Member takes

Implication

Hypothesis-generating for a distinct big-endothelin processing pathway; leaves open relevance to human cardiovascular therapies.

Key Points

To compare the cardiovascular and neuromodulatory activities of endothelin-1, -2, -3 and their respective proendothelins, and to evaluate their processing mechanisms using the enzyme inhibitors phosphoramidon and thiorphan.
Measured mean arterial pressure responses to intravenous bolus injections of mature endothelins and proendothelins in anaesthetized, ganglion-blocked rats with or without phosphoramidon or thiorphan (10 mg/kg i.v.).
Assessed twitch response potentiations in isolated, electrically stimulated rat vas deferens preparations exposed to mature endothelins, big-endothelins, and peptidase inhibitors (10–100 µM).
Intravenous ET-1, ET-2, and ET-3 induced transient hypotension followed by sustained pressor effects (ED50: 0.72 ± 0.05, 1.8 ± 0.2, and 2.7 ± 0.3 nmol/kg; max delta MAP: 84 to 89 mmHg) that were unaffected by phosphoramidon or thiorphan.
Phosphoramidon inhibited the pressor responses of big-ET-1, -2, and -3 by 60%, 80%, and 100%, respectively, whereas thiorphan produced no in vivo inhibition.
In the rat vas deferens, big-ET-1 and -2 matched mature peptide potency, while big-ET-3 was ~20-fold less potent than ET-3 and was concentration-dependently inhibited by thiorphan (31% and 71% reduction at 10 and 100 µM).

Structured PICO

Population

Anaesthetized, ganglion-blocked rats and electrically stimulated rat vas deferens

Intervention

Endothelin-1, -2, -3 and big-endothelin-1, -2, -3 administered intravenously or in vitro, with or without phosphoramidon or thiorphan

Comparator

Responses without protease inhibitors (phosphoramidon or thiorphan)

Outcome

Changes in mean arterial pressure (MAP) in vivo and twitch response enhancement in vitrosurrogate

Big-endothelins are processed in vivo via a phosphoramidon-sensitive enzymatic pathway distinct from neutral-endopeptidase 24.11.

Cite This Study

Mattera et al. (1993) studied this question.

synapsesocial.com/papers/6a830bbb4e20a508b1f464fb https://doi.org/10.1111/j.1476-5381.1993.tb13813.x

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Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Comparison of the cardiovascular and neural activity of endothelin‐1, −2, −3 and respective proendothelins: effects of phosphoramidon and thiorphan

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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