The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats

Abstract Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the...

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Autores principales:	Marie Román, Laura García, Myrna Morales, María J. Crespo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49da8c216c634d5dbac3cd3b8d2eee5d
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spelling	oai:doaj.org-article:49da8c216c634d5dbac3cd3b8d2eee5d2021-12-02T17:02:05ZThe combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats10.1038/s41598-021-89338-62045-2322https://doaj.org/article/49da8c216c634d5dbac3cd3b8d2eee5d2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89338-6https://doaj.org/toc/2045-2322Abstract Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.Marie RománLaura GarcíaMyrna MoralesMaría J. CrespoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marie Román Laura García Myrna Morales María J. Crespo The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
description	Abstract Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.
format	article
author	Marie Román Laura García Myrna Morales María J. Crespo
author_facet	Marie Román Laura García Myrna Morales María J. Crespo
author_sort	Marie Román
title	The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
title_short	The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
title_full	The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
title_fullStr	The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
title_full_unstemmed	The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
title_sort	combination of dantrolene and nimodipine effectively reduces 5-ht-induced vasospasms in diabetic rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/49da8c216c634d5dbac3cd3b8d2eee5d
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The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats

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