Vascular Toxicity Risk Assessment of MC18 and MC70, Novel Potential Diagnostic Tools for In Vivo PET Studies.
Basic Clin Pharmacol Toxicol
; 120(5): 434-441, 2017 May.
Article
em En
| MEDLINE
| ID: mdl-27888581
ABSTRACT
The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo. The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70. Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav 1.2 channel current (ICa1.2 ) of A7r5 cells were studied. At concentrations >10 µM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1-100 µM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67-14.49 µM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K+ (K60)-induced responses. In rings cultured for 7 days with both compounds (1-10 µM), 10 µM MC70 significantly reduced, while 10 µM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1-100 µM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 µM, respectively. These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta
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Tetra-Hidronaftalenos
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Compostos de Bifenilo
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Tetra-Hidroisoquinolinas
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Isoquinolinas
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article