Predicting in vivo cardiovascular properties of ß-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses.
FASEB J
; 25(12): 4486-97, 2011 Dec.
Article
em En
| MEDLINE
| ID: mdl-21865315
ABSTRACT
ß-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (ß1; HR) and hindquarters vascular conductance (ß2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P<0.05, ANOVA) at 5 doses between 6.7 and 670 µg/kg (i.v.) and shifted the dose-response curve for isoprenaline to higher agonist concentrations without altering HVC responses. In contrast, at doses of 67 µg/kg (i.v.) and above, ICI 118551 substantially reduced the HVC response to isoprenaline without affecting HR responses. ZD 7114, xamoterol, and bucindolol significantly increased basal HR (ΔHR +122 ± 12, + 129 ± 11, and + 59 ± 11 beats/min, respectively; n=6), whereas other ß-blockers caused significant reductions (all at 2 mg/kg i.v.). The agonist effects of xamoterol and ZD 7114 were equivalent to that of the highest dose of isoprenaline. Bucindolol, however, significantly antagonized the response to the highest doses isoprenaline. An excellent correlation was obtained between in vivo and in vitro measures of ß1-adrenoceptor efficacy (R(2)=0.93; P<0.0001).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fármacos Cardiovasculares
/
Antagonistas Adrenérgicos beta
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Reino Unido