RESUMO
The aim of the present study was to investigate the effects of the alpha2-adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose hypertensive (F) rats. The anterior hypothalamic area of control (C) and F rats was perfused with Ringer's solution containing 10 and 100 microg/mL yohimbine through a microdialysis concentric probe. The effects of yohimbine on mean arterial pressure (MAP) and HR, as well as on hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) levels, were measured according to perfusion time. Although intrahypothalamic perfusion of yohimbine increased blood pressure in C rats (DeltaMAP 9 +/- 1 and 11 +/- 2 mmHg for 10 and 100 microg/mL yohimbine, respectively; P < 0.05 vs Ringer's perfusion), the alpha-adrenoceptor antagonist did not modify MAP in F. Intrahypothalamic yohimbine had no effect on HR at either concentration tested. Intrahypothalamic perfusion of 10 and 100 microg/mL yohimbine increased DOPAC levels in C rats (135 +/- 6 and 130 +/- 5% of basal levels, respectively; both n = 6; P < 0.05 vs Ringer's perfusion), but not in F animals (115 +/- 6 and 102 +/- 6% of basal levels, respectively; both n = 6). In both C and F rats, yohimbine administration induced an increase in 5-HIAA dialysate levels. The results of the present study support the notion that alpha2-adrenoceptor tone of the anterior hypothalamus of normotensive rats, which contributes to normal blood pressure regulation, is not involved in the control of HR in either normotensive C or hypertensive F rats. The absence of changes in MAP after yohimbine perfusion in F rats suggests that the alpha2-adrenoceptor tone could be decreased in this group of rats and that this may be responsible for the maintenance of hypertension in this model. Intrahypothalamic perfusion of yohimbine increased DOPAC in the dialysate only in C rats, suggesting changes in presynaptic alpha2-adrenoceptor activity in fructose-overloaded rats. Conversely, increased 5-HIAA levels did not differ between C and F groups.
Assuntos
Frutose , Hipertensão/induzido quimicamente , Hipotálamo/fisiologia , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos alfa/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Núcleo Hipotalâmico Anterior/efeitos dos fármacos , Formação de Anticorpos/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ácido Hidroxi-Indolacético/farmacologia , Hipotálamo/metabolismo , Masculino , Perfusão/métodos , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ioimbina/administração & dosagem , Ioimbina/farmacologiaRESUMO
Pharmacokinetic-pharmacodynamic (PK-PD) modelling describes the relationship between the pharmacokinetics and pharmacodynamics of a drug allowing the prediction of clinically relevant parameters. PK-PD modelling has several advantages over classical dose-response studies because it allows a better pharmacodynamic characterisation of drugs and screening of dosage-regimen. However, PK-PD studies are limited by the need for simultaneous measurement of drug tissue levels and corresponding pharmacological effects at multiple time points. The microdialysis technique is a unique research tool that allows the simultaneous determination of unbound concentrations of drugs at several tissues and its action on biochemical and clinical markers during several hours and days. Therefore, microdialysis sampling is an attractive methodology for PK-PD studies. The aim of this review is to describe the applicability of the microdialysis technique for PK-PD modelling of therapeutic agents, including a description of PK-PD modelling concepts, an overview of the microdialysis technique and an analysis of PK-PD studies using microdialysis sampling both in the preclinical and clinical setting.