Pharmacokinetic-pharmacodynamic properties of metoprolol in chronic aortic coarctated rats.

The present study addressed possible alterations in the pharmacodynamic and pharmacokinetic properties of the beta1-adrenoceptor antagonist metoprolol in experimental hypertension induced by abdominal aortic coarctation (ACo). Metoprolol's pharmacokinetics and its relationship with its in vivo chronotropic and blood pressure effect were studied using the microdialysis technique. A pharmacokinetic-pharmacodynamic model with a separate effect compartment was used to analyse the data. No differences were found in the calculated pharmacokinetic parameters between sham-operated (SO) and ACo rats. Bradycardia was observed after the i.v. injection of metoprolol (3 or 10 mg/kg) without differences between the experimental groups. The decrease of mean arterial pressure (DeltaMAP) induced by metoprolol was greater in ACo than in SO rats: SO: -14+/-2 mmHg, n=5; ACo: -26+/-4 mmHg, n=5, P<0.05. The dissociation constant (expressed as pKb) of metoprolol and its inverse agonistic activity were studied in isolated atria. The pKb of metoprolol was similar in both groups of animals (SO: 7.49+/-0.20; ACo: 7.19+/-0.23). The inverse agonistic activity of metoprolol on spontaneous beating of isolated atria was established by means of a concentration/response curve. There were no differences in maximum response (Emax; SO: -28+/-2.0%, n=5; ACo: -27+/-4%, n=5) or the concentration eliciting a half-maximal effect (pEC50) (SO: 4.9+/-0.2, n=5; ACo: 5.2+/-0.2, n=5) between the experimental groups. These results suggest that chronic ACo does not modify the beta-adrenoceptor affinity of metoprolol or its inverse agonistic activity. Moreover, there was no difference in the in vivo chronotropic effect between the experimental groups, indicating the absence of cardiac sympathetic over-activity in this model of hypertension. The pharmacokinetic results suggest that the metabolism of metoprolol is not affected in chronic ACo rats. In addition, the greater sensitivity to the depressor effect of metoprolol in ACo rats in the chronic hypertensive stage suggests a participation of the beta-adrenoceptors in the maintenance of hypertension.