Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension

F. BERTERA; M. A. MAYER; J. OPEZZO; C.A. TAIRA; C HÖCHT

JOURNAL OF PHARMACY AND PHARMACOLOGY

PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN

Año: 2009 vol. 61 p. 79 - 87

0022-3573

Objectives The aim of this work was to evaluate the pharmacokinetic–pharmacodynamicproperties of diltiazem in an experimental model of high-renin hypertension, such as theaortic coarctated (ACo) rat, to further characterize the responsiveness of this model tocalcium channel blockers.Methods A ‘shunt’ microdialysis probe was inserted in a carotid artery of anaesthetizedACo and control sham-operated (SO) rats for simultaneous determination of diltiazemplasma concentrations and their effects on mean arterial pressure and heart rate after theintravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levelsand cardiovascular effects was established by fitting the data to a modified Emax model.Key findings Volume of distribution was greater in ACo than in SO rats. Diltiazemplasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO ratsafter administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo butnot in SO rats. No differences were observed in the maximal bradycardic effect comparingboth experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similarcomparing SO and ACo rats. Differences were not found in the maximal response of thehypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effectwas greater in ACo rats than in SO rats.Conclusions ACo induced profound changes in diltiazem pharmacokinetic behaviour. Inaddition, our results suggested an increased sensitivity to diltiazem blood pressure loweringeffect in experimental renovascular hypertension with high-renin levels.