Pharmacokinetics and the cardiovascular effects of irbesartan in aortic coarctated rats.
A pharmacokinetic-pharmacodynamic study of irbesartan (IRB) was performed in anesthetized sham-operated (SO) and aortic coarctated (ACo) rats. Anesthetized Wistar rats were used 7 days after ACo procedure or SO. A vascular shunt probe was inserted into the carotid artery for the study of plasma pharmacokinetics. In a separate experiment, a concentric probe was placed into the anterior hypothalamus for the study of the IRB distribution in the central nervous system. IRB (10 mg.kg(-1) i.v.) induced a rapid decrease of the heart rate (HR) in the ACo animals (Delta HR -19.2 +/- 2.0 bpm, n = 6; p < 0.05 vs. basal HR), but not in the SO rats (Delta HR -6.7 +/- 5.1 bpm, n = 6). Moreover, IRB reduced the mean arterial blood pressure in the animals of both experimental groups, but the hypotensive effect lasted longer in ACo rats than in SO animals. Analysis of blood samples showed a lower constant of elimination of IRB in ACo rats (Ke 0.67 +/- 0.28 h(-1), n = 5; p < 0.05) than in SO rats (Ke 1.72 +/- 0.30 h(-1), n = 6). Also, a greater distribution of IRB in the anterior hypothalamus was seen in the ACo rats (area under the curve 32 +/- 4 ng.ml(-1).h(-1), n = 6; p < 0.05) than in the SO rats (area under the curve 12 +/- 1 ng.ml(-1).h(-1)). The protein binding of IRB was similar in both experimental groups (SO rats 7.1 +/- 1.2%, n = 6; ACo rats 7.7 +/- 1.5%, n = 6). In conclusion, ACo reduces the plasma elimination of IRB, increasing the distribution in the central nervous system. The longer hypotensive effect of IRB observed in ACo animals could be explained by the slowest elimination of the drug in ACo rats. On the other hand, the effect of IRB on the HR suggested that angiotensin II modulates this parameter in ACo animals at an early stage of hypertension.
Höcht
Christian
C
Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. chocht@ffyb.uba.ar
Opezzo
Javier A W
JA
Taira
Carlos A
CA
D000804:Angiotensin II / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001011:Aorta / Q000601:surgery; D001017:Aortic Coarctation / Q000188:drug therapy* / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D007032:Hypothalamus, Anterior / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D000077405:Irbesartan; D008657:Metabolic Clearance Rate / Q000187:drug effects; D017551:Microdialysis; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
D057912:Angiotensin II Type 2 Receptor Blockers; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan