Hypothalamic antihypertensive effect of irbesartan in chronic aortic coarctated rats.
The aim of the present work was to study the central and plasma pharmacokinetics of irbesartan (IRB) and its possible hypothalamic antihypertensive effect in sham-operated (SO) and aortic-coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. Anesthetized Wistar rats were used 42 days after ACo or SO. For the study of plasma pharmacokinetics, a vascular shunt probe was inserted into the carotid artery. In a separated experiment, a concentric probe was placed into the anterior hypothalamus for the study of IRB distribution in the central nervous system. Based on the hypothalamic concentrations of IRB reached in ACo rats, the anterior hypothalamus of SO and ACo animals was perfused with a Ringer solution containing approximately 6 microg x ml(-1) of the drug. IRB (10 mg x kg(-1) i.v.) induced a late decrease of heart rate (HR) in ACo animals (DeltaHR: -42 +/- 10 bpm, n = 5, p < 0.05 vs. SO rats) but not in SO rats (DeltaHR: 11 +/- 13 bpm, n = 5). Systemic administration of the drug reduced the mean arterial pressure (MAP) of both experimental groups, but the hypotensive effect was greater in ACo (DeltaMAP: -39.9 +/- 5.0 mm Hg, n = 5, p < 0.05 vs. SO rats) than in SO rats (DeltaMAP: -25.4 +/- 2.1 mm Hg, n = 5). A similar pharmacokinetic profile was observed in both experimental groups. Hypothalamic distribution of IRB was greater in ACo (AUC: 730 +/- 130 ng x ml(-1) h(-1), n = 5, p < 0.05 vs. SO rats) than in SO animals (AUC: 283 +/- 87 ng x ml(-1) h(-1), n = 5). The IRB hypothalamic perfusion induced an antihypertensive effect in ACo (DeltaMAP: -15.1 +/- 1.0 mm Hg, n = 5, p < 0.05 vs. Ringer perfusion) but not in SO rats. In conclusion, the chronic aortic coarctation did not modify the plasma pharmacokinetics of IRB, but it increased the distribution of the drug in the central nervous system. The greater hypotensive effect of IRB observed in ACo animals suggests the involvement of AT1 receptors in the maintenance of the hypertensive stage in chronic ACo rats. The hypotensive effect of IRB in ACo animals could be explained, at least in part, due an action on the anterior hypothalamic angiotensin system.
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
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000378:metabolism; D001017:Aortic Coarctation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000378:metabolism; D002908:Chronic Disease; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D000077405:Irbesartan; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage* / Q000378:metabolism
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan