Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats.
Hypertension results in increased thickness and stiffness of large artery walls. The goal of our study was to assess the respective roles of humoral factors such as Ang II, endothelin and blood pressure in these aortic modifications. For this purpose, uninephrectomized rats received DOCA and high salt diet, and when hypertension was installed, they were treated for 5 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg/day), an ACE inhibitor, enalapril (3 mg/kg/day), or a mixed ETA and ETB endothelin receptor antagonist, bosentan (100 mg/kg/day). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry. DOCA-salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix. Elastin relative density decreased in DOCA rats. Enalapril had no effect on arterial pressure. Bosentan decreased slightly (by 12 mm Hg), but not significantly, blood pressure. None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta. In contrast, mibefradil almost normalized arterial pressure, prevented medial hypertrophy and increased elastin density. Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil.
Pharma Division, Preclinical Research, F. Hoffmann La Roche Ltd., Basel, Switzerland.
H
H
Karam
D
D
Heudes
M F
MF
Gonzales
B M
BM
Löffler
M
M
Clozel
J P
JP
Clozel
D000804:Angiotensin II / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001562:Benzimidazoles / Q000494:pharmacology; D001794:Blood Pressure; D000077300:Bosentan; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003900:Desoxycorticosterone; D004656:Enalapril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006978:Hypertension, Renovascular / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D020748:Mibefradil; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D000804:Angiotensin II; D020748:Mibefradil; D003900:Desoxycorticosterone; D004656:Enalapril; D000077300:Bosentan