Endothelin antagonism in end-organ damage of spontaneously hypertensive rats. Comparison with angiotensin-converting enzyme inhibition and calcium antagonism.
High blood pressure results in cardiac hypertrophy and fibrosis, increased thickness and stiffness of large artery walls, and decreased renal function. The objective of our study was to assess the role of endothelin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and endothelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats was used as control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and fibrosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creatinine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreased maximal coronary blood flow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased urinary excretion and decreased urea and creatinine clearances. No renal histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased left ventricular hypertrophy and fibrosis. Enalapril and mibefradil were both effective in significantly decreasing blood pressure, left ventricular hypertrophy, and aortic medial thickness and improving coronary blood flow, but in contrast to bosentan, they did not improve creatinine clearance. We conclude that in SHR, high blood pressure plays a major role in end-organ damage and that endothelin may partly mediate renal dysfunction and cardiac remodeling independently of a direct hemodynamic effect.
Karam
H
H
Pharma Division, F Hoffmann-La Roche Ltd, Basel, Switzerland.
Heudes
D
D
Bruneval
P
P
Gonzales
M F
MF
Löffler
B M
BM
Clozel
M
M
Clozel
J P
JP
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D000077300:Bosentan; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006332:Cardiomegaly / Q000473:pathology; D003326:Coronary Circulation / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005355:Fibrosis; D006352:Heart Ventricles; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D006973:Hypertension / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D020748:Mibefradil; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D013449:Sulfonamides / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D016232:Endothelins; D006728:Hormones; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D004656:Enalapril; D000077300:Bosentan