Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats.
We have previously shown that long-term angiotensin-converting enzyme (ACE) inhibition prevents the increase in aortic collagen in spontaneously hypertensive rats (SHRs), independent of blood pressure reduction. More recently, we reported that the effects of ACE inhibition in the prevention of aortic collagen accumulation were related to the inhibition of angiotensin II actions on angiotensin II type 1 receptors. Aldosterone, the synthesis of which is mainly modulated by angiotensin II through type 1 receptor stimulation, is known to promote cardiac fibrosis in different experimental models. The aim of the present study was to determine whether inhibition of aldosterone formation was able to prevent aortic fibrosis in SHRs. For this purpose, we compared the effects of a 4-month treatment with the aldosterone antagonist spironolactone with the ACE inhibitor quinapril in 4-week-old SHRs. Control SHRs and Wistar-Kyoto (WKY) rats received placebo for the same period of time. At the end of treatment, in conscious SHRs vs WKY controls, quinapril completely prevented the development of hypertension, whereas spironolactone produced only a slight but significant reduction in blood pressure. Aortic hypertrophy was significantly prevented by ACE inhibition but not by spironolactone. On the contrary, aortic collagen accumulation was completely prevented by both quinapril and spironolactone. In the latter case, collagen density was significantly below that of WKY controls. These results show that in SHRs, spironolactone can markedly prevent aortic fibrosis in the presence of a very slight antihypertensive effect. It is suggested that ACE inhibition or type 1 receptor antagonist-induced prevention of aortic collagen accumulation is at least partially related to aldosterone inhibition.
Benetos
A
A
Department of Internal Medicine, Broussais Hospital, Paris, France.
Lacolley
P
P
Safar
M E
ME
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001794:Blood Pressure; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D006339:Heart Rate; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D007546:Isoquinolines / Q000627:therapeutic use; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D000077583:Quinapril; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013148:Spironolactone / Q000627:therapeutic use*; D044005:Tetrahydroisoquinolines; D014652:Vascular Diseases / Q000517:prevention & control*
D007546:Isoquinolines; D000451:Mineralocorticoid Receptor Antagonists; D044005:Tetrahydroisoquinolines; D013148:Spironolactone; D003094:Collagen; D000077583:Quinapril