Raised blood pressure, not renin-angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats

Objectives: Elevated systemic arterial blood pressure is associated with le ft ventricular hypertrophy and fibrosis. It has been suggested that both ci rculating and local myocardial renin-angiotensin systems play a role in med iating these responses. Here we describe the natural history of ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat - a monogenetic m odel - which has a high tissue expression of the murine renin transgene, an d suffers severe hypertension. We further explored the relative contributio n of both hypertensive burden and circulating and tissue renin-angiotensin systems to the fibrotic process. Methods: The transgenic rats were treated from 28 days old with (1) a hypotensive dose of the ACE inhibitor ramipril which inhibited both tissue and circulating ACE activity, (2) the calcium a ntagonist amlodipine, or (3) a non-hypotensive dose of ramipril which inhib ited about 60% of tissue ACE activity with little effect on circulating ACE . Normotensive Sprague-Dawley rats were used as controls. Results: The tran sgenics developed left ventricular hypertrophy along with perivascular and interstitial fibrosis which became progressively worse up to 24 weeks of ag e. Both the high dose of ramipril and amlodipine prevented the hypertrophy and fibrosis, whereas tissue ACE inhibition without lowering blood pressure had no effect, and actually led to a worsening of the fibrosis by 24 weeks . Conclusions: These results suggest that the development of left ventricul ar hypertrophy and fibrosis in the transgenic (mRen2)27 rat are regulated b y blood pressure and not activity of the renin-angiotensin systems and that progression of fibrosis at 24 weeks involves a mechanism unrelated to loca l renin-angiotensin activity. (C) 2000 Elsevier Science B.V. All rights res erved.