FIBROSIS OF ATRIA AND GREAT-VESSELS IN RESPONSE TO ANGIOTENSIN-II OR ALDOSTERONE INFUSION

Objective: Myocardial fibrosis, associated with increased expression o f angiotensin converting enzyme (ACE) and bradykinin (BK) receptor bin ding at sites of tissue repair, accompanies chronic elevations in circ ulating angiotensin ii (AngII) and/or aldosterone (ALDO) that simulate chronic cardiac failure. A role for increased ventricular wall stress , associated with arterial hypertension, that can accompany such neuro hormonal activation when ventricular function is not compromised, has been held responsible for this structural remodeling. To address this proposition, we monitored morphology of right and left atria and pulmo nary artery, where stress is not increased, and compared these structu res with hypertensive aorta. Methods: Experimental groups included: (1 ) unoperated and untreated controls; (2) intact rats receiving AngII ( 9 mu g/h) for 2 weeks and which causes arterial hypertension; (3) unin ephrectomized control rats on a high sodium diet for 6 weeks; and (4) uninephrectomized rats receiving ALDO (0.75 mu g/h) and a high sodium diet for 6 weeks and which results in gradual onset arterial hypertens ion. Fibrosis was identified by light microscopy in sections stained w ith collagen specific picrosirius red, while ACE, AngII and BK recepto r binding were localized and quantitated by in vitro autoradiography u sing I-125-351A, I-125[Sar(1),Ile(8)]AngII, and I-125[Tyr(8)]BK, respe ctively. AngII receptor subtype was defined by the presence of excess AT(1) (losartan) or AT(2) (PD123177) receptor antagonists, respectivel y. Results: With either AngII or ALDO administration, and compared to controls, we found: (1) microscopic scarring that replaced lost myocyt es in both left and right atria; (2) an increase in adventitial collag en of both pulmonary artery and aorta (perivascular fibrosis); (3) mar kedly increased ACE binding at fibrous tissue sites in both atria and great vessels; (4) unchanged atrial and great vessel AT, receptor bind ing; and (5) significantly increased BK receptor binding at sites of a trial and perivascular fibrosis. Conclusions: Thus, the appearance of atrial fibrosis and perivascular fibrosis of aorta and pulmonary arter y, together with associated increase in ACE and BK receptor binding, i n rats receiving AngII or ALDO suggests these responses are not relate d to altered ventricular wall stress or arterial hypertension, but rat her to these effector hormones of the circulating renin-angiotensin-al dosterone system. Local BK, regulated by ACE found in fibrous tissue a nd BK receptor binding may play a role in structural remodeling of atr ia and great vessels in these rat models that simulate chronic cardiac failure. (C) 1997 Elsevier Science B.V.