Aldosterone Escape In Extra-adrenal Tissues Associated With Treatment By ACEI And It's Effects On Target Organ Fibrosis

Background: In the treatment of essential hypertension (EH), angiotensin-converting enzyme inhibitors (ACEI) produce an acute decrease in plasma aldosterone levels. Long-term ACEI is, however, associated with aldosterone suppression that is weak, variable, and unsustained which is called aldosterone escape. At present, this phenomenon has only been recognized on the level of plasma. Much evidence indicated that renin-angiotensin system in tissues plays a more crucial role than that in plasma on target organ damage of EH, and that extral-adrenal tissues such as vessels, heart and kidney can produce aldosterone. Therefore, we paid attention to the questions as follows: whether aldosterone escape occurs or not in extra-adrenal tissues, in addition to the plasma escape during long term ACEI treatment, whether angiotensin II receptor 1 antagonists (ATIRA) which represent a new class of antihypertensive agents can induce aldosterone escape or not in both plasma and extra-adren tissues, and whether the residual aldosterone has any effects on tissue fibrosis. Methods: Fourty eight of SHIP. were randomized to 6 groups including untreated SI-LR group as positive control, perindopril-(3mg/kg?&), perindopril plus spironolactone-(2OmgIkg~1 . d1), enapril-(2Omglkg?. d1), spironolactone, and losartan-(5Omglkg?d1), and treated for five months. Wistar rats were served as normal control. 2. Ex vivo perfusion of mesenteric artery, heart and kidney was performed. Aldosterone in the perfusate was measured by high performance liquid chromatography and radioimmunoassay. Expression of aldosterone synthase gene CYP1 1B2 mRNA in the tissues was determined by RI- PCR. 3. Myocardial fibrosis was evaluated by light microscopy with the aid of Van Gieson staining. Expression of collagen subtype I and III mRNA in myocardium was half-quantitated by RT-PCR and the sequences were verrified by sequencing. Results: 1. Both AngII and aldosterone in plasma elevated to the levels of untreated SHR regardless of chronic treament with tissue penetrative or non-tissue penetrative ACEI, which suggested aldosterone escape in plasma occured. The treament of spironolactone plus ACEI has significantly alleviated the degree of aldosterone escape in plasma, althought it had not effect on production of AngII in plasma. Non-tissue penetrative ACEI however could not inhibite the aldosterone production and gene expression in mesenteric artery and myocardium, although it was markely inhibited in kidney. Compared with it, tissue penetrative ACEI not only significantly inhibited the aldosterone production and gene expression in vessels and kidney but also lowered it to the levels of Wistar. Tissue penetrative or non penetrative ACEI didnt inhibite the aldosterone production and CYP1 1B2 mRNA expression in myocardium to the levels of Wistar. 2. Long-term losartan treatment did not produce aldosterone escape in plasma despite of elevated plasma AngII concentration, but markely reduced the level of aldosterone compared with those of ACEI treatment; It inhibited the aldosterone production and CYP1 1B2 mRNA expression in myocardium and mesenteric artery to the levels of Wistar, and significantly suppressed the production and CYP1 1B2 mRNA expression in kidney compared with those of untreated SHR. 3. Both losartan and tissue penetrative ACEI plus spironoiactone significantly inhibited the expres...