Effect Of Long-term RAAS Blockade On Cardiovascular Aldosterone Production In Rats With Congestive Heart Failure After Myocardial Infarction

Effect of long-term renin~angiotensin~aIdosterOfle-SYStem blockade on cardiovascular aldosterone production in rats with congestive heart failure after myocardial infarctionAbstractUntil recently, it was assumed that aldosterone was derived solely from adrenal glands via the circulation; however, there is now convincing evidence including ours that cells of the heart and vasculature express genes responsible for and capable of producing both aldosterone and corticosterone steroids. Angiotensin II (Mg II) is an intense irritant of aldosterone production. Angiotensinconverting enzyme (ACE) inhibitors are designed to block the renin-angiotensin system (RAS) and produce an acute decrease in plasma aldosterone levels in hypertension, congestive heart failure, and myocardial infarction. Long-term (> 3 months) ACE inhibition is, however, associated with aldosterone suppression that is weak, variable and unsustained which is called aldosterone escape. Angiotensin receptor blockers (ARB) were developed as agents that would better block the RAS and thus decrease the adverse effects seen with ACE inhibitors. Several reports indicate that treatment with losartan, a kind of ARB, lowered the level of plasma and tissue aldosterone, but the longest duration of observation has only been three months. We studied the effect of long-term angiotensin-aldosterone system blockade on cardiovascular aldosterone production in congestive heart failure rat after myocardial infarction to clarify the hypothetical possibility of aldosterone escape in cardiovascular tissues during the long-tenn ACE inhibition and Ang II receptor blockade.Metbods1. Rats \vith infarction-induced congestive heart failure were killed onemonih after the operation. Ex vivo meseneric artery and heed werePeffosed, radioimmunoassay was used to determine the angiotensin andaIdosterone, and RT-PCR for CYPllB2. Sham-oPerated rats served ascontrOl.2. One month after the ligaion, rats with infarctioninduced congestive heartfailure were treated with enalaPril (20mghg per day), perindopril (3mg/kgPer day), spironolactone (20mg/kg per day), perindopril plusspironolactone and Iosartan (15mg/kg per day) for 20 weeks, untreatedcongeStive heart falure and sham-oPerated rats were used as positive andnormal cofltrOls. Ex vivo mesentCric artery and heart Peffosion, highPefformance liquld chromatograPhy, and radioimmunoassay foraldosterone, and RT-PCR for CYPl l B2 were Pefformed.ResuItSl. In infarchoninduced congestive heart failure rat, aldosterone produchonand gene expression were increased in myocardium and mesenteric artery2. In myocardium, enaIapril can not significantly inhibite aIdosteroneproduction and gene expression, Perindopril and losartan significantlyinhibitC aldosterone production and gene expression compared to untreatedcongestive heart fai1ure rats.3. In mesenteric artery enalapril, Perindopril and losartan significantlyinhibited aldostCrone production 'compared to untreated congestive heart- 5 -failure rats; enalapril can not significantly inhibite aldosterone production and gene expression compared to that of sham rats in the mesenteric artery.4.Aldosterone production and gene expression of enalapril are higher than that of perindopril in either myocardium or mesenteric artery.Conclusions1.Congestive heart failure is associated with tissue-special activation of cardiovascular aldosterone synthesis.2.Long-term angiotensin converting enzyme inhibitions induced varying degrees of aldosterone escape in cardiovascular tissues with congestive heart failure.3.Losartan, a kind of Angiotensin receptor blockers, did not induce aldosterone escape in the mesenteric artery or plasma, and partly in myocardium in congestive heart failure rats.