Short-term ACE inhibition confers long-term protection against target organ damage

Abstract

Angiotensin converting enzyme (ACE) inhibitors reduce left ventricular (LV) hypertrophy and cardiovascular-renal fibrosis. Experimentally, changes in the LV and kidney persist even after cessation of treatment. The present study investigates whether brief ACE inhibition in spontaneously hypertensive rats (SHR) provides long-term protection against the LV and kidney damage induced by the nitric oxide synthase inhibitor N-x-nitro-L-arginine-methyl ester (L-NAME). SHR received the ACE inhibitor enalapril (n¼36) or tap water (n¼36). In all, 12 control and treated SHR were sacrificed after 2 weeks and remaining rats were taken off-treatment. After a 2-week washout, 12 controls or previously treated SHR were sacrificed and remaining rats were treated with L-NAME ((control (Con)+L, enalapril (Enal)+L) for 10 days. At sacrifice, blood pressure was recorded via carotid artery cannulation in anesthetized rats, and blood, the kidney and LV were isolated for analysis. LV mass and arterial pressure were significantly reduced by enalapril. LV mass showed a persistent reduction throughout the study. In LV, prior enalapril treatment provided significant (Po0.05) protection against L-NAME-induced increases in proliferating cells (Con+L: 11±10.0 mm 2 vs. Enal+L: 4±4.4 mm 2 ), interstitial fibrosis (Con+L: 3±2.5% vs. Enal+L: 1±1.0%) and tissue macrophages (Con+L: 12±9 mm 2 vs. Enal+L: 5±3.6 mm 2 ). In the kidney, prior enalapril treatment protected against L-NAME-induced interstitial fibrosis and vascular injury. There was no difference in glomerular size or glomerulosclerosis regardless of prior treatment. Plasma creatinine and urea were significantly increased in L-NAME treated rats. This study suggests that brief ACE inhibition confers protection against future heart and kidney injury, even in the absence of continued antihypertensive treatment.

Protection against L‐NAME‐induced reduction in cardiac output persists even after cessation of angiotensin‐converting enzyme inhibitor treatment

“…, , Hale et al . ). Indeed, we have demonstrated that the hearts of SHR previously treated with an ACE inhibitor show a reduced proliferative, fibrotic and inflammatory response to short‐term nitric oxide synthase (NOS) inhibition (Hale et al .…”

RAS-Mediated Adaptive Mechanisms in Cardiovascular Tissues: Confounding Factors of RAS Blockade Therapy and Alternative Approaches

“…ACEi are highly effective in controlling hypertension and reducing the risk of developing heart failure, left ventricular hypertrophy, insulin resistance, and microalbuminuria in diabetes [12,13,18,19,20]. Since ACE generates the vasoconstrictor peptide Ang II from Ang I and degrades the vasodilator bradykinin (BK), ACEi treatment improves vasodilatation by reducing Ang II and increasing BK.…”

“…Ang II would then bind to the Ang II type 1 receptor (AT1R) and induce signaling pathways that promote muscle constriction, salt and water retention, fibrosis, hypertrophy, and hyperplasia that underlie many metabolic diseases and poor cardiovascular and renal prognosis. Blockade of RAS can be exerted at multiple levels, via inhibition of renin, ACE, or AT1R signaling [6,7,8,9,10,11,12]. Efficient RAS blockers at all these levels have been developed and are currently in use to block overactivation of RAS and to offer protection from RAS-related metabolic diseases including diabetes [8,9,10,11,12,13].…”

“…Blockade of RAS can be exerted at multiple levels, via inhibition of renin, ACE, or AT1R signaling [6,7,8,9,10,11,12]. Efficient RAS blockers at all these levels have been developed and are currently in use to block overactivation of RAS and to offer protection from RAS-related metabolic diseases including diabetes [8,9,10,11,12,13]. However, evidence of increased adverse effects from randomized clinical trials such as Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) using double RAS blockade strongly advises against blocking RAS at multiple levels [14,15,16,17].…”

Prehypertension: Underlying pathology and therapeutic options

“…In addition, it is suggested that RAS contributes to the atherosclerotic process through angiotensin Ⅱ, which acts as a proinflammatory mediator directly inducing atherosclerotic plaque development and heart remodeling and exacerbate endothelial dysfunction [81,82] . On the other hand, blockade of RAS can offer protection from RAS-related metabolic diseases including diabetes [83][84][85][86][87][88] . The statement by Demirci et al [72] is further enforced by the observation that the ACE gene may be a determinant of serum ACE levels, but it does not appear to confer susceptibility to essential hypertension [89] , since there are many factors that influence the genetic make-up of dicate that endothelial vasodilator capacity is impaired in PHTN [106] .…”