AT1 receptor blocker, but not an ACE inhibitor, prevents kidneys from hypoperfusion during congestive heart failure in normotensive and hypertensive rats

Abstract

To provide novel insights into the pathogenesis of heart failure-induced renal dysfunction, we compared the effects of ACE inhibitor (ACEi) and AT1 receptor blocker (ARB) on systemic and kidney hemodynamics during heart failure in normotensive HanSD and hypertensive transgenic (TGR) rats. High-output heart failure was induced by creating an aorto-caval fistula (ACF). After five weeks, rats were either left untreated or treatment with ACEi or ARB was started for 15 weeks. Subsequently, echocardiographic, renal hemodynamic and biochemical measurements were assessed. Untreated ACF rats with ACF displayed significantly reduced renal blood flow (RBF) (HanSD: 8.9 ± 1.0 vs. 4.7 ± 1.6; TGR: 10.2 ± 1.9 vs. 5.9 ± 1.2 ml/min, both P < .001), ACEi had no major RBF effect, whereas ARB completely restored RBF (HanSD: 5.6 ± 1.1 vs. 9.0 ± 1.5; TGR: 7.0 ± 1.2 vs. 10.9 ± 1.9 ml/min, both P < .001). RBF reduction in untreated and ACEi-treated rats was accompanied by renal hypoxia as measured by renal lactate dehydrogenase activity, which was ameliorated with ARB treatment (HanSD: 40 ± 4 vs. 42 ± 3 vs. 29 ± 5; TGR: 88 ± 4 vs. 76 ± 4 vs. 58 ± 4 milliunits/mL, all P < .01). Unlike improvement seen in ARB-treated rats, ACE inhibition didn’t affect urinary nitrates compared to untreated ACF TGR rats (50 ± 14 vs. 22 ± 13 vs. 30 ± 13 μmol/mmol Cr, both P < .05). ARB was more effective than ACEi in reducing elevated renal oxidative stress following ACF placement. A marker of ACEi efficacy, the angiotensin I/angiotensin II ratio, was more than ten times lower in renal tissue than in plasma. Our study shows that ARB treatment, in contrast to ACEi administration, prevents renal hypoperfusion and hypoxia in ACF rats with concomitant improvement in NO bioavailability and oxidative stress reduction. The inability of ACE inhibition to improve renal hypoperfusion in ACF rats may result from incomplete intrarenal RAS suppression in the face of depleted compensatory mechanisms.

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

“…Given the recent discovery that elevated ANG 1-7/ANG II ratio predicts a beneficial outcome of HF [66], our present findings are significant in that they suggest that the initial compensatory response in the ACF-induced model of HF in TGR consists of the activation of the vasodilatory/natriuretic axis of the RAS, which may override the effects of activation of the vasoconstrictor/sodium retaining axis. At first glance, these findings seem to diverge from our previous studies in ACF TGR [37,51,67], in which we observed that plasma and kidney ANG II, aldosterone, and NE levels are much higher than in their sham-operated counterparts. Thus, in this HF model, the vasoconstrictor/sodium retaining axis of the RAS along with the sympathorenal axis appeared to be activated.…”

“…Likewise, the beneficial effects of ACEi treatment on the survival rate accord with our line of reasoning: it is generally agreed that even if activation of the vasoconstrictor/sodium retaining axis of the RAS may be initially beneficial, the long-lasting actions might be detrimental and importantly contribute to the progression of HF to the fatal end [6,14,15,63,64]. In addition, in previous studies, we clearly demonstrated that the activity of circulating and intrarenal vasoconstrictor/sodium retaining axis of the RAS is markedly increased in ACF TGR in the advanced HF phase [37,51], and that blockade of this axis by ACEi dramatically improves survival rate [30,37,41].…”

“…Chronic HF due to volume overload was induced by creating ACF using a needle technique. This procedure is routinely performed in our laboratory, and the technique's details were reported previously [26,31,32,37,51]. Shamoperated rats underwent an identical procedure but without creating the ACF.…”

“…This was done by analogy with the protocol used in normotensive rats, which after five weeks, develop an early, compensated phase HF [28,59,60,68]. However, such selection of the study time proved to be inappropriate in TGR: we demonstrated that the course of high-output HF in TGR is dramatically accelerated [31,37,41,51] when compared both with normotensive and even with spontaneously hypertensive rats (SHR) [69]. In TGR, five weeks after the creation of the ACF, already 50% mortality is observed, compared to simultaneous 100% survival rate in normotensive rats and SHR.…”

“…While the clinical term "cardiorenal syndrome" is a simplification as it does not encompass a spectrum of disorders involving the heart and the kidney [12], there is no doubt that the development of renal dysfunction predicts poor outcomes in patients with HF [3,[42][43][44]. We showed previously that ACF TGR seems to be an optimal model for evaluating cardiorenal interaction in the pathophysiology of HF [31,37,51,67]. Moreover, it was revealed that some beneficial impact on the course of high-output HF in ACF TGR can be achieved by preventing renal dysfunction, e.g., by pharmacological blockade of sEH or AT1 receptors [37,51].…”