Renal Sympathetic Denervation Attenuates Congestive Heart Failure in Angiotensin II-Dependent Hypertension: Studies with Ren-2 Transgenic Hypertensive Rats with Aortocaval Fistula

Abstract

<b><i>Objective:</i></b> We examined if renal denervation (RDN) attenuates the progression of aortocaval fistula (ACF)-induced heart failure or improves renal hemodynamics in Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension. <b><i>Methods:</i></b> Bilateral RDN was performed 1 week after creation of ACF. The animals studied were ACF TGR and sham-operated controls, and both groups were subjected to RDN or sham denervation. In separate groups, renal artery blood flow (RBF) responses were determined to intrarenal ANG II (2 and 8 ng), norepinephrine (NE) (20 and 40 ng) and acetylcholine (Ach) (10 and 40 ng) 3 weeks after ACF creation. <b><i>Results:</i></b> In nondenervated ACF TGR, the final survival rate was 10 versus 50% in RDN rats. RBF was significantly lower in ACF TGR than in sham-operated TGR (6.2 ± 0.3 vs. 9.7 ± 0.5 mL min<sup>−1</sup> g<sup>−1</sup>, <i>p</i> < 0.05), the levels unaffected by RDN. Both doses of ANG II decreased RBF more in ACF TGR than in sham-operated TGR (−19 ± 3 vs. −9 ± 2% and −47 ± 3 vs. −22 ± 2%, <i>p</i> < 0.05 in both cases). RDN did not alter RBF responses to the lower dose, but increased it to the higher dose of ANG II in sham-operated as well as in ACF TGR. NE comparably decreased RBF in ACF TGR and sham-operated TGR, and RDN increased RBF responsiveness. Intrarenal Ach increased RBF significantly more in ACF TGR than in sham-operated TGR (29 ± 3 vs. 17 ± 3%, <i>p</i> < 0.05), the changes unaffected by RDN. ACF creation induced marked bilateral cardiac hypertrophy and lung congestion, both attenuated by RDN. In sham-operated but not in ACF TGR, RDN significantly decreased mean arterial pressure. <b><i>Conclusion:</i></b> The results show that RDN significantly improved survival rate in ACF TGR; however, this beneficial effect was not associated with improvement of reduced RBF or with attenuation of exaggerated renal vascular responsiveness to ANG II.

Effects of renal sympathetic denervation on the course of congestive heart failure combined with chronic kidney disease: Insight from studies with fawn-hooded hypertensive rats with volume overload induced using aorto-caval fistula

“…Therefore, the effectiveness of RDN maintained till the 10 th week is sufficient for the studies to be performed. This notion is in agreement with our recent findings showing that untreated ACF TGR displayed the final survival rate of 9.7% (assessed 10 weeks after the sham-operation), and RDN markedly increased the survival rate, up to the final value of 50% (56). In this context, it is important to briefly address our findings regarding the intrarenal activity of RAS in ACF FHL and ACF FHH.…”

“…This notion is based on clinical and experimental studies demonstrating that enhanced renal NE spillover and tissue turnover, the recognized markers of increased SNS activity, is associated with increased morbidity in individuals with CHF (63-66). The concept of beneficial effects of RDN due to a removal of RSNA on the course of CHF is further supported by our recent findings showing that RDN improved survival rate in ACF TGR, a unique ANG II-dependent model of hypertension with proved over-activation of RAS (67,68), even despite that renal NE levels were not higher in these animals in comparison to their sham-operated (no ACF) counterparts (56). In view of this knowledge and particularly in the light of our finding that renal NE concentrations are dramatically increased in ACF FHH (indicating augmented RSNA), we expected that RDN should exhibit protective actions on the course of CHF.…”

“…In addition, in our recent study using the model of doxorubicin-induced CHF (chemotherapyinduced CHF), we also found very high variability of plasma NE concentrations, in contrast to very consistent responses in the intrarenal ANG II and NE levels (58). Finally, our newest study in ACF TGR showed that RDN reduced renal NE concentration by more than 90% but, again, the variability of plasma NE did not allow a clear conclusion regarding systemic SNS activity (56). Collectively, it can be concluded that NE concentration in the tissue is the only reliable index of organ SNS activity in CHF, or at least in the model of ACF-induced CHF.…”

“…This might limit the credibility of studies evaluating the effects of RDN on the animals´ survival, because such studies are designed as long-term experiments. However, in our recent study employing ACF model in Ren-2 transgenic hypertensive rats (TGR), we found that RDN procedure was fully effective for 10 weeks (based on renal concentration of NE), without altering intrarenal RAS activity (based on renal ANG II concentrations) (56). This is sufficiently long to study effects of RDN on the CHF-related mortality also in FHH rats, as is apparent from our recent study with this model (44).…”

“…( It is important to admit the limitation of the so designed study: plasma concentrations of NE, as a marker of systemic SNS activity, and plasma concentrations of ANG II, as a marker of systemic RAS activity, were not determined. The decision to abstain from these measurements was based on our previous studies which showed that even when plasma concentrations were measured in samples from decapitated animals, the variability was so high that it could not be accepted as a reliable marker of systemic SNS and RAS activity (38,44,56,57). The variability was particularly high for plasma NE levels and especially in ACF animals.…”