Altered Renal Vascular Responsiveness to Vasoactive Agents in Rats with Angiotensin II-Dependent Hypertension and Congestive Heart Failure

Abstract

Objective: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). Methods: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). Results: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. Conclusion: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

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

“…The main finding of our present study is that RDN substantially attenuated CHF-dependent mortality in ACF TGR. This is of critical importance because ACF-induced CHF is the model in which the interplay between the heart and kidney is crucial for the progression of CHF [12-14, 27, 31, 35]. Moreover, in ACF TGR, 2 additional detrimental factors are present: hyperactivity of the RAS and hypertension [2, 7, 25, 26], both present before the onset of CHF.…”

“…CHF due to volume overload was then induced by creating an ACF using a needle technique. This procedure is routinely performed in our laboratory, and the details of the technique were reported previously [13, 14]. Sham-operated rats underwent an identical procedure but without creating ACF.…”

“…Subsequently, a 10-min equilibration time was allowed, and then renal and systemic vascular responses to vasoactive agents were determined. We used the experimental protocol as in our previous studies [14, 35]: RBF responses to 2 intrarenal doses of ANG II (2 and 8 ng), NE (20 and 40 ng), and acetylcholine (Ach) (10 and 40 ng) were determined. In the same experimental animals, MAP and RBF responses to intravenous doses of ANG II (40 ng) were assessed.…”

“…At the end of experiment, MAP and RBF responses to intrarenal bolus administration of 8 ng of ANG II and intravenous bolus administration of 40 ng of ANG II were determined again, to confirm the action of intrarenal administration of losartan on the renal and systemic circulation. At the end, first the whole heart weight and then left ventricle weight(LVW) (including septum), right ventricle weight (RVW), and lung weight were assessed as described in our previous studies [13, 14, 31, 35]. In case of the lungs, the so-called “wet lung weight” was assessed, that is, the excised lung was only gently pressed and left for 5 min on the suction filter paper.…”

“…In addition, at the same stage, we evaluated renal vascular responsiveness to vasoactive agents in ACF TGR that were or were not subjected to RDN. This was done because we found recently that ACF TGR exhibit altered renal vascular responsiveness to vasoactive agents [14], possibly the mechanism underlying the development of renal dysfunction and acceleration of the progress of CHF in this hypertensive model.…”