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Journal of Renin-Angiotensin-Aldosterone System
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Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model

Alexander Nap

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands, a.nap{at}amc.uva.nl

Charly NW Belterman

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands

Marie-Jeanne Mathy

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands

Jippe C Balt

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands

Martin Pfaffendorf

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands

Pieter A van Zwieten

Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands

Congestive heart failure (CHF) is characterised by activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Both systems are known to interact and to potentiate each other's activities. We recently demonstrated that angiotensin II (Ang II) enhances sympathetic nerve traffic via prejunctionally-located AT1-receptors. At present, little is known about the effects of Ang II at the level of the sympathetic neurones in CHF.

Accordingly, we investigated the effect of Ang II in the presence and absence of the AT1-receptor antagonist, eprosartan, on stimulation-induced nerve traffic in isolated thoracic aorta preparations obtained from rabbits suffering from experimentally-induced CHF. Control-preparations were obtained from age-matched animals. Sympathetic activity was assessed by a [3H]noradrenaline spill-over model. Additionally, Ang II constrictor responses were compared between CHF and control vessels in the presence and absence of eprosartan. Additionally, to study postjunctional facilitation, the effects of Ang II on postsynaptic {alpha}-adrenoceptor-mediated responses were studied using noradrenaline.

Stimulation-evoked SNS-neurotransmission was similar in both groups (CHF versus control). Ang II (0.1 nM—0.1 µM) caused a concentration-dependent increase of the stimulation-evoked sympathetic outflow in both groups, with a maximum at 10 nM (control [n=7], FR 2/FR1 2.03±0.11 and CHF-preparations [n=7], FR2/FR 1 1.71±0.07). The enhancement by Ang II was decreased in CHF-preparations compared with controls (p<0.05). Eprosartan concentration-dependently attenuated the Ang II-enhanced (10 nM) sympathetic outflow in both CHF- and control preparations. The sympathoinhibitory potency of eprosartan was similar in both groups (control pIC50 8.81±0.31; CHF 8.65±0.42).

Ang II (1 nM—0.3 µM) concentration-dependently increased the contractile force in control preparations (Emax 21.64±3.86 mN, pD2 7.63±0.02, n=7). Eprosartan (1 nM—0.1 µM) influenced the Ang IIcontractions via a mixed form of antagonism. In CHF-preparations, Ang II caused impaired vascular contraction. The KCl-induced contraction was decreased in the CHF- compared with control preparations (13.02±0.64 mN versus 30.40±0.89 mN). The relative Ang II contraction (% of KCl) was also decreased (2.3% vs. 58.0%). Concentration-response curves to noradrenaline (%KCl) were similar (control pD2 6.93±0.05, Emax 131.0±2.7; CHF pD2 7.00±0.05, Emax 136.7±2.6) (p>0.05) and were not affected by Ang II.

We conclude that Ang II-enhanced sympathetic neurotransmission is mediated by the prejunctional AT1 -receptor in both control and CHF-preparations. The decreased facilitation of SNS effects by Ang II may be explained by down-regulation or desensitisation of the neuronal AT1-receptor. Additionally, the aortic contractile capacity in heart failure rabbits appears to be decreased, probably as a result of heart failure-associated neuroendocrine and functional changes.

Key Words: heart failure • sympathetic nervous system • renin-angiotensin-aldosterone system • AT1-receptor antagonist • facilitation • tritium

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 4, No. 4, 220-227 (2003)
DOI: 10.3317/jraas.2003.036
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