Reduction of Vascular Noradrenaline Sensitivity by AT ₁ Antagonists Depends on Functional Sympathetic Innervation

Abstract

Abstract-Blockade of angiotensin II type-1 (AT 1 ) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10 Ϫ12 to 10 Ϫ7 mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the ED 50 of the noradrenaline response (1.3Ϯ0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT 1 receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or ␣ 2 -adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED 50 values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and ␣ 2 -adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity (ED 50 5.5Ϯ1.3 versus 5.6Ϯ1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine (ED 50 7.1Ϯ0.8 versus 7.8Ϯ0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT 1 blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic ␣ 2 -mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT 1 blockers. 1 The mechanisms of the various interactions between the renin-angiotensin-aldosterone system and the sympathetic system have been established at different levels and have been shown to bear prominent pathophysiological implications. Angiotensin II (Ang II) stimulates the sympathetic system by activating central nervous tone and catecholamine release 2 and by facilitating the release of catecholamines from peripheral sympathetic neurons via ganglionic 3,4 and axonal presynaptic receptors. 5,6 Ang II has been shown to increase vascular sensitivity to noradrenaline in rats and isolated vessels, 7-9 so that Ang II and noradrenaline exert synergistic actions on vascular tone. As such, it could be proposed that blockade of endogenous Ang II by AT 1 blockers might alter vascular reactivity to exogenous noradrenaline. Indeed AT 1 blockers provoked a reduction in vascular sensitivity to noradrenaline in pithed rats, 6 although discrepant findings were obtained even where similar experimental approaches were pursued. 10 This controversy still requires clarification, particularly as regards the mechanisms by which AT 1 blockers might reduce vascular catecholamine sensitivity.In arterial smooth muscle, Ang II has been shown to potentiate noradrenaline sensitivity by activating protein kinase C and thereby increasing calcium sensitivity. 8 Moreover, short-duration in vivo pretreatment with Ang II also primes the is...

Stress sensitivity is increased in transgenic rats with low brain angiotensinogen

“…Assays were performed as recommended by the manufacturers (Raasch et al 2006, Müller et al 2007). Norepinephrine and epinephrine were measured in plasma that was obtained one day after catheter insertion by HPLC and electrochemically as previously described (Raasch et al 2004a(Raasch et al , 2005.…”

Physiological regulation of pro-inflammatory cytokines expression in rat cardiovascular tissues by sympathetic nervous system and angiotensin II

“…Both AT1 and AT2 receptors of ANG II are expressed in sympathetic fibers coursing the heart and vessels (presynaptic receptors) and in the tissue (Timmermans and Smith 1994). Based on the literature, we hypothesize that ANG II from circulation or locally synthesized acts through two pathways to influence the local synthesis IL-6 and TNF-α: 1) Sympathostimulator pathway where ANG II incites neurotransmitters release from sympathetic fibers including norepinephrine via AT1R (Gironacci et al 1994;Dendorfer et al 1998;Balt et al 2001;Raasch et al 2004). Norepinephrine (NE) assure its action through noradrenergic receptors (R) expressed on cardiac cells; 2) direct pathway where ANG II mediates directly its action on cardiac tissue via AT1R essentially but can also access to AT2 receptor.…”

“…Moreover, the blockage of ANG II receptor AT1R with losartan reduces NE release and enhances its reuptake by SNS terminal axon (Raasch et al 2004). However, little is known about the SNS-ANG II interaction on the proinflammatory cytokines expression in cardiovascular system.…”

“…The levels of IL-6 and TNF-α transcription were determined by RT-PCR in the left ventricle and aorta. Systolic blood pressure (SBP) was measured to check the efficacy of simple or combined treatment, since losartan and chemical sympathectomy are well known to reduce SBP (Dwyer et al 2004;Raasch et al 2004). …”

Physiological regulation of extracellular matrix collagen and elastin in the arterial wall of rats by noradrenergic tone and angiotensin II

“…[14][15][16] The AT1R blockade reduces NE release 14 and enhances its uptake by SNS terminal axons. 17 However, very few studies have described the interactions between the two systems in the vascular bed, 18,19 most often in pathological models.…”