In Field-Stimulated Guinea-Pig Atria an AT1-Receptor Mediated Increase of Noradrenaline Release by Angiotensin II is Seen only in the Presence of Prejunctional Autoinhibition

Brasch, Helmut; Sieroslawski, L.; Bergmann, Niklas; Dominiak, Peter

doi:10.1007/978-1-4899-0952-7_19

Cited by 10 publications

(12 citation statements)

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“…6 Such facilitation of norepinephrine (NE) release has frequently been investigated in isolated tissues under electrical stimulation 7,8 and appears to depend on a presynaptic autoinhibitory tone that is relieved in response to ANG. 9,10 The inability of ANG to induce catecholamine release from isolated tissues in the absence of electrical excitation 6,7,11 provoked the common view that facilitation of depolarization-induced catecholamine release represents the essential interaction of ANG with the peripheral sympathetic system in intact animals as well.…”

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confidence: 99%

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

et al. 2002

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Abstract-Angiotensin II (ANG) is known to facilitate catecholamine release from peripheral sympathetic neurons by enhancing depolarization-dependent exocytosis. In addition, a direct excitation by ANG of peripheral sympathetic nerve activity has recently been described. This study determined the significance of the latter mechanism for angiotensininduced catecholamine release in the pithed rat. Rats were anesthetized and instrumented for measuring either hemodynamics and renal sympathetic nerve activity or plasma catecholamine concentrations in response to successively increasing doses of angiotensin infusions. Even during ganglionic blockade by hexamethonium (20 mg/kg), angiotensin dose-dependently elevated sympathetic nerve activity, whereas blood pressure-equivalent doses of phenylephrine were ineffective. Independently of central nervous sympathetic activity and ganglionic transmission, angiotensin (0.1 to 1 g/kg) also induced an up-to 27-fold increase in plasma norepinephrine levels, reaching 2.65 ng/mL. Preganglionic electrical stimulation (0.5 Hz) raised basal norepinephrine levels 11-fold and further enhanced the angiotensin-induced increase in norepinephrine (4.04 ng/mL at 1 g/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 g/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 g/kg), but raised blood pressure at a significantly lower dose (0.01 g/kg). It is concluded that direct stimulation of ganglionic angiotensin type 1 (AT 1 ) receptors arouses electrical activity in sympathetic neurons, leading to exocytotic junctional catecholamine release. In both the absence and presence of preganglionic sympathetic activity, this mechanism contributes significantly to ANG-induced enhancement of catecholamine release. Key Words: angiotensin II Ⅲ angiotensin antagonist Ⅲ catecholamines Ⅲ sympathetic nervous system Ⅲ electric stimulation Ⅲ rats A ngiotensin II (ANG) potently enhances catecholamine release from the peripheral sympathetic system, an action that implies important pathophysiological consequences. Catecholamines released by this mechanism contribute to the vasoconstricting and sodium-retaining properties of ANG. 1 In particular, the chronic effects of ANG at moderately elevated levels are promoted by adrenergic pathways that are significantly involved in the development of hypertension 2,3 and in the concomitant myocardial damage that has elsewhere been attributed to a stimulation of cardiac ␤-adrenoceptors. 4 ANG activates the sympathetic system via several mechanisms. Central nervous sympathetic tone is increased by circulating or locally produced ANG in nuclei responsible for autonomic control. 5 In the peripheral sympathetic system, the termini of adrenergic neurons are equipped with prejunctional angiotensin type 1 (AT 1 ) receptors whose activation enhances the efficacy of catecholamine discharge induced by each acti...

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confidence: 99%

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

et al. 2002

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“…Blockade of the neuronal feedback mechanism of noradrenaline release by ␣ 2 -antagonists is known to abolish the facilitating activity of Ang II, suggesting that Ang II acts via an attenuation of autoinhibition. 28 Pharmacological suppression of autoinhibition by the ␣ 2 -antagonist rauwolscine in the present study did not reduce the desensitizing influence of losartan on vascular noradrenaline sensitivity (Table 3), indicating a minor contribution of endogenous noradrenaline release under basal conditions (Figure 4). In contrast, rauwolscine abolished the antiadrenergic action of losartan after blockade of NET by desipramine ( Table 2), signifying that ␣ 2 -mediated feedback and consequently AT 1 mediated facilitation became unmasked when the availability of endogenous noradrenaline was enhanced.…”

Section: Discussionmentioning

confidence: 44%

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

et al. 2004

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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...

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“…Furthermore, animals in this study were not treated with inhibitors of neuronal catecholamine reuptake and α 2 -autoreceptors which would have probably facilitated the detection of the effects of Ang II and both AT 1 antagonists losartan and HR 720. We have, for instance, recently demonstrated in the isolated, field-stimulated guinea pig atrium that Ang II releases noradrenaline only under the conditions of reuptake inhibition with cocaine or desipramine and of prejunctional autoinhibition with idazoxan [10]. These substances, however, have not been used in this study in order to avoid multiple pharmacological effects of these substances.…”

Section: Discussionmentioning

confidence: 99%

“…The animals were pithed with a stainless steel rod which has been coated with enamel except for the length of the thoracolumbar spinal cord (Th [4][5][6][7][8][9][10] ). In addition, the left carotid artery was cannulated (PE-50) to obtain blood samples, and a metal needle was placed under the skin on the back.…”

Section: Pithed Rat Preparationmentioning

confidence: 99%

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Effects of the AT1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats

Haüser¹,

Dendorfer²,

Nguyễn³

et al. 1998

Kidney Blood Press Res

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It has been demonstrated in isolated organs that angiotensin II mediates catecholamine release via presynaptically located AT₁ receptor subtypes. In the present study, the relevance of AT₁-mediated noradrenaline and adrenaline release in a whole-animal model, which reflects the peripherally sympathetic system (pithed rat), was investigated. Furthermore, the effects of a new AT₁ antagonist, HR 720, are demonstrated with respect to its pre- and postsynaptic actions in comparison to the AT₁ antagonist losartan. Dose-response curves to angiotensin II of blood pressure show a tenfold higher potency for HR 720 to compete for angiotensin II, thereby decreasing the maximum effects when compared with losartan. The electrically induced sympathetic outflow resulted in a dose-dependent increase after angiotensin II infusions. It could markedly be reduced with both AT₁ antagonists, whereby HR 720 again was ten times more potent than losartan. Neither with HR 720 nor with losartan an agonistic activity could be demonstrated. The results indicate an AT₁ receptor subtype mediated release of catecholamines in a whole-animal model. HR 720 is ten times more potent than the AT₁ antagonist losartan and acts in a noncompetitive manner.

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In Field-Stimulated Guinea-Pig Atria an AT1-Receptor Mediated Increase of Noradrenaline Release by Angiotensin II is Seen only in the Presence of Prejunctional Autoinhibition

Cited by 10 publications

References 7 publications

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

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

Effects of the AT1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats

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In Field-Stimulated Guinea-Pig Atria an AT1-Receptor Mediated Increase of Noradrenaline Release by Angiotensin II is Seen only in the Presence of Prejunctional Autoinhibition

Cited by 10 publications

References 7 publications

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

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

Effects of the AT1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats

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