Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

Abstract

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

“…In the pithed rat model, this basal release of noradrenaline is very low and results in hardly detectable plasma concentrations. 4 To evaluate the significance of facilitated noradrenaline release, its dependency on presynaptic autoinhibition was used. 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.…”

“…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][8][9] so that Ang II and noradrenaline exert synergistic actions on vascular tone.…”