Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure

Aggarwal, Anuradha; Esler, Murray; Morris, Margaret J.; Lambert, Gavin; Kaye, David M.

doi:10.1161/01.hyp.0000055779.93635.a2

Cited by 20 publications

(11 citation statements)

References 39 publications

(46 reference statements)

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“…Regionalized sympathetic activation has been convincingly demonstrated by direct nerve recordings in rabbits, 40 and Esler's group [41][42][43][44][45] has elucidated the importance of regionalized sympathetic activation in human cardiovascular disease by using NE spillover techniques. The finding in this study that CGx markedly attenuated enhanced depressor responses to ganglion blockade during Ang II salt hypertension implies that the majority of the sympathetic activation in this model is directed toward the splanchnic bed and supports the possibility of regionalized sympathetic activation.…”

Section: Discussionmentioning

confidence: 99%

Splanchnic Circulation Is a Critical Neural Target in Angiotensin II Salt Hypertension in Rats

2007

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Abstract-Chronic angiotensin II (Ang II) infusion, in rats fed high salt, engages the sympathetic nervous system to increase venomotor tone. The splanchnic sympathetic nervous system is the most important regulator of venous tone, indicating that splanchnic sympathetic nervous system activity may be increased in Ang II salt hypertension. We hypothesized that celiac ganglionectomy (CGx), to selectively disrupt sympathetic innervation to the splanchnic circulation, would attenuate arterial pressure (AP), and venous tone increases in Ang II salt hypertension. Rats fed 2% or 0.4% NaCl were instrumented to allow AP measurement by radiotelemetry at the same time as surgical CGx or sham operation. Ang II was delivered by minipump (150 ng/kg per minute) for 14 days. CGx reduced AP independent of salt diet during control. CGx markedly attenuated Ang II hypertension in rats on 2% NaCl but had little effect in rats fed 0.4% NaCl. To test the possibility that CGx exerted its effects via renal denervation, rats were subjected to the same protocol but received selective bilateral renal denervation. Renal denervation decreased AP during control but had no protective effect on Ang II hypertension and actually tended to exacerbate the pressor response. Finally, separate groups of rats underwent CGx or sham operation and were instrumented to allow repeated measures of mean circulatory filling pressure, an index of venous tone. In addition to attenuating Ang II salt hypertension, CGx completely prevented Ang II salt-induced increases in mean circulatory filling pressure and substantially attenuated depressor responses to acute ganglion blockade. We conclude that, in the presence of high salt, Ang II activates the splanchnic sympathetic nervous system to increase venomotor tone and AP. Key Words: angiotensin II Ⅲ sympathetic nervous system Ⅲ splanchnic circulation Ⅲ venomotor tone Ⅲ renal denervation W e have shown recently, using repeated measures of mean circulatory filling pressure (MCFP) in conscious undisturbed rats, that chronic infusion of angiotensin II (Ang II), only when administered in combination with a high-salt diet, activates the sympathetic nervous system (SNS) to increase venomotor tone. 1 This increase in venomotor tone may contribute to the pathogenesis of Ang II salt hypertension by increasing central blood volume, resulting in a translocation of blood from the highly compliant venous system to the less compliant arterial circulation. 1 This redistribution of blood volume and the well-documented impairment of renal excretory function caused by Ang II 2 would be major factors in increasing arterial pressure (AP) in this model. [3][4][5] Splanchnic veins and venules account for most of the active capacitance responses in the circulation and are richly innervated by the SNS. 6 -8 In fact, it has been estimated that innervation to the nonhepatic splanchnic organs accounts for half of the total norepinephrine (NE) released in the entire body. 9 Therefore, our recent observations in Ang II salt hypertension of neurog...

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Section: Discussionmentioning

confidence: 99%

Splanchnic Circulation Is a Critical Neural Target in Angiotensin II Salt Hypertension in Rats

2007

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“…The finding of regionalized sympathetic activation is consistent with other experimental findings demonstrating differential control of lumbar and renal sympathetic nerve activity in rabbits. 46 Furthermore, by using regional norepinephrine spillover techniques, Esler and colleagues [47][48][49][50][51] have elucidated the importance of regionalized sympathetic activation in human cardiovascular disease. However, the apparent regionalized sympathetic activation seen in this study may be because of the limitation of using HR as an index of sympathetic nerve activity or may be a result of temporal differences in the activation pattern.…”

Section: Discussionmentioning

confidence: 99%

Chronic Low-Dose Angiotensin II Infusion Increases Venomotor Tone by Neurogenic Mechanisms

King

Fink

2006

Hypertension

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Abstract-The purpose of this study was to identify changes in venomotor tone in the chronic low-dose angiotensin II (Ang II) model of hypertension and to establish the contribution of sympathetic nerve activation to these venomotor tone changes. Male Sprague-Dawley rats were acclimatized to a 0.4% or 2.0% NaCl diet for 7 days and then catheterized to allow chronic and repeated measures of arterial pressure, central venous pressure, and mean circulatory filling pressure (MCFP), an index of venous smooth muscle tone, in conscious undisturbed rats. After 4 days of recovery and a 3-day control period, an Ang II or physiological saline-filled osmotic minipump was implanted subcutaneously to deliver Ang II (150 ng/kg per minute) or vehicle control for 14 days. MCFP was measured in duplicate before and after acute ganglionic blockade with hexamethonium (30 mg/kg IV) on control day 2 and Ang II infusion on days 1, 3, 7, and 14. Blood volume was also measured on these days and was unchanged for the duration of the study in all of the groups. Arterial pressure was increased for the duration of Ang II infusion in rats on both 0.4% and 2% NaCl diets, but the increase was significantly greater in the 2% NaCl group and completely abolished by hexamethonium. MCFP was significantly increased for the entire Ang II infusion period only in rats fed 2% NaCl, and this increase was completely abolished by hexamethonium. We conclude that the combination of chronic low-dose Ang II infusion and high dietary salt intake engages the sympathetic nervous system to increase venomotor tone. Key Words: angiotensin II Ⅲ venomotor tone Ⅲ mean circulatory filling pressure Ⅲ sympathetic nervous system Ⅲ salt E merging evidence suggests that sympathetic nervous system activation may represent a common neurogenic mechanism of hypertension in both human essential hypertension 1-6 and many experimental animal models. 7-10 Angiotensin II (Ang II) has been identified as a humoral factor implicated in activating the sympathetic nervous system in human hypertension 11,12 ; and the pressor response to infusion of chronic low-dose Ang II in animals has been shown, at least in part, to be sympathetically driven. [13][14][15] Advances have been made in the elucidation of the central pathways involved in mediating this sympathoexcitatory effect, suggesting that systemically delivered Ang II likely activates critical circumventricular organs 16 -19 with efferent projections to brain centers known to influence sympathetic nervous system activity. 18 Oxidative stress may mediate this central sympathoexcitatory effect. 20 However, there is still substantial uncertainty as to the critical peripheral target and the hemodynamic response to this increased sympathetic activity.In this study, we investigated the possibility that the venous circulation may be an important target for Ang II-induced sympathetic nervous system activation. The venous system contains Ϸ70% of the blood volume, 21 mostly in the small veins and venules, and has been shown to be more sensitive t...

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“…10 Not surprisingly, IV infusion of the centrally acting ␣ 2 -adrenoceptor agonist clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure patients. 11 In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effects may counteract the salt and water retention that is a hallmark of the condition. In line with this notion is the recent demonstration of a strong negative predictive value of renal sympathetic activation on all-cause mortality and heart transplantation in patients with congestive heart failure, which is independent of overall sympathetic activity, glomerular filtration rate, and left ventricular ejection fraction.…”

Section: Role Of Renal Sympathetic Nerves In Cardiovascular and Kidnementioning

confidence: 99%

Renal Denervation as a Therapeutic Approach for Hypertension

et al. 2009

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Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure

Cited by 20 publications

References 39 publications

Splanchnic Circulation Is a Critical Neural Target in Angiotensin II Salt Hypertension in Rats

Splanchnic Circulation Is a Critical Neural Target in Angiotensin II Salt Hypertension in Rats

Chronic Low-Dose Angiotensin II Infusion Increases Venomotor Tone by Neurogenic Mechanisms

Renal Denervation as a Therapeutic Approach for Hypertension

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