Modulation of Noradrenaline Release in the Pithed Rabbit

Majewski, H.; Hedler, L; Schurr, Claudia; Starke, Klaus

doi:10.1097/00005344-198409000-00023

Cited by 64 publications

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“…First, Ang II acts presynaptically in sympathetic nerves to facilitate NE release. 8 This mechanism may explain the inhibited sympathetic response after enalaprilat since blood pressure reduction was accompanied by a fall in Ang II plasma concentrations. However, directly recorded muscle sympathetic nerve activity increased after dihydralazine, whereas no change was seen after enalaprilat.…”

Section: Discussionmentioning

confidence: 99%

“…4 Thus, it appears that vasodilators and ACE inhibitors produce different sympathetic nerve responses; the effects of the latter could be due to either a direct-acting central mechanism 5,6 or a reduction of angiotensin II (Ang II) facilitatory effects on norepinephrine (NE) release in peripheral sympathetic nerve endings. 7,8 The aim of the present study was to assess the effect of short-term ACE inhibition on the adrenergic drive in patients with hypertension and renal artery stenosis. Given that animal experiments indicate different effects on renal nerve activity and heart rate in response to Ang II, 9 we also wanted to explore whether there is regional differentiation in the sympathetic response to ACE inhibition and nonspecific vasodilatation, with the latter used as a positive control test.…”

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Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

et al. 2000

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Abstract-Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (PϽ0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (PϽ0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved. (Hypertension. 2000;36:543-548.)Key Words: hypertension, renovascular Ⅲ sympathetic nervous system Ⅲ renin-angiotensin system R enovascular hypertension is a condition associated with both an activated renin-angiotensin system and elevated sympathetic nerve activity. 1,2 Previous data, obtained in experimental models, indicate a positive interaction between the renin-angiotensin and the sympathetic nervous systems. 3 Therefore, in renovascular hypertension it may be favorable to use a therapeutic modality that does not reflexly further increase heart rate, renin secretion, and sympathetic nervous activity. It is well known that certain drugs used in cardiovascular medicine affect various indices of sympathetic activity. For example, sympathetic activity increases in response to nonspecific vasodilators, whereas therapy with angiotensin-converting enzyme (ACE) inhibitors has demonstrated reduced peroneal sympathetic activity. 4 Thus, it appears that vasodilators and ACE inhibitors produce different sympathetic nerve responses; the effects of the latter could be due to either a direct-acting central mechanism 5,6 or a reduction of angiotensin II (Ang II) facilitatory e...

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Section: Discussionmentioning

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Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

et al. 2000

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“…Angiotensin II is known to enhance action-potential evoked sympathetic transmitter release in vitro (see Starke, 1977;Zimmerman, 1978) and in vivo (Majewski et al, 1984) by activating release-enhancing presynaptic angiotensin II receptors at the sympathetic terminals. However, although converting enzyme inhibitors decrease whole body noradrenaline release in the pithed rat with stimulated sympathetic outflow (Majewski, 1989), they appear to have no effect on the tachycardia exerted by either electrical stimulation of the cardiac sympathetic nerves (Boura et al, 1983a,b;Rose'Meyer et al, 1989) or the tachycardia due to cardiac sympathetic nerve activation by the ganglion stimulant McNeil A343 (Boura et al, 1983a) in this model.…”

Section: Introductionmentioning

confidence: 99%

A facilitatory effect of anti‐angiotensin drugs on vagal bradycardia in the pithed rat and guinea‐pig

Rechtman

Majewski

1993

British J Pharmacology

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1 In pithed rats, preganglionic vagal nerve stimulation (at 5 Hz) elicited a bradycardia. This bradycardia was potentiated by the angiotensin converting enzyme inhibitor, captopril (1 mg kg-', i.v.) by about 40%. Subsequent angiotensin II infusion (0.03 gg kg-' min-') reversed this effect. A similar facilitatory effect was also seen with the angiotensin receptor antagonist, losartan (1Omg kg-', i.v.). These results suggest a tonic inhibitory effect of endogenous angiotensin II on vagal transmission. 2 The effect of captopril in potentiating vagal bradycardia appears to be at the level of vagal neurones, since the bradycardia elicited by the muscarinic agonist, methacholine was unaffected. 3 After the pithed rats were nephrectomized, captopril had no effect on vagally-induced bradycardia, suggesting that the formation of the endogenous angiotensin II responsible for the effect was dependent on renin release from the kidney. 4 When the sympathetic nerves of the pithed rat were electrically stimulated there was a tachycardia, and this was unaffected by captopril. However, when the sympathetic and vagus nerves were activated concurrently, the resulting tachycardia was inhibited by captopril. 5 In pithed guinea-pigs, captopril also potentiated the bradycardia caused by vagal nerve stimulation. This appears to be a tissue-selective effect since the bronchoconstriction due to the vagal stimulation was not affected by captopril. 6 These results suggest that endogenous angiotensin II can have a tonic inhibitory effect on cardiac vagal transmission. Disruption of this mechanism by anti-angiotensin drugs may attenuate the reflex tachycardia associated with the fall in blood pressure in anti-hypertensive therapy.

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“…ANG increases noradrenaline release from sympathetic nerve endings by stimulating presynaptic AT 1 receptors (Brasch et al, 1993). Hence, inhibition of ANG biosynthesis by ACE inhibitors reduces the release of catecholamines (Majewski et al, 1984). In the past, many clinical trials evaluated the pronounced antihypertensive and cardioprotective effects of ACE inhibitors, and in this context, the contributions of diminished plasma noradrenaline levels to their antihypertensive and cardioprotective effects were discussed.…”

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Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

Raasch¹,

Bartels²,

Gieselberg³

et al. 2002

J Pharmacol Exp Ther

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Antihypertensive and cardioprotective effects of angiotensin I-converting enzyme (ACE) inhibitors are well established and have usually been attributed to the inhibition of angiotensin II (ANG)-mediated effects at vascular or ventricular (angiotensin type 1) AT 1 receptors. One other important mechanism involves ANG-induced interactions with the sympathetic nervous system, which might include alterations of cardiac catecholamine concentrations during ACE inhibition due to a modulation of monoamine oxidase (MAO) activity. Tissue catecholamines were studied in spontaneously hypertensive rats that were long-term treated with captopril (50 or 0.5 mg/kg/day), enalapril (10 or 0.1 mg/kg/day), an AT 1 receptor antagonist (candesartan-cilexetil, 3 mg/kg/day), or a calcium antagonist (mibefradil, 18 mg/kg/day). The kinetic parameters of MAO were then determined in vitro in the presence of ANG, captopril, enalaprilat, or candesartan. Noradrenaline and adrenaline contents were doubled in the left ventricle by captopril, enalapril, or candesartan independently of hypotensive potency but not in liver or cortex. In parallel, cardiac MAO activity was reduced by all doses of captopril (49/29%), enalapril (52/24%), or candesartan (38%). Mibefradil, which does not interact with the renin-angiotensin system, did not alter cardiac catecholamines or MAO activity when an equipotent antihypertensive dose was applied. In vitro MAO activity was not influenced by ANG, enalaprilat, or captopril at concentrations of up to 1 mM. It is concluded that diminished AT 1 receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT 1 antagonists had no effect on MAO activity in vitro. This action contributes to an increase in cardiac catecholamine content that may improve cardiac sympathetic control during therapy.Angiotensin I-converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and heart failure. They decrease angiotensin II (ANG) generation by blocking the circulating and local renin-angiotensin systems (RAS) and by preventing the degradation of bradykinin. Both mechanisms seem to be involved in the antihypertensive and cardioprotective effects. Both ANG and bradykinin interact with other neurohumoral systems such as the sympathetic system. ANG increases noradrenaline release from sympathetic nerve endings by stimulating presynaptic AT 1 receptors (Brasch et al., 1993). Hence, inhibition of ANG biosynthesis by ACE inhibitors reduces the release of catecholamines (Majewski et al., 1984). In the past, many clinical trials evaluated the pronounced antihypertensive and cardioprotective effects of ACE inhibitors, and in this context, the contributions of diminished plasma noradrenaline levels to their antihypertensive and cardioprotective effects were discussed. The therapeutic significance of this action was revealed for the treatment of heart failure where a pathological sympathetic stimulation was associated with decreased cardiac noradren...

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Modulation of Noradrenaline Release in the Pithed Rabbit

Cited by 64 publications

References 0 publications

Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

A facilitatory effect of anti‐angiotensin drugs on vagal bradycardia in the pithed rat and guinea‐pig

Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

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