Role of sympathetic nerve inhibition in the vasodepressor effect of bromocriptine in normotensive and hypertensive rats.

Oguro, Minako; Takeda, Kazuo; Itoh, Hiroshi; Takesako, Toshiyuki; Tanaka, Michitaka; Takenaka, Ken; Hirata, Masahiro; Nakata, Tetsuo; Tanabe, Shingo; Hayashi, Junko; Sasaki, Susumu; Nakagawa, Masao

doi:10.1253/jcj.56.943

Cited by 9 publications

(11 citation statements)

References 18 publications

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“…Several studies [2][3][4][5][6][7] have evaluated the effects of bromocriptine on the sympathetic nervous system mainly with the aim of clarifying whether this drug exerts only peripheral effects or whether it also has central effects. So far, it is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…As a matter of fact, it has been shown in experimental animals that bromocriptine increases the ventricular fibrillation threshold by 50% 2 and decreases plasma levels of catecholamines. 3 Whereas peripheral actions of bromocriptine have been well elucidated not only under resting conditions 4 but also in response to hemodynamic maneuvers, 5-7 a centrally mediated reduction in sympathetic outflow has not been demonstrated so far.With this in mind, the design of the present study was aimed at evaluating the effects of acute bromocriptine administration on cardiac sympathovagal balance by means of power spectral analysis. Taking into account that domperidone (DM) is a peripheral D 2 -like receptor antagonist that is able to counteract the peripheral effects of bromocriptine, 8,9 we analyzed the influence of preadministration of DM on the sympathovagal balance with subjects in supine and sitting positions to unmask the central activity of bromocriptine.…”

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Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance

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Abstract-Bromocriptine, a dopamine agonist, is known to lower cardiovascular mortality in L-dopa-treated patients withParkinson's disease, probably by reducing the cardiac sympathetic activity. We aimed at unmasking the central effects of bromocriptine on the heart by power spectrum analysis. Ten healthy subjects (aged 31Ϯ2 years) in supine and sitting positions were evaluated after the administration of bromocriptine (2.5 mg) alone and after pharmacological peripheral D 2 -like blockade by domperidone (20 mg). We calculated (autoregressive method) the following: the low-frequency (LF) component (an index of cardiac sympathetic tone), the high-frequency (HF) component (an index of cardiac vagal tone), and the LF/HF ratio (an index of cardiac sympathovagal balance). With subjects in the supine position, bromocriptine alone induced a significant increase in the LF component and the LF/HF ratio, together with a reduction in norepinephrine plasma levels and blood pressure values. These conflicting effects can be explained as the combined result of direct and indirect (reflex-mediated) actions of bromocriptine in vivo. No changes in cardiac autonomic drive were observed with subjects in the sitting position. After domperidone pretreatment, bromocriptine induced a reduction in the LF component and in the LF/HF ratio. The sitting position caused an increase in heart rate and in the LF/HF ratio. We demonstrated both peripheral and central effects of bromocriptine. In particular, pretreatment with a peripheral antagonist (domperidone) allowed us to unmask the central effect of bromocriptine on cardiac sympathetic drive. Key Words: autonomic nervous system Ⅲ sympathetic nervous system Ⅲ dopamine Ⅲ heart rate B romocriptine is a D 2 -like receptor agonist that is known to inhibit sympathetic output and to lower the cardiovascular mortality in L-dopa-treated patients with Parkinson's disease. 1 The cardioprotective effect of bromocriptine can be related to a withdrawal of the cardiac sympathetic activity, which could diminish the risk of potentially lifethreatening ventricular arrhythmias. As a matter of fact, it has been shown in experimental animals that bromocriptine increases the ventricular fibrillation threshold by 50% 2 and decreases plasma levels of catecholamines. 3 Whereas peripheral actions of bromocriptine have been well elucidated not only under resting conditions 4 but also in response to hemodynamic maneuvers, 5-7 a centrally mediated reduction in sympathetic outflow has not been demonstrated so far.With this in mind, the design of the present study was aimed at evaluating the effects of acute bromocriptine administration on cardiac sympathovagal balance by means of power spectral analysis. Taking into account that domperidone (DM) is a peripheral D 2 -like receptor antagonist that is able to counteract the peripheral effects of bromocriptine, 8,9 we analyzed the influence of preadministration of DM on the sympathovagal balance with subjects in supine and sitting positions to unmask the central activity of br...

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Section: Discussionmentioning

confidence: 99%

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Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance

et al. 2001

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“…It also lowers blood pressure in the spontaneously hypertensive rat (SHR) (Kanayama et al, 1987; Nagahama et al, 1984; Oguro et al, 1992; Racz et al, 1986; van den Buuse and Lambrechts, 1989), DOCA-salt hypertensive rats (Nagahama et al, 1985), and normal and hypertensive humans (Franchi et al, 2001; Kok et al, 2006; Mannelli et al, 1984; Sowers, 1981). The possible basis for this hypotensive action is a reduction in sympathetic activity, as plasma and urine norepinephrine levels are reduced in most studies in rats (Kanayama et al, 1987; Nagahama et al, 1984; 1985; Oguro et al, 1992; Racz et al, 1986)and humans (Carey et al, 1983; Mannelli et al, 1984; Sowers, 1981). Thus, the development of salt-sensitive hypertension after one week’s treatment with bromocriptineis perhaps surprising given these reports of its hypotensive action, and is an indicator of the importance of the accompanying γ-MSH deficiency coupled with the high sodium diet in blood pressure regulation.…”

Section: γ-Msh and Glucose Metabolismmentioning

confidence: 99%

Cardiovascular effects of melanocortins

Humphreys

Pearce

2011

European Journal of Pharmacology

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Melanocortins (MSH’s) are three structurally related peptides derived from proopiomelanocortin. They regulate several physiologic functions including energy metabolism, appetite, and inflammation. Recent work in rodents has also identified important effects of MSH’s, particularly γ-MSH, on sodium metabolism and blood pressure regulation. Normal rats and mice respond to a high sodium diet with an increase in the plasma concentration of γ-MSH, and remain normotensive, while those with genetic or pharmacologic γ-MSH deficiency become hypertensive on a high sodium diet. This hypertension is corrected by exogenous administration of the peptide. Mice lacking the γ-MSH receptor (the melanocortin 3 receptor, Mc3r) also become hypertensive on a high sodium diet but remain so when administered γ-MSH, and infusions of physiologic levels of the peptide stimulate urinary sodium excretion in normal rats and mice, but not in mice with deletion of Mc3r. The salt-sensitive hypertension in rodents with impaired γ-MSH signaling appears due to stimulation of noradrenergic activity, since plasma noradrenaline is increased and the hypertension is rapidly corrected with infusion of the α-adrenoceptor antagonist phentolamine. In contrast to the antihypertensive property of physiologic levels of γ-MSH, intravenous or intracerebroventircular injections of high levels of the peptide raise blood pressure. This occurs in mice lacking Mc3r, indicating an interaction with some other central receptor. Finally, the salt-sensitive hypertension in rodents with disruption of γ-MSH signaling is accompanied by insulin resistance, an observation which offers a new window into the study of the association of salt-sensitive hypertension with insulin resistance and type II diabetes.

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“…Bromocriptine‐QR (B‐QR), a quick‐release formulation of micronized bromocriptine, is the only sympatholytic dopamine‐agonist US FDA‐approved for the treatment of type 2 diabetes. In several preclinical and clinical studies, bromocriptine administration has repeatedly been demonstrated to reduce measures of elevated SNS activity such as reduction of elevated sympathetic outflow, plasma norepinephrine, BP and/or conversion of nondipper profile of circadian mean arterial pressure to a dipper profile. A critical aspect of dopaminergic control of autonomic function is via circadian modulation of the central biological clock pacemaker circuit (circadian neuronal afferent signals to and including the suprachiasmatic nuclei [SCN]) (see below).…”

Section: Introductionmentioning

confidence: 99%

Circadian‐timed quick‐release bromocriptine lowers elevated resting heart rate in patients with type 2 diabetes mellitus

Chamarthi

Vinik

Ezrokhi

et al. 2019

Endocrino Diabet & Metabol

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Objective: Sympathetic nervous system (SNS) overactivity is a risk factor for insulin resistance and cardiovascular disease (CVD). We evaluated the impact of bromocriptine-QR, a dopamine-agonist antidiabetes medication, on elevated resting heart rate (RHR) (a marker of SNS overactivity in metabolic syndrome), blood pressure (BP) and the relationship between bromocriptine-QR's effects on RHR and HbA1c in type 2 diabetes subjects.Design and Subjects: RHR and BP changes were evaluated in this post hoc analysis of data from a randomized controlled trial in 1014 type 2 diabetes subjects randomized to bromocriptine-QR vs placebo added to standard therapy (diet ± ≤2 oral antidiabetes medications) for 24 weeks without concomitant antihypertensive or antidiabetes medication changes, stratified by baseline RHR (bRHR). Results: In subjects with bRHR ≥70 beats/min, bromocriptine-QR vs placebo reduced RHR by −3.4 beats/min and reduced BP (baseline 130/79; systolic, diastolic, mean arterial BP reductions [mm Hg]: −3.6 [P = .02], −1.9 [P = .05], −2.5 [P = .02]). RHR reductions increased with higher baseline HbA1c (bHbA1c) (−2.7 [P = .03], −5 [P = .002], −6.1 [P = .002] with bHbA1c ≤7, >7, ≥7.5%, respectively] in the bRHR ≥70 group and more so with bRHR ≥80 (−4.5 [P = .07], −7.8 [P = .015], −9.9 [P = .005]). Subjects with bRHR <70 had no significant change in RHR or BP. With bHbA1c ≥7.5%, %HbA1creductions with bromocriptine-QR vs placebo were −0.50 (P = .04), −0.73 (P = .005) and −1.22 (P = .008) with bRHR <70, ≥70 and ≥80, respectively. With bRHR ≥70, the magnitude of bromocriptine-QR-induced RHR reduction was an independent predictor of bromocriptine-QR's HbA1c lowering effect. Conclusion:Bromocriptine-QR lowers elevated RHR with concurrent decrease in BP and hyperglycaemia. These findings suggest a potential sympatholytic mechanism contributing to bromocriptine-QR's antidiabetes effect and potentially its previously demonstrated effect to reduce CVD events. K E Y W O R D Sdopamine, sympathetic nervous system, type 2 diabetes

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Role of sympathetic nerve inhibition in the vasodepressor effect of bromocriptine in normotensive and hypertensive rats.

Cited by 9 publications

References 18 publications

Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance

Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance

Cardiovascular effects of melanocortins

Circadian‐timed quick‐release bromocriptine lowers elevated resting heart rate in patients with type 2 diabetes mellitus

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