Involvement of Sympathetic Nervous System Inhibition in the Hypotensive Effect of Bromocriptine in Spontaneously Hypertensive Rats

Kanayama, Yoshiharu; Kohno, Masakazu; Takaori, Kazuo; Itoh, Satoko; Yasunari, Kenichi; Takeda, Tadanao

doi:10.1111/j.1440-1681.1987.tb00969.x

Cited by 6 publications

(4 citation statements)

References 9 publications

(10 reference statements)

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“…Long‐term bromocriptine therapy is well known to reduce elevated sympathetic tone in hypertensive animals and humans . The present study extends the specifics of these findings on vascular hemodynamics and uncovers an important relationship between B‐QR impact on RHR and glycaemic control in type 2 diabetes subjects.…”

Section: Discussionsupporting

confidence: 72%

“…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%

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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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Section: Discussionsupporting

confidence: 72%

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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“…Studies in normal rats indicate that it has an acute renal vasodilatory and hypotensive action (Stier et al 1982) and also lowers blood pressure in the spontaneously hypertensive rat (Nagahama et al 1984; Racz et al 1986; Kanayama et al 1987; van den Buuse & Lambrechts, 1989; Oguro et al 1992), deoxycorticosterone–salt hypertensive rats (Nagahama et al 1985) and normal and hypertensive humans (Sowers, 1981; Mannelli et al 1984; Franchi et al 2001; Kok et al 2006). The possible basis for this hypotensive action is a reduction in sympathetic activity, since plasma and urine noradrenaline levels are reduced in most studies in rats (Nagahama et al 1984, 1985; Racz et al 1986; Kanayama et al 1987; Oguro et al 1992) and humans (Sowers, 1981; Carey et al 1983; Mannelli et al 1984). Our observation of elevated plasma noradrenaline concentration in Bromo–HSD rats indicates that the combination of Bromo treatment with ingestion of the HSD leads to sympathoexcitation, in contrast to the above effects of Bromo by itself.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of γ‐melanocyte‐stimulating hormone

Dijk

Pearce

et al. 2009

Experimental Physiology

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A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the γ-melanocytestimulating hormone (γ-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted γ-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg −1 i.p., daily for 1 week; Bromo) to cause relative γ-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of γ 2 -MSH, or of the α-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; γ 2 -MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative γ-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by γ 2 -MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative γ-MSH deficiency.

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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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Involvement of Sympathetic Nervous System Inhibition in the Hypotensive Effect of Bromocriptine in Spontaneously Hypertensive Rats

Cited by 6 publications

References 9 publications

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

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

Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of γ‐melanocyte‐stimulating hormone

Cardiovascular effects of melanocortins

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