Dopaminergic regulation of circadian rhythms of blood pressure, renin and aldosterone in essential hypertension

Sowers, James R.; Stern, Naftali; Nyby, Michael D.; Jasberg, Keith

doi:10.1093/cvr/16.6.317

Cited by 17 publications

(6 citation 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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“…Arterial pressure likewise changed little throughout the day, and we saw no evidence of the diurnal pattern in blood pressure reported in supine normal volunteers or in patients with essential hypertension (Mann e f a/. 1979;Sowers et a/. 1982).…”

Section: Discussionmentioning

confidence: 52%

Stability and Inter‐relationships of Hormone, Haemodynamic and Electrolyte Levels in Heart Failure in Man

Fitzpatrick

Nicholls

Ikram

et al. 1985

Clin Exp Pharma Physio

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Relationships between clinical status, haemodynamic measurements, hormone and biochemical indices, and maintenance diuretic dose in patients with chronic cardiac failure, are not clear. This study assessed such relationships and their stability under standardized conditions in 21 hospitalized patients. The daily maintenance dose of frusemide correlated closely and in a positive fashion with plasma levels of renin activity, angiotensin II and aldosterone (P less than 0.001), and to a lesser extent with plasma noradrenaline. Although there was some overlap, patients most incapacitated by their heart failure had the highest circulating levels of renin activity, angiotensin II, aldosterone and noradrenaline. Plasma aldosterone correlated closely with concomitant angiotensin II levels (r = 0.70, P less than 0.001) but not with its other secretagogues ACTH (as reflected by plasma cortisol) or plasma potassium. Close positive correlations between angiotensin II and plasma levels of urea and creatinine (P less than 0.01) were observed. Both renin and angiotensin II showed positive relationships with right heart pressures, but were inversely related to cardiac index and arterial pressure. These results show close relationships between clinical and haemodynamic indices on one hand, and hormones on the other. The renin-angiotensin system appears to be the primary regulator of aldosterone under these conditions, and its activity relates closely to haemodynamic measurements and to the degree of azotaemia.

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“…In a large, randomized trial of T2D subjects, the majority (75%) of whom were without pre-existing cardiovascular disease (CVD), the circadian-timed (within 2 h of morning waking) administration of this therapy significantly reduced cardiovascular events by 40–55% over a single year [ 3 , 4 , 5 , 6 ]. Because these protective cardiovascular (CV) effects could not be explained by major changes in plasma lipids, HbA1c, or blood pressure, a plausible explanation for the beneficial CV effect may be related to the reduced chronic overactivation of sympathetic tone [ 7 , 8 , 9 , 10 , 11 ], a pathophysiologic abnormality that both causes and exacerbates the metabolic syndrome (MS), T2D and CVD [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Although poorly appreciated, the scientific literature is replete with studies that corroborate a prominent role of the chronic elevation of sympathetic nervous system (SNS) tone in the genesis and amplification of cellular/tissue oxidative stress and the resultant inflammation, particularly within the immune system [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], which promotes insulin resistance and CVD [ 14 , 30 , 31 , 32 , 33 , 34 , 37 , 38 , 39 , 40 , 41 , 4...…”

Section: Introductionmentioning

confidence: 99%

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects

Cincotta

Cersósimo

Alatrach

et al. 2022

IJMS

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Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body’s systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3β, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1β, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3β (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1β, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

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Dopaminergic regulation of circadian rhythms of blood pressure, renin and aldosterone in essential hypertension

Cited by 17 publications

References 0 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

Stability and Inter‐relationships of Hormone, Haemodynamic and Electrolyte Levels in Heart Failure in Man

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects

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