I1-imidazoline receptor-mediated cardiovascular and metabolic effects in high-fat diet-induced metabolic syndrome in rats

Nascimento, Alessandro; Gomes, Fabiana Oliveira dos Santos; Machado, Marcus Vinícius Ribeiro; Gonçalves-de-Albuquerque, Cassiano Felippe; Bousquet, Pascal; Tibiriçá, Eduardo

doi:10.1016/j.autneu.2018.12.007

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…While we are the first to demonstrate blunted reflex bradycardia by short-term HFD, there are some inconsistencies with previous research regarding HFD-induced resting tachycardia. Indeed, some studies reported no change in HR 44 , 45 while others report a resting tachycardia similar to that seen here 5 , 46 – 48 . Notably, these latter studies all recorded HR using methods that require limited experimenter interaction with test subjects and minimize animal stress, such as radiotelemetry, and therefore, our results are consistent with most previous reports, and emphasize the utility of telemetry recordings when examining HFD’s impact on cardiovascular regulation.…”

Section: Discussionsupporting

confidence: 82%

Early central cardiovagal dysfunction after high fat diet in a murine model

Strain

Espinoza

Fedorchak

et al. 2023

Sci Rep

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High fat diet (HFD) promotes cardiovascular disease and blunted cardiac vagal regulation. Temporal onset of loss of cardiac vagal control and its underlying mechanism are presently unclear. We tested our hypothesis that reduced central vagal regulation occurs early after HFD and contributes to poor cardiac regulation using cardiovascular testing paired with pharmacology in mice, molecular biology, and a novel bi-transgenic mouse line. Results show HFD, compared to normal fat diet (NFD), significantly blunted cardio/pulmonary chemoreflex bradycardic responses after 15 days, extending as far as tested (> 30 days). HFD produced resting tachycardia by day 3, reflected significant loss of parasympathetic tone. No differences in bradycardic responses to graded electrical stimulation of the distal cut end of the cervical vagus indicated diet-induced differences in vagal activity were centrally mediated. In nucleus ambiguus (NA), surface expression of δ-subunit containing type A gamma-aminobutyric acid receptors (GABAA(δ)R) increased at day 15 of HFD. Novel mice lacking δ-subunit expression in vagal motor neurons (ChAT-δnull) failed to exhibit blunted reflex bradycardia or resting tachycardia after two weeks of HFD. Thus, reduced parasympathetic output contributes to early HFD-induced HR dysregulation, likely through increased GABAA(δ)Rs. Results underscore need for research on mechanisms of early onset increases in GABAA(δ)R expression and parasympathetic dysfunction after HFD.

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Section: Discussionsupporting

confidence: 82%

Early central cardiovagal dysfunction after high fat diet in a murine model

Strain

Espinoza

Fedorchak

et al. 2023

Sci Rep

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“…LNP599 is a little-studied pure I1 agonist [46]. The compound has thus far been shown to improve metabolic syndrome, reduce blood pressure and heart rate and reduce plasma catecholamine levels in rodent models [85][86][87][88]. LNP599 also rescues the hyperactive phenotype.…”

Section: Discussionmentioning

confidence: 99%

Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD

Sveinsdóttir¹,

Christensen²,

Þorsteinsson³

et al. 2022

Neuropsychopharmacol.

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ADHD is a highly prevalent neurodevelopmental disorder. The first-line therapeutic for ADHD, methylphenidate, can cause serious side effects including weight loss, insomnia, and hypertension. Therefore, the development of non-stimulant-based therapeutics has been prioritized. However, many of these also cause other effects, most notably somnolence. Here, we have used a uniquely powerful genetic model and unbiased drug screen to identify novel ADHD non-stimulant therapeutics. We first found that adgrl3.1 null (adgrl3.1−/−) zebrafish larvae showed a robust hyperactive phenotype. Although the hyperactivity was rescued by three ADHD non-stimulant therapeutics, all interfered significantly with sleep. Second, we used wild-type zebrafish larvae to characterize a simple behavioral phenotype generated by atomoxetine and screened the 1200 compound Prestwick Chemical Library® for a matching behavioral profile resulting in 67 hits. These hits were re-assayed in the adgrl3.1−/−. Using the previously identified non-stimulants as a positive control, we identified four compounds that matched the effect of atomoxetine: aceclofenac, amlodipine, doxazosin, and moxonidine. We additionally demonstrated cognitive effects of moxonidine in mice using a T-maze spontaneous alternation task. Moxonidine, has high affinity for imidazoline 1 receptors. We, therefore, assayed a pure imidazoline 1 agonist, LNP599, which generated an effect closely matching other non-stimulant ADHD therapeutics suggesting a role for this receptor system in ADHD. In summary, we introduce a genetic model of ADHD in zebrafish and identify five putative therapeutics. The findings offer a novel tool for understanding the neural circuits of ADHD, suggest a novel mechanism for its etiology, and identify novel therapeutics.

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“…In addition, some drugs can improve capillaries' structure and function and increase the number of capillaries in the skeletal muscle. It was recently shown that a new experimental drug, I 1imidazoline agonist, was able to reverse functional and structural capillary rarefaction in the skeletal muscle of obese rats, as well as reducing blood pressure, heart rate, and plasma catecholamine levels [37].…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular and Autonomic Responses after a Single Bout of Resistance Exercise in Men with Untreated Stage 2 Hypertension

Machado

Barbosa

Chrispino

et al. 2021

International Journal of Hypertension

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The aim of this paper is to assess the integrated responses of ambulatory blood pressure (BP), cardiac autonomic modulation, spontaneous baroreflex sensitivity (BRS), and vascular reactivity after a single bout of resistance exercise (RE) in men with stage 2 hypertension who have never been treated before. Ten hypertensive men were subjected to a RE session of three sets of 20 repetitions and an intensity of 40% of the 1-repetition maximum (RM) test in seven different exercises. For the control (CTR) session, the volunteers were positioned on the exercise machines but did not perform any exercise. Forearm blood flow was measured by venous occlusion plethysmography. We also analyzed the heart rate variability (HRV), ambulatory BP, blood pressure variability (BPV), and BRS. All measurements were performed at different timepoints: baseline, 20 min, 80 min, and 24 h after both RE and CTR sessions. There were no differences in ambulatory BP over the 24 h between the RE and CTR sessions. However, the area under the curve of diastolic BP decreased after the RE session. Heart rate (HR) and cardiac output increased for up to 80 and 20 min after RE, respectively. Similarly, forearm blood flow, conductance, and vascular reactivity increased 20 min after RE ( p < 0.05 ). In contrast, HRV and BRS decreased immediately after exercise and remained lower for 20 min after RE. We conclude that a single bout of RE induced an increase in vascular reactivity and reduced the pressure load by attenuating AUC of DBP in hypertensive individuals who had never been treated with antihypertensive medications.

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I1-imidazoline receptor-mediated cardiovascular and metabolic effects in high-fat diet-induced metabolic syndrome in rats

Cited by 6 publications

References 35 publications

Early central cardiovagal dysfunction after high fat diet in a murine model

Early central cardiovagal dysfunction after high fat diet in a murine model

Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD

Cardiovascular and Autonomic Responses after a Single Bout of Resistance Exercise in Men with Untreated Stage 2 Hypertension

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