In vitro evidence that endothelium-dependent vasodilatation induced by clozapine is mediated by an ATP-sensitive potassium channel

Mateus, Luiza Silva; Albuquerque, Agnes Afrodite Sumarelli; Celotto, Andréa Carla; Évora, Paulo Roberto Barbosa

doi:10.1016/j.pharep.2019.02.010

Cited by 4 publications

(5 citation statements)

References 17 publications

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“…For example, the concentration of KCl (30 mM) was tested and selected because it has been found that nebivolol was failed to induce relaxation when higher concentration (60 mM) of KCl was used in the experimental protocol (data not shown). In addition to this, the concentrations of glibenclamide and KCl used in the present study were in line with previous in vitro studies in the rat aorta (Ito et al, 1997;Erdei et al, 2006;Mateus et al, 2019).…”

Section: Discussionsupporting

confidence: 90%

The Involvement of ATP-Sensitive Potassium Channels in the Nebivolol-Induced Relaxation of Endothelium-Intact Aorta Isolated from Rats

Altunkaynak-Camca¹

2020

Middle Black Sea Journal of Health Science

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Objective: Nebivolol is a highly selective beta-1 adrenergic receptor blocker with additional vasorelaxant properties. The vasorelaxant effect of nebivolol has been mainly attributed to endothelium-dependent mechanisms including beta-adrenergic receptors. However, the involvement of ATP-sensitive potassium (KATP) channels, another potential mechanism for vasorelaxant effect, in the vasorelaxant response to nebivolol remains unclear. Therefore, this study was aimed to investigate the role of KATP channels in the nebivolol-induced vasorelaxation in the isolated rat aorta Methods: The rat thoracic aortic rings isolated from Sprague-Dawley rats were mounted in organ bath chambers containing Krebs-Henseleit solution at 37 o C continuously bubbled with 95% O2 and 5% CO2. After an equilibration period, the presence of endothelium was confirmed by the response (more than 50%) to acetylcholine (10 μM) in aortic rings precontracted with phenylephrine (1 μM). After washout, in control group, the endothelium-intact aortic rings were contracted by potassium chloride (30 mM) before the cumulative addition of nebivolol (0.0001-100 μM). In some experiments, the relaxant response to nebivolol (0.0001-100 μM) was also obtained in the presence of glibenclamide (KATP channel blocker, 10 μM) or Nω-Nitro-L-arginine methyl ester (L-NAME: eNOS inhibitor, 100 μM) in the endothelium-intact aortic rings precontracted with potassium chloride (30 mM). Data were presented as means±SEM. Multiple comparisons of groups were performed by using ANOVA followed by post-hoc Bonferroni test. Results: Nebivolol elicited a concentration dependent vasorelaxant effect in the endothelium-intact aortic rings. Relaxant response to nebivolol was significantly inhibited by the presence of glibenclamide or L-NAME (p< 0.05). Although Emax values were not found significantly different among groups, pD2 values of nebivolol were reduced in the endothelium-intact aortic rings incubated with glibenclamide or L-NAME. Conclusion: These results demonstrate for the first time the involvement of KATP channels in the nebivololinduced vasorelaxation in the endothelium-intact aorta precontracted with potassium chloride.

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Section: Discussionsupporting

confidence: 90%

The Involvement of ATP-Sensitive Potassium Channels in the Nebivolol-Induced Relaxation of Endothelium-Intact Aorta Isolated from Rats

Altunkaynak-Camca¹

2020

Middle Black Sea Journal of Health Science

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“…While we did not observe significant effects of CNO on feeding, BAT temperature, and cardiovascular parameters in control mice, the tail temperature was found slightly but significantly increased by CNO treatment in control mice (although the effect was much smaller than that of DREADD activation of PVN MC4R+ neurons). Since clozapine has been shown to have a vasodilatory effect [ 45 , 46 ], we speculate that this small increase of tail temperature could be due to vasodilation caused by clozapine that converted from CNO. It is therefore worthwhile to test in the future whether optogenetic activation of PVN MC4R+ neurons can replicate some of the functional observations made in the present study.…”

Section: Discussionmentioning

confidence: 99%

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Singh

Jiang

Saito

et al. 2022

Molecular Metabolism

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Objective The paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVN MC4R+ ) is involved in feeding regulation, the neuroanatomical organization of PVN MC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input–output organization of PVN MC4R+ neurons and test their physiological functions beyond feeding. Methods Using a combination of viral tools, we mapped PVN MC4R+ circuits and tested the effects of chemogenetic activation of PVN MC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. Results We found that PVN MC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVN MC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVN MC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior. Conclusions Our results elucidate the neuroanatomical organization of PVN MC4R+ circuits and shed new light on the roles of PVN MC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

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“…While did not observe significant effects of CNO on feeding, BAT thermogenesis and cardiovascular parameters in control mice, it is worthy to note that tail temperature was slight but significantly increased by CNO treatment in control mice (although the effect was much smaller than that of DREADD activation of PVN MC4R+ neurons). Since the clozapine has been shown to have a vasodilatory effect[46; 47], we speculate that this small increase of tail temperature could be due to vasodilation caused by clozapine that converted from CNO. It is therefore worthwhile to test in future whether optogenetic activation of PVN MC4R+ neurons can replicate some of functional observations made in the present study.…”

Section: Discussionmentioning

confidence: 99%

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Cui

Singh

Saito

et al. 2021

Preprint

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Objective: The paraventricular nucleus of hypothalamus (PVN) is an integrative center in the brain orchestrating a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is undoubtedly involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ pathway and its role in diverse physiological and behavioral regulations have not been fully understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and further test their potential functional roles beyond feeding. Methods: Using a combination of viral tools, we performed a comprehensive mapping of PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermogenesis, cardiovascular control and other behavioral regulations beyond feeding. Results: We found that PVNMC4R+ neurons broadly innervate many different brain regions known to be important not only for feeding but also for neuroendocrine and autonomic control of thermogenesis and cardiovascular function, including but not limited to preoptic area, median eminence, parabrachial nucleus, locus coeruleus, nucleus of solitary tract, ventrolateral medulla and thoracic spinal cord. Contrary to broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs from limited brain regions, including medial preoptic nucleus, arcuate and dorsomedial hypothalamic nuclei, and supraoptic nucleus. Consistent with broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure and brown adipose tissue thermogenesis. Strikingly, these physiological changes accompanied an unexpected repetitive bedding-removing behavior followed by hypoactivity and resting-like behavior. Conclusions: Our results clarify the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermogenesis, cardiovascular function and other behavioral regulations.

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In vitro evidence that endothelium-dependent vasodilatation induced by clozapine is mediated by an ATP-sensitive potassium channel

Cited by 4 publications

References 17 publications

The Involvement of ATP-Sensitive Potassium Channels in the Nebivolol-Induced Relaxation of Endothelium-Intact Aorta Isolated from Rats

The Involvement of ATP-Sensitive Potassium Channels in the Nebivolol-Induced Relaxation of Endothelium-Intact Aorta Isolated from Rats

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

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