Physiological approaches to assess diminished sympathetic activity in the conscious rat

Zahner, Matthew R.; Liu, Chang‐Ning; Bernardo, Vincent; Northcott, Carrie A.; Tyszkiewicz, Cheryl; Okerberg, Carlin V.; Boucher, Magalie; Pardo, Ingrid; Somps, Chris

doi:10.1016/j.vascn.2017.06.002

Cited by 6 publications

(9 citation statements)

References 31 publications

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“…Because PF-05231023 rapidly elevates blood pressure and heart rate after dosing, we hypothesized that PF-05231023 is acting through the sympathetic nervous system to mediate its effects. To assess the potential effect of PF-05231023 on the sympathetic nervous system, we performed cardiac baroreflex tests by decreasing arterial pressure using the systemic vasodilator sodium nitroprusside [ 19 , 20 ]. The maximal dose of sodium nitroprusside reduced arterial pressure to 70 mmHg.…”

Section: Resultsmentioning

confidence: 99%

“…To further elucidate the involvement of FGF21-driven sympathetic activation on blood pressure and heart rate, we used guanethidine to permanently deplete sympathetic post-ganglionic neurons as previously reported [ 20 , 21 ]. Guanethidine treatment resulted in a 44% reduction in the number of superior cervical ganglionic (SCG) neurons ( Fig 6A and 6B ).…”

Section: Resultsmentioning

confidence: 99%

“…On the day of the experiment (few days after venous catheter surgery), telemetry devices were activated and cardiovascular measurements were recorded at a frequency of 500Hz. The indwelling venous catheter was connected to an 18″–24″ piece of polyethylene tubing for the administration of sodium nitroprusside (SNP) for vasodilation as previously described [ 20 ]. Rats were jacketed and connected to a tether to protect the polyethylene tubing from becoming damaged and given at least 60 min to acclimate to the tether and to allow blood pressure and heart rate to stabilize from handling.…”

Section: Methodsmentioning

confidence: 99%

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FGF21 increases water intake, urine output and blood pressure in rats

et al. 2018

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Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FGF21 increases water intake, urine output and blood pressure in rats

et al. 2018

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“…Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered IP to rats in order to kill postganglionic sympathetic neurons as described previously. [22][23][24] Following the last dose, animals were allowed to recover for 1, 3, or 6 months. These time points were chosen based on studies in sensory ganglia 14,15 in which peak neuron losses following chemical treatment were observed at 1 month with recovery by 2 to 3 months.…”

Section: Discussionmentioning

confidence: 99%

“…20 To test our hypothesis that neuron loss in the sympathetic ganglia may be replaced over time, we used guanethidine, an antihypertensive drug, 21 as a model toxicant that at high doses cause selective destruction of postganglionic adrenergic neurons within the sympathetic ganglia in the rat. 22 We have shown previously that daily administration of high-dose guanethidine (100 mg/kg/d) to rats for 11 days causes significant reductions in sympathetic neurons in T3 23 and cranial (superior) cervical 24 ganglia following a 3-to 4-week recovery period. The objective of the work described here was to determine whether any restoration of neurons occurs after a 3-or 6-month recovery following administration of high-dose (100 mg/kg/d) guanethidine to rats.…”

Section: Introductionmentioning

confidence: 99%

No Evidence of Neurogenesis in Adult Rat Sympathetic Ganglia Following Guanethidine-Induced Neuronal Loss

Walters

Boucher

et al. 2019

Toxicol Pathol

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The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations. Both morphometric and stereologic evaluations confirmed neuron loss following guanethidine treatment. Morphometric analysis revealed a 50% to 60% lower number of tyrosine hydroxylase (TH)-positive neurons per unit area of SCG at both 3 and 6 months of recovery, compared to ganglia of age-matched controls, with no evidence of restoration of neuron density between 3 and 6 months. Reductions in TH-positive neurons following guanethidine treatment were corroborated by unbiased stereology of total hematoxylin and eosin-stained neuron numbers in SCG. Stereologic analyses revealed that total neuron counts were lower by 37% at 3 months of recovery when compared to age-matched vehicle controls, again with no obvious restoration between 3 and 6 months. Thus, no evidence was found that postganglionic neurons of the sympathetic nervous system in the adult rat have a neurogenic capacity.

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