Neurophysiological assessment of sympathetic cardiovascular activity after loss of postganglionic neurons in the anesthetized rat

Zahner, Matthew R.; Liu, Chang‐Ning; Okerberg, Carlin V.; Opsahl, Alan; Bobrowski, Walter F.; Somps, Chris

doi:10.1016/j.vascn.2016.04.010

Cited by 5 publications

(9 citation statements)

References 51 publications

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“…Although fewer neurons were present in the SCG of guanethidine-treated animals, we observed that the remaining neurons were larger in comparison to the neurons found in the control group ( Fig 6C ). In contrast to the published model [ 21 ], we observed some residual effects of guanethidine on baseline blood pressure 28 days post-treatment ( Fig 6E ). The baseline heart rate was not significantly changed in guanethidine-treated animals ( Fig 6D ) while baseline MAP was elevated by approximately 7 mmHg (control: 104.5 ± 0.9 bpm, guanethidine: 111.3 ± 1.3 bpm, p = 0.06, Student t-test).…”

Section: Resultscontrasting

confidence: 99%

“…It has been previously shown that guanethidine treatment produces profound and significant permanent depletion of sympathetic postganglionic neurons in experimental animals and the morphometric analysis of postganglionic neurons in the current study is in agreement with published literature [ 21 , 40 – 45 ]. However, PF-05231023 was still capable of elevating blood pressure and heart rate in rats in which approximately 40% of the sympathetic post-ganglionic neurons were ablated.…”

Section: Discussionsupporting

confidence: 93%

“…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%

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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: Resultscontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…It is assumed these same factors affected data presented in prior publications by other authors. When neurons were killed by a test article such as guanethidine, the remaining neurons increased in size after a recovery period ( Zahner et al , 2016 ). Following recovery in the current study, the neuron size/area of tanezumab-treated animals was not larger than control neurons, consistent with neurons not being killed in these studies.…”

Section: Discussionmentioning

confidence: 99%

From the Cover: Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment

Bélanger

Butler

Butt

et al. 2017

Toxicological Sciences

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Tanezumab, a humanized monoclonal antibody against nerve growth factor is in development for treatment of chronic pain. Three nonclinical studies assessed effects of clinically relevant and supratherapeutic doses of tanezumab on the sympathetic nervous system (SNS) of adult nonhuman primates. Study 1 evaluated potential effects of subcutaneous (SC) tanezumab (1.2 mg/kg every 8 weeks [Q8W]) on SNS in cynomolgus monkeys for 3 or 6 months and reversibility or persistence of any effects through a nondosing/recovery period. Study 2 evaluated whether neuronal cell death occurs shortly after a single SC tanezumab injection (1.2 mg/kg). Assessments for these two studies included evaluations of superior cervical and cervicothoracic ganglia for neuronal cell death and morphology. Study 3 evaluated effects of SC tanezumab (1.2 mg/kg Q8W and 30 mg/kg/week) over 6 months on sympathetic control of cardiovascular function. Tanezumab exposure was associated with stereologic changes in sympathetic ganglia, including smaller ganglion volume, and smaller average neuron size/area beginning at 2 weeks and reaching maximal levels by 1 month with no further progression through 6 months. These changes were not associated with clinical signs, completely reversed upon tanezumab withdrawal, and were not considered adverse. Tanezumab had no adverse effects on sympathetic control of cardiovascular function. These data support the conclusion that tanezumab administration for up to 6 months has no adverse effects on SNS morphology or function and does not cause neuronal cell death in adult nonhuman primates.

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“…See Mouton (Mouton, 2011) for further discussion of stereology methods applied to SCG in this paper. Statistically significant loss of H&E-stained neurons could be readily detected in rat sympathetic ganglia following exposure to high dose guanethidine using this procedure (Zahner et al, 2016 SCG were embedded in a plastic resin, sectioned, stained and processed for stereology. Ganglia were embedded in 5% agarose using 5-mm specially designed silicone molds -also called isectors (Nyengaard and Gundersen, 1992).…”

Section: Number Of Neurons and Nuclei And Volume Of Th Immunoreactivimentioning

confidence: 99%

Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats

Marcek

Okerberg

Liu

et al. 2016

Journal of Chemical Neuroanatomy

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Neurophysiological assessment of sympathetic cardiovascular activity after loss of postganglionic neurons in the anesthetized rat

Cited by 5 publications

References 51 publications

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

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

From the Cover: Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment

Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats

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