Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig

AbstractRecent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment.

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Effect of Propofol on Carotid Body Chemosensitivity and Cholinergic Chemotransduction

Anesthesiology ◽

10.1097/00000542-200501000-00019 ◽

2005 ◽

Vol 102 (1) ◽

pp. 110-116 ◽

Cited By ~ 23

Author(s):

Malin M. Jonsson ◽

Sten G. E. Lindahl ◽

Lars I. Eriksson

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Carotid Body ◽

Acetylcholine Receptors ◽

Carotid Sinus ◽

Aminobutyric Acid ◽

Receptor Complex ◽

Gamma Aminobutyric Acid ◽

General Anesthetics ◽

Carotid Sinus Nerve

Background Propofol decreases the acute hypoxic ventilatory response in humans and depresses in vivo carotid body chemosensitivity. The mechanisms behind this impaired oxygen sensing and signaling are not understood. Cholinergic transmission is involved in oxygen signaling, and because general anesthetics such as propofol have affinity to neuronal nicotinic acetylcholine receptors, the authors hypothesized that propofol depresses carotid body chemosensitivity and cholinergic signaling. Methods An isolated rabbit carotid body preparation was used. Chemoreceptor activity was recorded from the whole carotid sinus nerve. The effect of propofol on carotid body chemosensitivity was tested at three different degrees of PO2 reduction. Nicotine-induced chemoreceptor response was evaluated using bolus doses of nicotine given before and after propofol 10-500 microM. The contribution of the gamma-aminobutyric acid A receptor complex was tested by addition of gamma-aminobutyric acid A receptor antagonists. Results Propofol reduced carotid body chemosensitivity; the magnitude of depression was dependent on the reduction in PO2. Furthermore, propofol caused a concentration-dependent (10-500 microM) depression of nicotine-induced chemoreceptor response, with a 50% inhibitory concentration (propofol) of 40 microM. Bicuculline in combination with propofol did not have any additional effect, whereas addition of picrotoxin gave a slightly more pronounced inhibition. Conclusions It is concluded that propofol impairs carotid body chemosensitivity, the magnitude of depression being dependent on the severity of PO2 reduction, and that propofol causes a concentration-dependent block of cholinergic chemotransduction via the carotid sinus nerve, whereas it seems unlikely that an activation of the gamma-aminobutyric acid A receptor complex is involved in this interaction.

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Murine Carotid Body Responses to Hypoxia: In vivo Carotid Sinus Nerve Recordings in the DBA/2J and A/J Strains.

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1026.19 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Luis Pichard ◽

Francis Sgambati ◽

Eric Kostuk ◽

Pejmon Bashai ◽

Robert Fitzgerald ◽

...

Keyword(s):

Carotid Body ◽

Carotid Sinus ◽

Carotid Sinus Nerve ◽

Nerve Recordings

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Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation

Frontiers in Neuroscience ◽

10.3389/fnins.2021.725751 ◽

2022 ◽

Vol 15 ◽

Author(s):

Silvia V. Conde ◽

Joana F. Sacramento ◽

Bernardete F. Melo ◽

Rui Fonseca-Pinto ◽

Mario I. Romero-Ortega ◽

...

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Sympathetic Nervous System ◽

Metabolic Diseases ◽

Carotid Sinus ◽

Acute Hypoxia ◽

Therapeutic Modality ◽

Carotid Sinus Nerve ◽

Peripheral Chemoreceptor ◽

Sympathetic Nervous

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

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A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics

Scientific Reports ◽

10.1038/s41598-021-92628-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ling Li ◽

Mohamad I. Itani ◽

Kevan J. Salimian ◽

Yue Li ◽

Olaya Brewer Gutierrez ◽

...

Keyword(s):

Argon Plasma Coagulation ◽

Argon Plasma ◽

Large Animal Model ◽

Swine Model ◽

Large Animal ◽

High Grade ◽

Gi Tract ◽

Endoscopic Techniques ◽

Approved Drugs

AbstractGastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.

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Autoradiographic Studies on the Effects of Chronic Unilateral Sectioning of a Carotid Sinus Nerve on 5-HT and SP Binding Sites in the Carotid Body and NTS

Chemoreceptors and Chemoreceptor Reflexes ◽

10.1007/978-1-4684-8938-5_44 ◽

1990 ◽

pp. 305-309 ◽

Cited By ~ 2

Author(s):

M. R. Dashwood ◽

D. S. McQueen ◽

M. de Burgh Daly ◽

K. M. Spyer ◽

Y. Evrard

Keyword(s):

Carotid Body ◽

Binding Sites ◽

Carotid Sinus ◽

Carotid Sinus Nerve

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The Effect of Intermittent Carotid Sinus Nerve and Carotid Body Stimulation on Respiratory Output

CHEST Journal ◽

10.1016/s0012-3692(15)32696-9 ◽

1972 ◽

Vol 61 (2) ◽

pp. 44S ◽

Cited By ~ 1

Author(s):

Frederic L. Eldridge

Keyword(s):

Carotid Body ◽

Carotid Sinus ◽

Carotid Sinus Nerve

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Niobium Carbide Loaded by Macrophage for Targeted Phototherapy Ablation of Breast Cancer

10.1101/2020.12.09.417154 ◽

2020 ◽

Author(s):

Chiara Da Pieve ◽

Gabriela Kramer Marek ◽

Jolanta Saczko ◽

Anant Shah ◽

Florian Raes

Keyword(s):

Animal Study ◽

Human Body ◽

Targeted Delivery ◽

Near Infrared ◽

Niobium Carbide ◽

Reactive Oxygen Species Generation ◽

Large Animal Model ◽

Large Animal ◽

Photodynamic Effect

ABSTRACTAltough nanomaterial-mediated phototherapy has been extensively studied, the major antitumor success is limited to treating subcutaneous tumor on nude, lacking of clinically-relevant big animal study. Therefore, it is urgent to make further investigation on the typical big model, which is more closely related to the human body. In this work, niobium carbide (NbC) was selected as photoactive substance in virtue of its outstanding near infrared (NIR) absorption properties and resultantly NIR-triggered hyperthemia and reactive oxygen species generation for the synergetic photothermal and photodynamic effect. Moreover, macrophage was used as bio-carrier for the targeted delivery of NbC and the phagocytosis of macrophages was proved to be able to retain the photothermal/photodynamic effect of NbC. Resultantly, macrophage loaded NbC could realize complete removal of solid tumor on both of nude mice and big animal of rabbits. Meanwhile, two-dimensional ultrasound, shave wave elastography (SWE) and contrast-enhanced ultrasound (CEUS) have been applied for monitoring the physiological evolutions of in vivo tumor post treatment, which clearly disclosed the photoablation process of tumor and provided a new way for the surveillance of tumor on the big animal study. Hence, large animal model study in this work presented higher clinical significance than the previous studies.SignificanceFindings show that niobium carbide carried by macrophages can be used for targeted phototherapy. At the same time, we applied the rabbit tumor model which is closer to the human body microenvironment.

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Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction

Cells ◽

10.3390/cells10102571 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2571

Author(s):

Cristina Prat-Vidal ◽

Verónica Crisóstomo ◽

Isabel Moscoso ◽

Claudia Báez-Díaz ◽

Virginia Blanco-Blázquez ◽

...

Keyword(s):

Myocardial Infarction ◽

Growth Factor ◽

Progenitor Cells ◽

Large Animal Model ◽

Cardiac Progenitor Cells ◽

Large Animal ◽

Insulin Growth Factor ◽

Decellularized Extracellular Matrix ◽

Preclinical Animal Models

Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.

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