Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Apr 23;149(17):1394-1396.
doi: 10.1161/CIRCULATIONAHA.123.067331. Epub 2024 Apr 22.

Autonomic Dysfunction Linked to Inhibition of the Nav1.7 Sodium Channel

Christopher P Regan #  1 , Pierre Morissette #  1 , Richard L Kraus  2 , Erjia Wang  1 , Leticia Arrington  3 , Marissa Vavrek  3 , Jan de Hoon  4 , Marleen Depre  4 , Thomas Lodeweyck  4 , Ignace Demeyer  5 , Tine Laethem  6 , Aubrey Stoch  6 , Arie Struyk  6
Affiliations

Autonomic Dysfunction Linked to Inhibition of the Nav1.7 Sodium Channel

Christopher P Regan et al. Circulation. .
No abstract available

Keywords: NAV1.7 voltage-gated sodium channel; baroreflex; clinical study; heart rate control; pain.

PubMed Disclaimer

Conflict of interest statement

Disclosures Drs Regan, Morissette, and Kraus, M. Vavrek, and Drs Wang, T. Laethem, A. Stoch, and A. Struyk are employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ. L. Arrington is employed by Amgen Inc. but was employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, at the time of the study. Drs de Hoon, Dupre, and T. Lodeweyck are employed by the University of Leuven, Belgium. Dr Demeyer is employed by the Military Hospital Queen Astrid, Belgium.

Figures

Figure.
Figure.
Effects of MK-2075 on cardiac autonomic nervous system balance and reflex control through the assessment of HRV and sBRS in telemetered rhesus monkey at 2 to 6 hours postdose (A–D). Adult male rhesus monkeys (n=4) were given increasing subcutaneous doses of MK-2075 and continuous ECG was evaluated for changes in heart rate (HR, A), the time domain HRV parameter, standard deviation of N-N intervals (SDNN, B), baroreceptor effectiveness index (sBRS, C), and both high-frequency (HF) and low-frequency (LF) domain heart rate variability (HRV, D). To further clarify persistent effects during the diurnal phase, continuous data extracted as 15-minute means were aggregated into a 4-hour time period (2–6 hours postdose). A dose-dependent trend in SDNN, sBRS, and HRV decreases can be observed with a statistically significant (P<0.05) difference in all parameters at the 6 mg/kg SC dose. Statistical significance from vehicle was determined for change from baseline data using a linear mixed-effects model (Y=Group×Time+ID+error) where Group×Time capture the fixed group and time effects and their interactions; ID characterizes the between-subject random effects. E and F, Effect of supratherapeutic doses of MK-2075 on heart rate and diastolic blood pressure. Adult male rhesus monkeys (n=5) were given a continuous 8-hour intravenous infusion through jacketed infusion pumps to determine the effect of MK-2075 on HR (E) and diastolic blood pressure (F) parameters at supratherapeutic exposures (50 mg/kg over 8 hours). Increased HR and no change in diastolic pressure were observed during the infusion. Note that postinfusion handling procedures (noted as “room entry” on the graphs) caused an expected increase in HR and diastolic blood pressure in vehicle-treated animals (VEH), but the HR increase was attenuated and the diastolic blood pressure paradoxically decreased after administration of MK-2075 suggestive of compromised cardiovascular autonomic regulation. G through L, In situ hybridization Nav1.7 mRNA expression in rhesus and human tissues. G, H, and I represent Nav1.7 staining in formalin-fixed paraffin-embedded rhesus sinoatrial node, cardiac ganglia, and dorsal root ganglia, and J, K, and L represent Nav1.7 staining in human sinoatrial node, cardiac ganglia, and dorsal root ganglia, respectively. Nav1.7 is not detected in rhesus sinoatrial node, but mildly expressed in human sinoatrial node (40×). It highly expressed in cardiac ganglia and dorsal root ganglia of both rhesus and human subjects (20×).
See this image and copyright information in PMC

References

    1. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, et al. . An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–898. doi: 10.1038/nature05413 - PMC - PubMed
    1. Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, et al. . Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39. doi: 10.1002/ana.22485 - PubMed
    1. Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, Malcangio M, Wood JN. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat Commun. 2012;3:79. - PMC - PubMed
    1. Rothenberg ME, Tagen M, Chang JH, Boyce-Rustay J, Friesenhahn M, Hackos DH, Hains A, Sutherlin D, Ward M, Cho W. Safety, tolerability, and pharmacokinetics of GDC-0276, a novel NaV1.7 inhibitor, in a first-in-human, single- and multiple-dose study in healthy volunteers. Clin Drug Investig. 2019;39:873–887. doi: 10.1007/s40261-019-00807-3 - PubMed
    1. Ballard JE, Pall PS, Vardigan J, Zhao F, Holahan MA, Zhou X, Jochnowitz N, Kraus RL, Klein RM, Henze DA, et al. . Translational pharmacokinetic-pharmacodynamic modeling of NaV1.7 inhibitor MK-2075 to inform human efficacious dose. Front Pharmacol. 2021;12:786078. doi: 10.3389/fphar.2021.786078 - PMC - PubMed

Publication types

MeSH terms

Substances