148: The Mechanism of Action of an Innovative Respiratory Stimulant, ENA-001

Statement of Purpose, Innovation or Hypothesis: Respiration, a fundamental physiological process regulated by the brainstem, incorporates inputs from the cortex and peripheral nerves. Chemoreceptors, responsive to various chemical stimuli such as oxygen and carbon dioxide tension, as well as pH, are distributed in the brainstem and peripheral vasculature. Notably, the carotid bodies, located on the type I glomus cells at the carotid artery bifurcation, serve as primary peripheral sensors for hypoxia. These cells transmit signals via the carotid sinus nerve to the nucleus tractus solitarius (NTS) in the brainstem, a pivotal termination site for respiratory-related sensory inputs from the lungs, airways, and peripheral chemoreceptors. The pre-Bötzinger complex, identified as the primary pacemaker for normal respiration in rats, is connected to the NTS. In humans, the stimulation of the respiratory control arc involves the activation of several ion channels (e.g., BK, TASK-1, and TASK-3) within the glomus cells of the carotid body. Interruption of this intricate respiratory control system is a common iatrogenic occurrence in the peri-procedural setting and can be the result of the medical procedure, drug treatments (such as anesthesia and opioids), or underlying diseases like central/sleep apnea or combination of these factors.

Description of Methods & Materials: The post-procedural setting poses challenges in predicting the onset, duration, and severity of pulmonary complications, with numerous contributing factors like drug sensitivity, pharmacokinetics, and concomitant medications. Patients with additional risk factors, such as advanced age or pre-existing respiratory pathology, are particularly prone to respiratory compromise, necessitating acute intervention and potentially increasing morbidity and mortality.

Data & Results: In response to these challenges, ENA-001 is being developed as an innovative intravenous therapeutic agent designed for short to intermediate-term use to stimulate ventilation and address respiratory depression in post-operative patients. Its primary mechanism of action involves the functional inhibition of large-conductance Ca²⁺ and voltage-activated K+ channels (Maxi-K, BK, BK(Ca²⁺), KCNMA1, Slo1) in the carotid body, leading to increased minute ventilation primarily through enhanced tidal volume and secondarily through minor increases in respiratory rate. The effect of ENA-001 on BK channels is evidenced by electrophysiology studies, demonstrating reversible, concentration-dependent inhibition of single BK channel activity. Additionally, in glomus cells isolated from rat carotid body, ENA-001 selectively inhibits BK-like K⁺ current. The beneficial impact on respiration is attributed to the mimicry of hypoxic inhibition of BK channels, promoting depolarization of carotid body type I cells and inducing voltage-gated Ca²⁺ influx. This cascade results in increased neurotransmitter release, activating sensory afferent discharge to the brainstem via the carotid sinus nerve, ultimately leading to corrective changes in breathing. Experimental evidence further supports the proposed mechanism of action of ENA-001, particularly in rats with carotid sinus nerve transection, which resulted in a significant blunting of the response to ENA-001.

Interpretation, Conclusion or Significance: In conclusion, the mechanism of action of ENA-001, independent of opioids and other agents used in the peri-operative environment, is a potentially promising solution for reversing respiratory depressant effects without interfering with the primary pharmacology of analgesic or anesthetic compounds. This novel therapeutic agent holds considerable potential in mitigating respiratory compromise and improving patient outcomes in post-operative settings.

Disclosures: Research was funded by Enalare Therapeutics Inc.  TM and JM are employees of Enalare Therapeutics.  EG, RR and JP receive consulting fees from Enalare Therapeutics.

Citations/References:

Additional Information/Authors: N/A