Introduction
The autonomic nervous system plays a pivotal role in regulating cardiovascular function. In the context of heart failure (HF), there is a notable withdrawal of parasympathetic influence alongside increased sympathetic activation, collectively contributing to detrimental outcomes. Heart rate variability (HRV) serves as a surrogate marker for autonomic regulation, with diminished HRV reflecting an impaired balance between sympathetic and parasympathetic activity. Similarly, baroreflex sensitivity (BRS) provides insight into the cardiovascular system's regulatory capacity in response to fluctuations in blood pressure, where impaired baroreflex function indicates reduced cardiovascular adaptability.
BAY 2413555 is a positive allosteric modulator specific to the muscarinic M2 receptor, demonstrating high selectivity over other muscarinic receptors. As a positive allosteric modulator, BAY 2413555 exhibits no intrinsic agonistic or antagonistic activity but enhances the effects of the endogenous ligand acetylcholine for the M2 receptor. This mechanism supports the physiological regulation of parasympathetic signaling while enhancing the effects of endogenous signaling at the M2 receptor. The objective of this study was to characterize BAY 2413555 following oral administration in healthy pigs and dogs, focusing on HRV, BRS, and cardiac function. Additionally, hemodynamic effects were compared to those observed after beta-blocker administration.
Methods
Telemetry devices were implanted in six pigs and six dogs to record left ventricular pressure, aortic pressure, and electrocardiograms in conscious animals. In a crossover-designed study, animals were treated with placebo and three different dosages of BAY 2413555. To investigate the effect of BAY 2413555 in combination with a beta-blocker, additional experiments were conducted in dogs using metoprolol succinate alone or in combination with BAY 2413555.
Results
Oral treatment with BAY 2413555 resulted in a dose-dependent and significant (p < 0.05) reduction in heart rate in both dogs and pigs over a 19-hour time course. Furthermore, a dose-dependent increase in BRS and HRV was observed for all tested dosages. No effects on cardiovascular parameters, activity, or body temperature were noted. In comparison to the placebo group, a depression in cardiac contractility was observed whenever the beta-blocker was used. BAY 2413555 alone did not affect cardiac contractility and did not further diminish contractility when combined with metoprolol.
Conclusion
BAY 2413555 enhances parasympathetic activity, leading to increased baroreflex sensitivity and heart rate variability, as well as a reduction in heart rate in telemetric animals. As a positive allosteric modulator of the M2 receptor, it could become the first therapeutic option for heart failure, directly addressing parasympathetic regulation and adjusting the autonomic nervous system.
