Analysis of baroreflex and heart rate variability – Tools in cardiovascular pre-clinical safety studies

Cardiovascular reflexes and drug effects on the autonomic nervous system may contribute to hypotension/hypertension and bradycardia/tachycardia and pose a safety risk for patients. Thus, there is a need to assess autonomic and cardiovascular reflex responses to pharmacologic compounds in pre-clinical safety studies. To validate techniques assessing baroreflex function and cardiac autonomic modulation based on hemodynamic parameters commonly recorded in pre-clinical safety studies. Following three escalating oral doses of the vasodilator hydralazine or the α 1 ‑agonist midodrine hemodynamic responses were monitored for 24 h via telemetry (PhysioTel Digital L21, DSI, St. Paul, MN) in conscious male beagle dogs, and compared to vehicle control data. Baroreceptor-HR reflex function was assessed by the gain of the transfer function between systolic blood pressure (BP) and heart rate (HR). Cardiac autonomic modulation was assessed by low frequency (LF, sympathetic and parasympathetic modulation) and high frequency (HF, parasympathetic modulation) spectral power of inter-beat interval variability and the time-domain HR variability parameters SDNN (sympathetic and parasympathetic modulation) and RMSSD (parasympathetic modulation). As expected, hydralazine and midodrine caused opposite dose-dependent effects on BP and HR. Hydralazine at mid and high doses caused prolonged tachycardia beyond the hypotensive response. Tachycardia was explained by reduced cardiac parasympathetic modulation as demonstrated by marked reductions in SDNN, RMSSD, LF and HF spectral powers, and LF/HF ratio. Despite pronounced hypertensive responses to midodrine at mid and high doses, only low and mid doses caused bradycardia as expected from baroreflex responses. Interestingly, the low midodrine dose increased the gain of the BP-HR transfer function, while the mid and high doses decreased transfer function gain. Thus, bradycardia at the low midodrine dose is explained by augmentation of baroreflex function, while the lack of bradycardia at the high dose may be related to inhibition of baroreflex function. The results of this study demonstrate that assessing baroreceptor reflex function and autonomic effects on the cardiovascular system can provide important insights on hemodynamic effects of pharmacological compounds. Adding such assessments to pre-clinical safety studies may expand evaluation of complex autonomic inputs to help understand drug-induced cardiovascular responses.