Effects of HCN Channels in the Rostral Ventrolateral Medulla Contribute to the Cardiovascular Effects of Propofol

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were reported to express in the well-known vasomotor region, rostral ventrolateral medulla (RVLM), and can be inhibited by propofol. However, whether HCN channels in RVLM contribute to propofol-induced cardiovascular depression remains unclear. We recorded the hemodynamic changes when either continuous intravenous infusions or microinjections of propofol and ZD-7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride; HCN channel blocker) in RVLM. Expressions of HCN channels in RVLM neurons of mice of different ages were examined by quantitative real-time polymerase chain reaction and Western blotting. The effects of propofol and ZD-7288 on HCN channels and the excitability of RVLM neurons were examined by electrophysiological recording. Propofol (1.25, 2.5, 5, and 7.5 mg/kg per minute, i.v., 10 minutes) decreased mean arterial pressure (MAP) and heart rate (HR) in a concentration-dependent manner in wild-type mice that were markedly attenuated in HCN1 knockout mice. Bilateral microinjection of propofol (1%, 0.1 μl) in RVLM caused a sharp and pronounced drop in MAP and HR values, which were abated by pretreatment with ZD-7288. In electrophysiological recording, propofol (5, 10, and 20 μM) concentration-dependently inhibited HCN current, increased input resistance, decreased firing rate, and caused membrane hyperpolarization in RVLM neurons. These actions of propofol were attenuated by ZD-7288 pretreatment. The mRNA and protein level of HCN channels increased in an age-dependent manner, which may contribute to the age-dependent increase in the sensitivity to propofol. Our results indicated that the inhibition of HCN channels in RVLM neurons may contribute to propofol-induced cardiovascular inhibition.