Propofol Effects on Chloride and Calcium Channels
Propofol directly affects both chloride and calcium channels: it enhances chloride influx through GABA-A receptors and inhibits L-type calcium channels.
Mechanism of Action on Chloride Channels
Propofol's primary sedative mechanism operates through positive modulation of GABA-A receptors, which are ligand-gated chloride channels. 1 The drug reduces the rate of dissociation of GABA from its receptor, prolonging the duration of contact between GABA and the receptor site. 2 This action promotes extended chloride influx into neurons, leading to hyperpolarization of the neuronal cell membrane and subsequent sedation. 2
The American Gastroenterological Association confirms that propofol potentiates GABA by reducing the rate of dissociation of the GABA receptor, with onset of action occurring within 30-45 seconds. 3
Research demonstrates that propofol-activated currents are chloride-selective and show outward-rectification, with maximum channel conductance increasing dose-dependently from less than 15 pS at 10 μM to approximately 60 pS at 500 μM propofol. 4
When propofol is combined with GABA, the maximum chloride channel conductance increases to approximately 100 pS, demonstrating synergistic enhancement of chloride channel activity. 4
Effects on Calcium Channels
Propofol selectively inhibits L-type voltage-gated calcium channels without affecting N-type or P/Q-type calcium channels. 5
L-Type Calcium Channel Inhibition
Propofol selectively reduces L-type high-voltage activated (HVA) calcium currents in cortical neurons, with an IC50 of approximately 3.9 μM for this effect. 5
In cardiac myocytes, propofol decreases the probability of L-type calcium channels being open during depolarization, reduces mean open times, and increases mean closed times without altering channel conductance. 6
In vascular smooth muscle cells, propofol inhibits calcium entry through L-type channels activated by endothelin-1 and phorbol esters in a dose-dependent manner, contributing to its vasodilatory effects. 7
Clinical Significance of Calcium Channel Effects
The inhibition of L-type calcium channels contributes to propofol's cardiovascular effects, including decreased cardiac output, systemic vascular resistance, and blood pressure. 3, 1
In immature neurons, propofol's activation of GABA-A receptors paradoxically increases intracellular calcium through L-type channels due to reversed chloride gradients in developing neurons, which may contribute to neurotoxicity concerns in pediatric populations. 8
Sodium Channel Effects
- Propofol also inhibits the persistent fraction of sodium currents (IC50 3.9 μM) while having negligible effects on fast sodium currents, even at concentrations up to 300 μM. 5 This contributes to its antiepileptic properties by modulating neuronal excitability.
Clinical Implications
The dual action on chloride and calcium channels explains propofol's rapid onset, cardiovascular depression, and lack of analgesic properties. The enhancement of chloride influx produces sedation and amnesia, while L-type calcium channel inhibition contributes to negative inotropic and vasodilatory effects. 3, 1, 5