In vitro vascular ion channel screening for drug-induced vascular liability

Abstract

The control of blood pressure is complex, but vascular ion channels play a key role (Tykocki et al., 2017). Estimates suggest 20–30% of commonly prescribed medications can influence blood pressure; here we investigate the role of vascular ion channels in drug-induced blood pressure changes, offering the potential to establish a screen early in drug discovery.

Sixteen marketed drugs known to affect blood pressure were tested against a panel of vascular ion channels: Kv1.1, Kv2.1, Kv7.2/7.3, Kv7.3/7.5, CaV1.2, CaV3.2, Kir2.1. Drugs were tested in vitro by automated patch clamp (QPatch II, Sophion Biosciences). Drugs known to reduce blood pressure, like nifedipine and verapamil, showed activity at several ion channels, most notable vascular calcium channels. Clozapine which also changes blood pressure, showed activity at multiple vascular ion channels including Kv2.1 and Kv7.3/7.5 with IC50s of 13.0 and 42.1 suggesting a possible mechanism of action for clozapine. The data suggest that activity at ion channels is a potential mechanism for the effect of drugs on blood pressure. Thus, when testing unknown compounds as part of a screening strategy, activities at any of these ion channels may implicate possible effect on blood pressure. However, a negative result at these vascular ion channels cannot rule out the potential for effects on blood pressure by non-ion channel mediated mechanisms. Future work will build the panel by examining other relevant ion channels such as the KATP and K2P channels.