Pharmacological properties of YM-254890, a specific Gαq/11 inhibitor, on thrombosis and neointima formation in mice

Abstract

The pharmacological properties of YM-254890, a specific G(alpha)q/11 inhibitor, on acute thrombosis and chronic neointima formation after vascular injury have been investigated. FeCl3 was used to induce vascular injury in the carotid artery of mice. For the thrombosis studies, the test drug was either intravenously or orally administered before vascular injury. For the neointima studies, the test drug was orally administered 1 h before and twice daily for 1 week after vascular injury. Histological analysis was then performed 3 weeks later. YM-254890 significantly inhibited ex vivo platelet aggregation 5 min after intravenous bolus injection at 0.03 mg/kg or more, and 1 h after oral administration at 1 mg/kg. YM-254890 significantly inhibited thrombus formation after intravenous bolus injection at 0.03 mg/kg as well as after oral administration at 1 mg/kg, but tail transection bleeding time was significantly prolonged at 0.1 mg/kg for intravenous injection and 3 mg/kg for oral administration. Furthermore, oral administration of YM-254890 dose-dependently inhibited neointima formation 3 weeks after vascular injury with significant effects at 1 mg/kg twice daily for 1 week. Clopidogrel also significantly inhibited neointima formation at its antithrombotic dose, but its inhibitory potency was less than that of YM-254890. However, YM-254890 significantly reduced systemic blood pressure at doses 3 times higher than those that produced significant inhibitory effects on thrombosis and neointima formation. Though the systemic use of YM-254890 may be limited, owing to its narrow therapeutic window, this unique compound is a useful research tool for investigating the physiological roles of G(alpha)q/11 .

Targeted inhibition of G q signaling induces airway relaxation in mouse models of asthma

“…A G q inhibitor isolated from Chromobacterium sp. QS3666 (YM-254890) illustrated the therapeutic potential of pharmacological G protein inhibition, because it promoted antithrombotic and vasodilatory effects in mice, rats, and monkeys (20)(21)(22)(23). However, in these studies, the G q inhibitor was often administered as a bolus injection directly into the bloodstream, yielding depression of the cardiovascular system.…”

Gq signaling causes glomerular injury by activating TRPC6

“…An alternative treatment strategy might be to target a final common pathway activated by each of these receptor systems such as Gq α subunits. YM254890 is a specific Gq inhibitor that has been tested in experimental animals (49)(50)(51). In these studies, YM254890 reduced systemic BP and inhibited platelet aggregation without apparent adverse effects.…”

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

“…17,79 Importantly, the degree of injury can be modulated by the concentration of the ferric chloride and the time of exposure. The model has been applied to demonstrate the roles of platelet aggregation inhibitors, such as aspirin, clopidogrel, ticagrelor, and other clinically approved or experimental compounds, 56,58,[80][81][82] on preventing arterial thrombosis. In parallel to these studies, transgenic/ knockout mouse lines have been used to demonstrate the critical role of different platelet receptors using this model.…”