The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Abstract

Abstract.We demonstrated the inhibitory effect of NNC 55-0396, a T-type Ca 2+ channel inhibitor, on voltage-dependent K + (K V ) channels in freshly isolated rabbit coronary arterial smooth muscle cells. NNC 55-0396 decreased the amplitude of K V currents in a concentration-dependent manner, with an IC 50 of 0.080 mM and a Hill coefficient of 0.76. NNC 55-0396 did not affect steady-state activation and inactivation curves, indicating that the compound does not affect the voltage sensitivity of K V channel gating. Both the K V currents and the inhibitory effect of NNC 55-0396 on K V channels were not altered by depletion of extracellular Ca 2+ or intracellular ATP, suggesting that the inhibitory effect of NNC 55-0396 is independent of Ca 2+ -channel activity and phosphorylation-dependent signaling cascades. From these results, we concluded that NNC 55-0396 dose-dependently inhibits K V currents, independently of Ca 2+ -channel activity and intracellular signaling cascades.

The selective serotonin reuptake inhibitor dapoxetine inhibits voltage‐dependent K+ channels in rabbit coronary arterial smooth muscle cells

“…For example, several protein kinase modulators, such as LY 294002 (a PI3 kinase inhibitor), H‐89 (a protein kinase A inhibitor), genistein (a tyrosine kinase inhibitor), bisindolylmaleimide (I) (a protein kinase C inhibitor), YC‐1 (a guanylyl cyclase activator), and Y‐27632 (a Rho‐associated protein kinase inhibitor), have been shown to inhibit vascular Kv channels without affecting their own function . In addition, Ca 2+ channel inhibitors, including verapamil, mibefradil, efonidipine, and NNC 55‐0396, directly inhibit vascular Kv channels independent of Ca 2+ channel inhibition . Calmodulin inhibitors, such as trifluoperazine, W‐7, and CGS 9343B, have also been reported to inhibit the vascular Kv current irrespective of calmodulin inhibition .…”

W-7 inhibits voltage-dependent K+ channels independent of calmodulin activity in rabbit coronary arterial smooth muscle cells

“…However, similar to W-7, several chemicals have been reported to affect the Kv channels besides their own functions. The Ca 2þ channel inhibitors verapamil, efonidipine, mibefradil, and NNC 55-0396 directly inhibited vascular Kv channels (Park et al, 2013;Ko et al, 2010aKo et al, , 2010bHong et al, 2012;Son et al, 2014). Several kinase inhibitors, such as LY 294002 (a PI3 kinase inhibitor), bisindolylmaleimide (I) (a protein kinase C Tail current was elicited by 30-50 ms short depolarizing step pulses between À 80 and þ 60 mV in steps of 10 mV at a holding potential of À 80 mV.…”

The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

“…For example, inhibitors of PKC (bisindolylmaleimide (I) and staurosporine), protein kinase A (PKA; H-89), tyrosine kinase (genistein), and PI3 kinase (LY 294002) directly inhibit vascular Kv channels, independent of their own functions (Park et al, 2005a,b;Son et al, 2006;Ko et al, 2009;Hong et al, 2013). Several Ca 2+ channel inhibitors, such as verapamil, efonidipine, mibefradil, and NNC 55-0396, also inhibited Kv channel in vascular smooth muscle cells Ko et al, 2010;Park et al, 2013;Son et al, 2014). Considering the physiological relevance of vascular Kv channels and the Ca 2+ /calmodulin-dependent signaling cascade, the effect of CGS 9343B on Kv channels should be considered when using CGS 9394B in vascular function studies.…”