Ca2+-activated K+ channels of small and intermediate conductance control eNOS activation through NAD(P)H oxidase

TRAM-34, a Putatively Selective Blocker of Intermediate-Conductance, Calcium-Activated Potassium Channels, Inhibits Cytochrome P450 Activity

“…For example, numerous previous in vitro studies have used TRAM-34 at concentrations ≥10 µM [20], [29]–[39]. At these concentrations, some CYP isoforms are clear targets of TRAM-34.…”

Control and Coordination of Vasomotor Tone in the Microcirculation

“…However, NOS inhibition with analogues of L-arginine is a slow, timedependent process and, on occasion, blockade of NO production with these drugs has been observed to be incomplete (Vanheel & Van de Voorde, 2000;Figueroa et al, 2001;Stoen et al, 2003;Stankevicius et al, 2006), and then, the residual NO production observed in presence of NOS inhibitors may contribute to the vasodilation associated with the smooth muscle hyperpolarization attributes to EDHF. In addition, the findings reported recently by Gaete et al (Gaete et al, 2011) are another important point to take into account in the interaction between EDHF and NO. In this work Gaete et al, demonstrated that SK Ca and IK Ca channels control the Ca 2+ -dependent NO release, and thereby, the inactivation of these K + channels is associated with an increase in NAD(P)H oxidase-mediated superoxide production, which leads to the inhibition of eNOS primarily by its phosphorylation at threonine 495 (Gaete et al, 2011).…”

“…In addition, the findings reported recently by Gaete et al (Gaete et al, 2011) are another important point to take into account in the interaction between EDHF and NO. In this work Gaete et al, demonstrated that SK Ca and IK Ca channels control the Ca 2+ -dependent NO release, and thereby, the inactivation of these K + channels is associated with an increase in NAD(P)H oxidase-mediated superoxide production, which leads to the inhibition of eNOS primarily by its phosphorylation at threonine 495 (Gaete et al, 2011). These findings highlight the relevance of these K + channels in the control of vascular function and indicate that the participation of superoxide in the EDHF-mediated response associated to SK Ca and IK Ca channels must be evaluated.…”

Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A

“…In that study, a significant decrease in Ca 2ϩ -activated K ϩ (K Ca ) channel current and mRNA and protein expression was observed in aortic endothelial cells from Gla-deficient mice and WT mice treated with Gb3. Also, pharmacological blockade of the small-and intermediate-conductance K Ca channels has been demonstrated to increase superoxide formation and enhance eNOS phosphorylation at Thr 495 without changes in the total eNOS protein levels (10). Thus Gb3 accumulation may lead to the earlier onset and profound endothelial dysfunction through direct effects on K Ca channel activity and an endothelial plasma membrane defect, which results in impaired or altered signaling of multiple endothelium-dependent relaxing factors, including NO and endothelium-derived hyperpolarizing factor.…”