Novel role of endothelial BK_Ca channels in altered vasoreactivity following hypoxia

Abstract

The systemic vasculature exhibits attenuated vasoconstriction following hypobaric chronic hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle (VSM) cell hyperpolarization. We hypothesized that increased activity of endothelial cell (EC) large-conductance, calcium-activated potassium (BK(Ca)) channels contributes to this response. Gracilis resistance arteries from hypobaric CH (barometric pressure = 380 mmHg for 48 h) rats demonstrated reduced myogenic reactivity and hyperpolarized VSM membrane potential (E(m)) compared with controls under normoxic ex vivo conditions. These differences were eliminated by endothelial disruption. In the presence of cyclooxygenase and nitric oxide synthase inhibition, combined intraluminal administration of the intermediate and small-conductance, calcium-activated K(+) channel blockers TRAM-34 and apamin was without effect on myogenic responsiveness and VSM E(m) in both groups; however, these variables were normalized in CH arteries by intraluminal administration of the BK(Ca) inhibitor iberiotoxin (IBTX). Basal EC E(m) was hyperpolarized in arteries from CH rats compared with controls and was restored by IBTX, but not by TRAM-34/apamin. K(+) channel blockers were without effect on EC basal E(m) in controls. Similarly, IBTX blocked acetylcholine-induced dilation in arteries from CH rats, but was without effect in controls, whereas TRAM-34/apamin eliminated dilation in controls. Acetylcholine-induced EC hyperpolarization and calcium responses were inhibited by IBTX in CH arteries and by TRAM-34/apamin in controls. Patch-clamp experiments on freshly isolated ECs demonstrated greater K(+) current in cells from CH rats that was normalized by IBTX. IBTX was without effect on K(+) current in controls. We conclude that hypobaric CH induces increased endothelial BK(Ca) channel activity that contributes to reduced myogenic responsiveness and EC and VSM cell hyperpolarization.

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

“…Given the greater selectivity of IBTX for BK channels than NS1619 in tissue preparations, we suggest that our previous ex vivo studies (36) using the same model reflect the current findings of enhanced BK channel Ca 2ϩ affinity and activity in the LTH fetus. In a rat model of chronic hypoxia, the hind-limb vascular endothelial BK channel activity increased to reduce myogenic responsiveness and vasoconstriction (21). This hypoxia-induced increase in BK activity was accompanied by increased channel sensitivity to Ca 2ϩ and channel colocalization to caveolin-1 (54), similar to what we found for the LTH fetus in the present study (Figs.…”

Impairment of IKCachannels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy

“…6). Our data are in agreement with reported deficiency of BK Ca channels in mediating Ca 2ϩ -activated currents in ECs freshly dissociated from arteries and arterioles of healthy subjects (17,29,31,46). BK Ca channel function can be induced in ECs during some vascular disease states.…”

“…BK Ca channel function can be induced in ECs during some vascular disease states. For example, increased BK Ca channel activity has been reported in ECs of gracilis resistance arteries after exposure of rats to hypoxia (31). We found no significant effect of paxilline on Ca 2ϩ -activated currents in ECs of diabetic rats.…”

Hydrogen sulfide dilates rat mesenteric arteries by activating endothelial large-conductance Ca2+-activated K+ channels and smooth muscle Ca2+ sparks

“…The demonstration that H 2 S activates EC BK Ca channels (34) led us to test whether EC BK Ca channels were the IbTx-sensitive target of H 2 S in mesenteric arteries. We used luminal application of IbTx to specifically target EC BK Ca channels as previously described (6). Importantly, luminal application of IbTx did not significantly affect VSMC E m although abluminal application of the same concentration depolarized VSMC (Fig.…”