Apelin-13 Inhibits Large-Conductance Ca2+-Activated K+ Channels in Cerebral Artery Smooth Muscle Cells via a PI3-Kinase Dependent Mechanism

Abstract

Apelin-13 causes vasoconstriction by acting directly on APJ receptors in vascular smooth muscle (VSM) cells; however, the ionic mechanisms underlying this action at the cellular level remain unclear. Large-conductance Ca2+-activated K+ (BKCa) channels in VSM cells are critical regulators of membrane potential and vascular tone. In the present study, we examined the effect of apelin-13 on BKCa channel activity in VSM cells, freshly isolated from rat middle cerebral arteries. In whole-cell patch clamp mode, apelin-13 (0.001-1 μM) caused concentration-dependent inhibition of BKCa in VSM cells. Apelin-13 (0.1 µM) significantly decreased BKCa current density from 71.25±8.14 pA/pF to 44.52±7.10 pA/pF (n=14 cells, P<0.05). This inhibitory effect of apelin-13 was confirmed by single channel recording in cell-attached patches, in which extracellular application of apelin-13 (0.1 µM) decreased the open-state probability (NPo) of BKCa channels in freshly isolated VSM cells. However, in inside-out patches, extracellular application of apelin-13 (0.1µM) did not alter the NPo of BKCa channels, suggesting that the inhibitory effect of apelin-13 on BKCa is not mediated by a direct action on BKCa. In whole cell patches, pretreatment of VSM cells with LY-294002, a PI3-kinase inhibitor, markedly attenuated the apelin-13-induced decrease in BKCa current density. In addition, treatment of arteries with apelin-13 (0.1 µM) significantly increased the ratio of phosphorylated-Akt/total Akt, indicating that apelin-13 significantly increases PI3-kinase activity. Taken together, the data suggest that apelin-13 inhibits BKCa channel via a PI3-kinase-dependent signaling pathway in cerebral artery VSM cells, which may contribute to its regulatory action in the control of vascular tone.

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

“…This is consistent with studies showing that apelin-induced endothelium-dependent vasorelaxation is attenuated by coadministration of nitro-Larginine methyl ester, suggesting an endothelium-derived nitric oxide-dependent mechanism (24). However, apelin may also induce vasoconstriction via its direct effects on vascular smooth muscle cells (24,26,28,39). Studies investigating vascular actions of apelin in pregnancy are necessary to elucidate the role and mechanisms of action of this peptide in maternal and fetal vasculature.…”

Apelin/APJ system: a promising therapy target for hypertension

“…In our lab, we also validated that apelin exhibits a strong vasodilation depend on endothelium-dependent manner, yet in ex vivo vascular rings of spontaneous hypertensive rat (SHR), the effect of apelin on vasodilation was attenuated, and moreover, present contraction the vascular rings as the NO pathway disordered [20]. The ionic mechanism of apelin on vasoconstriction have been studied by Modgil et al [21], they stated that apelin-13 via a phosphorylation phosphoinositide 3 kinase (PI3K)-dependent signaling pathway to inhibit large-conductance Ca (2?) -activated K (?)…”

“…Combined with previous discussion, we can confer that apelin/APJ system inhibits sodium retention by the regulation of AVP release, RAS activation and NO production to improve hypertension. However, the above discussion result have presented that central apelin could increase SNS activity [21], which would further enhance sodium retention, and the ambiguity role of apelin on AVP release also need a uniform interpretation. In generally, the exactly effect of apelin/APJ system on sodium retention caused hypertension may be according to the main contributor of sodium retention.…”

The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

“…For example, activating the apelin/APJ axis induces endothelium-and NO-dependent peripheral arterial relaxation (69,70). However, apelin/APJ signal can inhibit NO-induced cerebral artery relaxation by blocking calcium-activated K (BK Ca ) channels in male rats, which can be mediated by a PI3K/AKT-dependent signaling pathway (71,72). Meanwhile, the specific effect of apelin on oxidative/nitrosative stresses in ischemic stroke remains to be further determined.…”