Hypersensitivity of BK _Ca to Ca ²⁺ Sparks Underlies Hyporeactivity of Arterial Smooth Muscle in Shock

Abstract

Abstract-Large conductance Ca 2ϩ -activated K ϩ channels (BK Ca ) play a critical role in blood pressure regulation by tuning the vascular smooth muscle tone, and hyposensitivity of BK Ca to Ca 2ϩ sparks resulting from its altered ␤1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BK Ca to Ca 2ϩ sparks that contributes to hypotension and blunted vasoreactivity in acute hemorrhagic shock. In arterial smooth muscle cells under voltage-clamp conditions (0 mV), the amplitude and duration, but not the frequency, of spontaneous transient outward currents of BK Ca origin were markedly enhanced in hemorrhagic shock, resulting in a 265% greater hyperpolarizing current. Concomitantly, subsurface Ca 2ϩ spark frequency was either unaltered (at 0 mV) or decreased in hyperpolarized resting cells. Examining the relationship between spark and spontaneous transient outward current amplitudes revealed a hypersensitive BK Ca activity to Ca 2ϩ spark in hemorrhagic shock, whereas the spark-spontaneous transient outward current coupling fidelity was near unity in both groups. Importantly, we found an acute upregulation of the ␤1 subunit of the channel, and single-channel recording substantiated BK Ca hypersensitivity at micromolar Ca 2ϩ , which promotes the ␣ and ␤1 subunit interaction. Treatment of shock animals with the BK Ca inhibitors iberiotoxin and charybdotoxin partially restored vascular membrane potential and vasoreactivity to norepinephrine and blood reinfusion. Thus, the results underscore a dynamic regulation of the BK Ca -Ca 2ϩ spark coupling and its therapeutic potential in hemorrhagic shock-associated vascular disorders. sparks beneath the plasma membrane activate 10 to 100 large conductance Ca 2ϩ -activated K ϩ channels (BK Ca ) in the adjacent sarcolemma and elicit the discharge of spontaneous transient outward currents (STOCs), resulting in membrane hyperpolarization and, subsequently, dilation of vascular smooth muscle. 3,4 Recent studies have revealed that the coupling between sparks and STOCs can continuously regulate, by negative feedback, the vascular tone in intact arteries. 5-8 Furthermore, it has been recently shown that the spark-STOC coupling efficiency is altered during hypertension, because of modulation of the subunit stoichiometry of BK Ca in vascular smooth muscle. 5 Severe shock is well characterized by a sequence of events, including release of endogenous vasoconstrictors, delayed vascular decompensation, and refractory hypotension that is defined as a progressive vasodilatation, as well as a continuous decrease in peripheral vascular resistance resulting in death, despite augmentation of sympathetic nervous activity or treatment with vasoconstrictors. 9 Various factors, such as ␣-adrenoceptor desensitization, metabolic acidosis, cytokine release, transcription factor activation, endothelial cell (EC) damage, and overproduction of nitric oxide (NO) have been shown to be involved in this process. 10 -13 Nevertheless, the ...

Nitric-Oxide Synthase Knockout Modulates Ca2+-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries

“…In smooth muscle cells, the BK channel contributes to vascular tone by facilitating feedback regulation against an increase in [Ca 21 ] i , membrane depolarization, and vasoconstriction, thus promoting a K 1 outward current leading to membrane hyperpolarization (Zhao et al, 2007). The current findings suggest that NO from eNOS may interact with PvN CaSR signaling that leads to BK channel activation to reduce hyperpolarization of smooth muscle cells and cause relaxation.…”

Exercise Prevents Upregulation of RyRs–BK Ca Coupling in Cerebral Arterial Smooth Muscle Cells From Spontaneously Hypertensive Rats

“…18,30 The Ca 2+ spark-BK Ca coupling is changed in some vascular disorders; which has made the sparks a therapeutic target. [31][32][33] Their frequency and properties, that is, amplitude, mean rise rate, and decay halftime, are used as markers of in situ RyR activity. The results showed that the amplitude of the Ca 2+ sparks was significantly higher in SHRs, with little change in the frequency of sparks.…”

Stoking Up BK Ca Channels in Hemorrhagic Shock

“…Although the new findings of Zhao and colleagues elegantly support a role for the ␤1 subunit in HS, 15 we would modify their scheme to include that Slo probably also enhances Ca 2ϩ -senstivity of BK Ca (see Figure above). On a cautionary note, whether these mechanisms translate into the in vivo situation remains inconclusive because endothelial-derived factors or circulating hormones could well alter how BK Ca…”

“…13,14 In this issue, Zhao and colleagues investigate the mechanism by which BK Ca are enhanced in acute hemorrhagic shock (HS). 15 They tested the hypothesis that increased ␤1-subunit expression is responsible for enhanced coupling of Ca 2ϩ sparks to BK Ca , and this contributes to vascular hyporeactivity and hypotension in HS. …”