Intermittent Hypoxia in Rats Increases Myogenic Tone Through Loss of Hydrogen Sulfide Activation of Large-Conductance Ca ²⁺ -Activated Potassium Channels

Abstract

Rationale Myogenic tone, an important regulator of vascular resistance, is dependent on vascular smooth muscle (VSM) depolarization, can be modulated by endothelial factors, and is increased in several models of hypertension. Intermittent hypoxia (IH) elevates blood pressure and causes endothelial dysfunction. Hydrogen sulfide (H2S), a recently described endothelium-derived vasodilator, is produced by the enzyme cystathionine γ-lyase (CSE) and acts by hyperpolarizing VSM. Objective Determine whether IH decreases endothelial H2S production to increase myogenic tone in small mesenteric arteries. Methods and Results Myogenic tone was greater in mesenteric arteries from IH than Shamfrom sham rat arteries, and VSM membrane potential was depolarized in IH in comparison with Shamsham arteries. Endothelium inactivation or scavenging of H2S enhanced myogenic tone in Shamsham arteries to the level of IH. Inhibiting CSE also enhanced myogenic tone and depolarized VSM in Shamsham but not IH arteries. Similar results were seen in cerebral arteries. Exogenous H2S dilated and hyperpolarized Shamsham and IH arteries, and this dilation was blocked by iberiotoxin, paxilline, and KCl preconstriction but not glibenclamide or 3-isobutyl-1-methylxanthine. Iberiotoxin enhanced myogenic tone in both groups but more in Shamsham than IH. CSE immunofluorescence was less in the endothelium of IH than in Shamsham mesenteric arteries. Endogenouse H2S dilation was reduced in IH arteries. Conclusions IH appears to decrease endothelial CSE expression to reduce H2S production, depolarize VSM, and enhance myogenic tone. H2S dilatation and hyperpolarization of VSM in small mesenteric arteries requires BKCa channels.

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

“…Under these conditions, NaHS induced a robust dilation (ϳ70%) at relatively low concentrations (1 mol/l), whereas in arteries pressurized to 60 mmHg luminal pressure, NaHS elicited a much smaller dilation (7). This enhanced H 2 S-induced vasodilation with increasing luminal pressure is consistent with H 2 S acting as a hyperpolarizing agent and an endogenous inhibitor of myogenic tone (7,15). That is, since increasing luminal pressure stimulates VSMC depolarization and myogenic tone, H 2 S-induced vasodilation is amplified at higher pressures, perhaps due to enhanced spark-hyperpolarization coupling at these pressures.…”

“…As noted above, some studies suggest H 2 S activates the channel (7,15,17,28,34), whereas others find H 2 S inhibits BK Ca activity (13,30,31). Because the cell types in these two groups of studies do not overlap, it is possible that tissue-specific expression of subunits or other associated proteins modify the effect of H 2 S on BK Ca channels.…”

“…This hypothesized pathway explains several apparently disparate observations of H 2 S dilation in small arteries. Specifically, it has been observed that H 2 S 1) activates BK Ca channels in microvascular EC (34); 2) increases microvascular EC [Ca 2ϩ ] (22); 3) dilates perfused mesenteric beds in a cytochrome P-450, K Ca channel, and EC-dependent manner (2,3,3); and 4) hyperpolarizes small mesenteric artery VSMC E m in a BK Ca -dependent manner (7). In this model, EC BK Ca channels are the primary target of H 2 S in small mesenteric arteries.…”

Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries

“…Although opening of K ATP channels has been widely accepted as a main mechanism underlying H 2 S-induced vasorelaxation, some studies have found only a small or no involvement of K ATP channels (Kubo et al, 2007;Kiss et al, 2008;Cheang et al, 2010). Other potassium channels (K channels) have also been reported to play a role in H 2 S relaxation such as voltage-gated K channels (Cheang et al, 2010), K V 7 channels (Schleifenbaum et al, 2010;Martelli et al, 2013;Hedegaard et al, 2014), and large conductance calcium-activated potassium channels (BK Ca ) (Jackson-Weaver et al, 2011Li et al, 2012). It has been shown that the H 2 S donors NaHS and Na 2 S activate calcium sparks (Liang et al, 2012;Jackson-Weaver et al, 2013) and also that they reduce global [Ca 21 ] in cerebral arterioles (Liang et al, 2012).…”

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

“…Whereas maintenance of CIH-induced hypertension is generally agreed to depend on increased systemic vascular resistance, the underlying mechanisms are complex and involve changes in vascular reactivity (1,(22)(23)(24)47) as well as chronically elevated sympathetic nerve activity (SNA) (16,32,60). The latter has been strongly linked to sensitization of the arterial chemoreflex (15,32,45,50,67), which results in tonic activation of sympathetic outflow even at normoxic arterial PO 2 .…”