H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that increased generation of reactive oxygen species (ROS) in the carotid body enhances the chemosensory reflex and triggers hypertension. CO generated by heme oxygenase-2 (HO-2) induces a signaling pathway that inhibits hydrogen sulfide (H2S) production by cystathionine γ-lyase (CSE), leading to suppression of carotid body activity. We found that ROS inhibited CO generation by HO-2 in the carotid body and liver through a mechanism that required Cys(265) in the heme regulatory motif of heterologously expressed HO-2. We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations in the carotid body, which stimulated its neural activity. In rodents, blockade of H2S synthesis by CSE, by either pharmacologic or genetic approaches, inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, our results indicate that oxidant-induced inactivation of HO-2, which leads to increased CSE-dependent H2S production in the carotid body, is a critical trigger of hypertension in rodents exposed to intermittent hypoxia.

Combined direct and indirect bypass for moyamoya: quantitative assessment of direct bypass flow over time.

BACKGROUND: The optimal revascularization strategy for symptomatic adult moyamoya remains controversial. Whereas direct bypass offers immediate revascularization, indirect bypass can effectively induce collaterals over time. OBJECTIVE: Using angiography and quantitative magnetic resonance angiography, we examined the relative contributions of direct and indirect bypass in moyamoya patients after combined direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass and indirect encephaloduroarteriosynangiosis (EDAS). METHODS: A retrospective review of moyamoya patients undergoing combined STA-MCA bypass and EDAS was conducted, excluding pediatric patients and hemorrhagic presentation. Patients with quantitative magnetic resonance angiography measurements of the direct bypass immediately and > 6 months postoperatively were included. Angiographic follow-up, when available, was used to assess EDAS collaterals at similar time intervals. RESULTS: Of 16 hemispheres in 13 patients, 11 (69%) demonstrated a significant (> 50%) decline in direct bypass flow at > 6 months compared with baseline, averaging a drop from 99 ± 35 to 12 ± 7 mL/min. Conversely, angiography in these hemispheres demonstrated prominent indirect collaterals, in concert with shrinkage of the STA graft. Decline in flow was apparent at a median of 9 months but was evident as early as 2 to 3 months. CONCLUSION: In this small cohort, a reciprocal relationship between direct STA bypass flow and indirect EDAS collaterals frequently occurred. This substantiates the notion that combined direct/indirect bypass can provide temporally complementary revascularization.

The selective M1 muscarinic cholinergic agonist CDD-0102A enhances working memory and cognitive flexibility.

Various neurodegenerative diseases and psychiatric disorders are marked by alterations in brain cholinergic function and cognitive deficits. Efforts to alleviate such deficits have been limited by a lack of selective M(1) muscarinic agonists. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A) is a partial agonist at M(1) muscarinic receptors with limited activity at other muscarinic receptor subtypes. The present studies investigated the effects of CDD-0102A on working memory and strategy shifting in rats. CDD-0102A administered intraperitoneally 30 min before testing at 0.1, 0.3, and 1 mg/kg significantly enhanced delayed spontaneous alternation performance in a four-arm cross maze, suggesting improvement in working memory. In separate experiments, CDD-0102A had potent enhancing effects on learning and switching between a place and visual cue discrimination. Treatment with CDD-0102A did not affect acquisition of either a place or visual cue discrimination. In contrast, CDD-0102A at 0.03 and 0.1 mg/kg significantly enhanced a shift between a place and visual cue discrimination. Analysis of the errors in the shift to the place or shift to the visual cue strategy revealed that in both cases CDD-0102A significantly increased the ability to initially inhibit a previously relevant strategy and maintain a new, relevant strategy once selected. In anesthetized rats, the minimum dose required to induce salivation was approximately 0.3 mg/kg i.p. Salivation increased with dose, and the estimated ED(50) was 2.0 mg/kg. The data suggest that CDD-0102A has unique memory and cognitive enhancing properties that might be useful in the treatment of neurological disorders at doses that do not produce adverse effects such as salivation.