There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O₂⁻) production than young. Acute inhibition of both NOS, with N^G-nitro-l-arginine methyl ester, and arginase, with 2( S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O₂⁻ production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O₂⁻ production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

Rationale : Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S -nitrosylation in young vessels, a process that is reversed in aging. Objective : We sought to determine whether endothelium-dependent NO regulates TG2 activity by S -nitrosylation and whether this contributes to age-related vascular stiffness. Methods and Results : We first demonstrate that NO suppresses activity and increases S -nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix–associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2 ^−/− mice chronically treated with the NOS inhibitor l - N ^G -nitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S -nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged. Conclusions : Decreased S -nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension.

BACKGROUND: The optimal regional technique for analgesia and improved quality of recovery after video-assisted thoracic surgery (a procedure associated with considerable postoperative pain) has not been established. The main objective in this study was to compare quality of recovery in patients undergoing serratus plane block (SPB) with either ropivacaine or normal saline on the first postoperative day. Secondary outcomes were analgesic outcomes, including postoperative pain intensity and opioid consumption. METHODS: Ninety patients undergoing video-assisted thoracic surgery were randomized to receive ultrasound-guided SPB with 0.4 mL/kg of either 0.375% ropivacaine (SPB group) or normal saline (control group) after anesthetic induction. The primary outcome was the 40-item Quality of Recovery (QoR-40) score at 24 hours after surgery. The QoR-40 questionnaire was completed by patients the day before surgery and on postoperative days 1 and 2. Pain scores, opioid consumption, and adverse events were assessed for 2 days postoperatively. RESULTS: Eighty-five patients completed the study: 42 in the SPB group and 43 in the control group. The global QoR-40 scores on both postoperative days 1 and 2 were significantly higher in the SPB group than in the control group (estimated mean difference 8.5, 97.5% confidence interval [CI], 2.1–15.0, and P = .003; 8.5, 97.5% CI, 2.0–15.1, and P = .004, respectively). The overall mean difference between the SPB and control groups was 8.5 (95% CI, 3.3–13.8; P = .002). Pain scores at rest and opioid consumption were significantly lower up to 6 hours after surgery in the SPB group than in the control group. Cumulative opioid consumption was significantly lower up to 24 hours postoperatively in the SPB group. CONCLUSIONS: Single-injection SPB with ropivacaine enhanced the quality of recovery for 2 days postoperatively and improved postoperative analgesia during the early postoperative period in patients undergoing video-assisted thoracic surgery.

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.

Chronic obstructive pulmonary disease (COPD) is a risk factor that increases the incidence of postoperative cardiopulmonary morbidity and mortality after lung resection. Dexmedetomidine, a selective α2-adrenoreceptor agonist, has been reported previously to attenuate intrapulmonary shunt during one-lung ventilation (OLV) and to alleviate bronchoconstriction. The objective is to determine whether dexmedetomidine improves oxygenation and lung mechanics in patients with moderate COPD during lung cancer surgery. A randomised, double-blinded, placebo-controlled study. Single university hospital. Fifty patients scheduled for video-assisted thoracoscopic surgery who had moderate COPD. Patients were randomly allocated to a control group or a Dex group (n = 25 each). In the Dex group, dexmedetomidine was given as an initial loading dose of 1.0 μg kg(-1) over 10 min followed by a maintenance dose of 0.5 μg kg(-1) h(-1) during OLV while the control group was administered a comparable volume of 0.9% saline. Data were measured at 30 min (DEX-30) and 60 min (DEX-60) after dexmedetomidine or saline administration during OLV. The primary outcome was the effect of dexmedetomidine on oxygenation. The secondary outcome was the effect of dexmedetomidine administration on postoperative pulmonary complications. Patients in the Dex group had a significantly higher PaO2/FIO2 ratio (27.9 ± 5.8 vs. 22.5 ± 8.4 and 28.6 ± 5.9 vs. 21.0 ± 9.9 kPa, P < 0.05), significantly lower dead space ventilation (19.2 ± 8.5 vs. 24.1 ± 8.1 and 19.6 ± 6.7 vs. 25.3 ± 7.8%, P < 0.05) and higher dynamic compliance at DEX-30 and DEX-60 (P = 0.0001 and P = 0.0184) compared with the control group. In the Dex group, the PaO2/FIO2 ratio in the postoperative period was significantly higher (P = 0.022) and the incidence of ICU admission was lower than in the control group. Dexmedetomidine administration may provide clinically relevant benefits by improving oxygenation and lung mechanics in patients with moderate COPD undergoing lung cancer surgery. ClinicalTrial.gov identifier: NCT 02185430.