Effects of a 12-week workplace counseling program on physical activity and low back pain: A pilot randomized controlled study.

BACKGROUND: Physical activity (PA) is essential in the management and rehabilitation of low back pain (LBP). However, it is not clear that PA interventions in the workplace can improve LBP. OBJECTIVE: This study aimed to investigate the effects of workplace counseling on PA and LBP among workers. METHODS: We recruited 37 people with 12 weeks of LBP who worked in a manufacturing company in Aichi, Japan. Participants were randomly assigned to the intervention (n= 20) or control group (n= 17). All participants of both groups were affixed with waist-worn accelerometers to monitor PA. The intervention group also received a program of face-to-face counseling with a physical therapist or nurse once a week for 12 weeks to reassure and encourage participants to maintain a high level of PA. PA and LBP severity were assessed at baseline, 3 and 6 months. RESULTS: PA was significantly higher in the intervention group than in the control group at 3 and 6 months. In the intervention group, PA significantly increased at 3 and 6 months from baseline, and LBP severity at 6 months improved significantly from baseline. CONCLUSIONS: Our data suggest that workplace PA intervention can increase PA and improve LBP among workers.

Involvement of Gi protein-dependent BKCa channel activation in ß2-adrenoceptor-mediated dilation of retinal arterioles in rats.

Circulating catecholamines contribute to the regulation of retinal vascular tone. Our previous studies have demonstrated that the activation of large-conductance Ca2+-activated K+ (BKCa) channels is involved in the ß2-adrenoceptor-mediated dilation of retinal arterioles in rats. The present study aimed to examine the role of Gi protein in the ß2-adrenoceptor-mediated activation of BKCa channels in the retinal arterioles. Images of in vivo rat ocular fundi were captured, and the diameters of retinal arterioles were measured. Systemic blood pressure and heart rate were recorded continuously. Intravenous infusion of formoterol (0.01-0.3 µg/kg/min), a ß2-adrenoceptor agonist, increased the diameter of retinal arterioles but decreased mean arterial pressure in a dose-dependent manner. Intravitreal injection of iberiotoxin (20 pmol/eye), an inhibitor of BKCa channels, significantly attenuated the formoterol-induced dilation of retinal arterioles. Similar results were obtained when salbutamol (0.03-3 µg/kg/min), another ß2-adrenoceptor agonist, was used instead of formoterol. However, iberiotoxin had no significant effect on retinal vasodilator responses to intravenous infusion of denopamine (1-30 µg/kg/min; a ß1-adrenoceptor agonist), CL316243 (0.3-10 µg/kg/min; a ß3-adrenoceptor agonist), prostaglandin I2 (0.03-10 µg/kg/min; a prostanoid IP receptor agonist), and forskolin (1-10 µg/kg/min; an adenylyl cyclase activator). Intravitreal injection of pertussis toxin (66 ng/eye; a Gi protein inhibitor) significantly attenuated the dilation of retinal arterioles induced by formoterol but not by denopamine and CL316243. In the presence of pertussis toxin, iberiotoxin had no inhibitory effect on formoterol-induced dilation of retinal arterioles. These results suggest that stimulation of ß2-adrenoceptors dilates retinal arterioles through pertussis toxin-sensitive Gi protein-dependent activation of BKCa channels in rats in vivo.

Co-treatment with clonidine and a GRK2 inhibitor prevented rebound hypertension and endothelial dysfunction after withdrawal in diabetes.

Hypertension and diabetes are associated with a risk of cardiovascular disease. Clonidine is currently used as a fourth-line drug therapy for hypertension because of its rebound hypertensive effect and short half-life. The purpose of this study was to investigate the combined effect of an antihypertensive drug (clonidine) and a G-protein-coupled receptor kinase 2 (GRK2) inhibitor on rebound hypertension and endothelial dysfunction. The clonidine and/or GRK2 inhibitor were administered by continuous infusion for 14 days by using an osmotic pump that was implanted subcutaneously. To test the effects of GRK2 inhibitotr, we measured blood pressure by using a tail-cuff system in diabetic mice in which rebound hypertension was induced by withdrawal after clonidine treatment and measured vascular responses in isolated aortas from these mice. The mice were then euthanized 7 days later. We observed that, in diabetes mellitus (DM) mice, blood pressure began to decline after 3 days of clonidine or clonidine + GRK2-inhibitor infusion. However, 15 days after initiation of treatment, the blood pressure of the clonidine only-treated DM mice began to increase and resulted in a high final blood pressure. At 21 days, clonidine withdrawal triggered rebound hypertension together with impaired endothelium-dependent relaxation, increased GRK2 activity, and reduced Akt/endothelial NO synthase (eNOS)/NO production in aortas. Conversely, withdrawal of the combination clonidine/GRK2-inhibitor treatment did not cause rebound hypertension, and normal induction of endothelium-dependent relaxation, decreased GRK2 activity, and increased Akt/eNOS were observed in aortas from DM mice. These results suggest that suppression of GRK2 activity affects rebound hypertension-associated vascular endothelial dysfunction by targeting the Akt/eNOS signaling pathway.

Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis.

Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver. Suppressed GRK2 levels in the liver markedly improved glucose homeostasis, as well as improved the impaired endothelial Akt/eNOS-dependent signal activation (insulin-stimulated phosphorylation of Akt and eNOS) and vascular responses (clonidine-induced and insulin-induced endothelial-dependent relaxation response and phenylephrine-induced contractile response) in type 2 diabetic aortas. Interestingly, insulin-stimulated Akt/eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2. Our results clarified the relationship among hepatic GRK2, glucose homeostasis, and vascular endothelial function. Liver-targeting GRK2 siRNA delivery represents a novel therapeutic tool to restore glucose homeostasis and reduce endothelial dysfunction.

Dietary polyphenol morin rescues endothelial dysfunction in a diabetic mouse model by activating the Akt/eNOS pathway.

SCOPE: Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications. Polyphenols may represent beneficial dietary components eliciting cardiovascular protection. Although we previously reported that the polyphenol morin (MO) ameliorated diabetes-induced endothelial dysfunction, the underlying mechanism remains unclear. Here, we investigated protective effects and mechanisms of MO in streptozotocin STZ induced diabetic aorta endothelial dysfunction. METHODS AND RESULTS: Diabetes was induced by tail vein injection of STZ (200 mg/kg). At 12 wk after injection, the thoracic aorta was isolated and endothelial function was assessed by acetylcholine (ACh) induced, endothelial-dependent vasorelaxation in aortas. Nitric oxide (NO) levels and endothelial NO synthase (eNOS), phosphorylated-eNOS (p-eNOS), Akt, and phosphorylated-Akt (p-Akt) levels were also evaluated in aortas. Diabetic aortas showed attenuated endothelial function, which was improved by MO treatment. MO treatment alone increased NO levels and endothelial-dependent relaxation responses via Akt signaling, although ACh did not activate this pathway. Moreover, MO upregulated p-Akt (at Ser473 and Thr308) and p-eNOS (at Ser1177) expression in diabetic aortas, but ACh stimulation had no effect on p-Akt and p-eNOS levels. CONCLUSION: These results indicate a novel role for MO in protection against endothelial dysfunction in diabetes. The protective effects of MO are dependent on Akt-dependent activation of eNOS signaling.