Abstract-Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endotheliumdependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-␣ and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-␣, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. 1 Hypertension can cause renal damage if it is not properly controlled.2 The impaired vasodilator response is a risk factor for renal function loss in patients with essential hypertension.3 Persistent hypertension alters functional characteristics of vascular endothelial cells and is associated with impaired vasodilatory function.4 Diminished production and function of endothelium-derived NO leads to endothelial dysfunction, 5 a crucial initial step culminating in vascular events in hypertension.Dipeptidyl peptidase 4 (DPP-4), also known as CD26, is a ubiquitous enzyme detectable in the endothelium.6 Glucagonlike peptide 1 (GLP-1) produced by L-type cells in the intestine, is a substrate for DPP-4. 7 GLP-1 improves glucose use in patients with type 2 diabetes mellitus by increasing insulin secretion and inhibiting glucagon secretion. 8,9 Sitagliptin, a highly selective DPP-4 inhibitor, 10 inhibits the inactivation and degradation of GLP-1, 11 which is used for the treatment of type 2 diabetes mellitus as monotherapy or in combination with other antiglycemic agents, such as metformin. 12The effect of GLP-1 on blood pressure has been reported in both animal and human hypertension.

Abstract-Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8 −/− mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flowmediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/ Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had Materials and Methods Animal TreatmentWe obtained male spontaneously hypertensive rats (SHR) and WistarKyoto rats (WKY) from Charles Rivers Laboratories (Malvern, PA) and obtained TRPM8 −/− mice from the laboratory of Dr Patapoutian. 6To maintain an isogenic strain, heterozygous knockout mice and their wild type (WT) littermates were maintained and used for experiments, as previously described 7 (online-only Data Supplement). Cell CultureVascular smooth muscle cells (VSMCs) were obtained from the thoracic aortas of mice and cultured by the tissue explant method, as previously described 14 (online-only Data Supplement). Intracellular Calcium MeasurementsFluorescence measurements were performed at 510 nm emission, with excitation wavelengths of 340 and 380 nm (Fluoroskan Ascent Fluorometer; Thermo Helsinki, Finland; online-only Data Supplement). Blood Pressure MeasurementAnimals were implanted surgically with telemetric transmitters (Data Sciences International, MN), and 24-hour ambulatory systolic and diastolic pressures were measured by telemetry in conscious unrestrained animals 16 (online-only Data Supplement). Prehypertensive Participant CharacteristicsPrehypertensive participants aged between 45 to 65 years were included in this study. The prehypertension diagnosis was based on systolic blood pressure (SBP) of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg (online-only Data Supplement). Flow-Mediated VasodilationFlow-mediated vasod...

BackgroundDiabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect.MethodsTRPV1-/-, UCP2 -/- and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed.ResultsUnder high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2 -/- mice exposed to high-glucose levels.ConclusionTRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.