sepiapterin and Obesity

Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and L-citrulline (L-Cit) is converted to endothelial nitric oxide synthase substrate, L-arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice.. Db/db and C57BLKS/J mice at 6 to 8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and ± dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice.. Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway.

Topics: Age Factors; Animals; Biopterins; Cardiotonic Agents; Cells, Cultured; Citrulline; Coronary Circulation; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Endothelial Cells; Isolated Heart Preparation; Mice, Inbred C57BL; Mice, Obese; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Phosphorylation; Protein Multimerization; Pterins; Time Factors; Vasodilation; Ventricular Function, Left

The aim of this study was to investigate aerobic exercise training as a means to prevent erectile dysfunction (ED) and coronary artery disease (CAD) development associated with inactivity and diet-induced obesity. Male Sprague-Dawley rats were fed a Western diet (WD) or a control diet (CD) for 12 wk. Subgroups within each diet remained sedentary (Sed) or participated in aerobic interval treadmill running throughout the dietary intervention. Erectile function was evaluated under anesthesia by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, in the absence or presence of either apocynin, an NADPH oxidase inhibitor, or sepiapterin, a tetrahydrobiopterin precursor. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of ACh applied to preconstricted segments of the left anterior descending coronary artery. CAEF was assessed in the absence or presence of apocynin or sepiapterin. Erectile function (P < 0.0001) and CAEF (P < 0.001) were attenuated in WD-Sed. Exercise preserved erectile function (P < 0.0001) and CAEF (P < 0.05) within the WD. Erectile function (P < 0.01) and CAEF (P < 0.05) were augmented by apocynin only in WD-Sed, while sepiapterin (P < 0.05) only augmented erectile function in WD-Sed. These data demonstrate that a chronic WD induces impairment in erectile function and CAEF that are commonly partially reversible by apocynin, whereas sepiapterin treatment exerted differential functional effects between the two vascular beds. Furthermore, exercise training may be a practical means of preventing diet-induced ED and CAD development.

Topics: Acetophenones; Animals; Biopterins; Coronary Artery Disease; Coronary Vessels; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Exercise Therapy; Male; NADPH Oxidases; Obesity; Oxidative Stress; Penile Erection; Pterins; Rats; Rats, Sprague-Dawley; Sedentary Behavior; Time Factors; Vasodilation; Vasodilator Agents