Type 2 diabetic mice have increased arteriolar tone and blood pressure: Enhanced release of COX-2-derived constrictor prostaglandins

Objective - Type 2 diabetes mellitus (T2-DM) is frequently associated with vascular dysfunction and elevated blood pressure, yet the underlying mechanisms are not completely understood. We hypothesized that in T2-DM, the regulation of peripheral vascular resistance is altered because of changes in local vasomotor mechanisms. Methods and Results - In mice with T2-DM (C57BL/KsJ-db ^-/db⁺), systolic and mean arterial pressures measured by the tail cuff method were significantly elevated compared with those of control (db⁺/db^-) animals (db/db, 146±5 and 106±2 mm Hg versus control, 133±4 and 98±4 mm Hg, respectively; P<0.05). Total peripheral resistance, calculated from cardiac output values (measured by echocardiography) and mean arterial pressure were significantly elevated in db/db mice (db/db, 25±6 versus control, 15±1 mm Hg[middot]mL^-1[middot]min^-1). In isolated, pressurized gracilis muscle arterioles (diameter ≈80 μm) from db/db mice, stepwise increases in intraluminal pressure (from 20 to 120 mm Hg) elicited a greater reduction in diameter than in control vessels at each pressure step (at 80 mm Hg, db/db, 66±4% versus control, 79±3%). The passive diameters of arterioles (obtained in Ca²⁺-free solution) and the calculated myogenic index were not significantly different in the 2 groups. The presence of the prostaglandin H₂/thromboxane A₂ receptor antagonist SQ29548 did not affect arteriolar diameters of control mice but reduced the enhanced arteriolar tone of db/db mice back to control levels (at 80 mm Hg, 80±4%). The inhibitor of cyclooxygenase-1 (COX-1), SC-560, did not affect the basal tone of arterioles, whereas NS-398, an inhibitor of COX-2, caused a significant shift in the arteriolar pressure-diameter curve of vessels from db/db mice (at 80 mm Hg, 76±3%) but not in those of control mice. Also, in aortas of db/db mice, expression of COX-2 was enhanced compared with controls. Conclusions -Collectively, these findings suggest that in mice with T2-DM, the basal tone of skeletal muscle arterioles is increased because of an enhanced COX-2-dependent production of constrictor prostaglandins. These alterations in microvascular prostaglandin synthesis may contribute to the increase in peripheral resistance and blood pressure in T2-DM.