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.


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 approximately 80 microm) 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.
Bagi
Zsolt
Z
Division of Physiology, New York Medical College, Valhalla, NY, USA. bagizs@jaguar.unideb.hu
Erdei
Nora
N
Toth
Attila
A
Li
Wei
W
Hintze
Thomas H
TH
Koller
Akos
A
Kaley
Gabor
G
D000818:Animals; D001011:Aorta / Q000502:physiology; D016718:Arachidonic Acid / Q000494:pharmacology; D001160:Arterioles / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000098:blood supply; D011453:Prostaglandins / Q000378:metabolism*; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D011453:Prostaglandins; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2