Arterial Pressure Increases in Dogs with Chronic Hyperinsulinemia if COX-2 Is Inhibited.
A series of studies has shown that chronic insulin and glucose infusion does not increase mean arterial pressure (MAP) in dogs, but we have shown that the same infusion protocol or infusion of the glucose alone increases arterial pressure in rats. Thromboxane (TX) and prostaglandin (PG) production increase during the infusion, and the pressor response in rats is TX-dependent. This study tested whether in dogs PG production prevents arterial pressure from increasing. Six dogs were instrumented and assigned in random crossover design to chronic cyclooxygenase-2 (COX-2) inhibition or vehicle. Following control measurements, hyperinsulinemia was induced in all dogs with a 6-day iv. infusion of 50% dextrose (950 ml or 475 g glucose/day), which raised plasma insulin from 14±3 to 45±5 μU/ml with no significant change in blood glucose during the infusion. MAP (measured 24 h/d) decreased in control dogs during glucose infusion as shown previously but increased significantly in the dogs with COX-2 inhibition (between-group difference ∼ 9 mm Hg). Heart rate increased similarly in both groups, as shown previously, and there were no between-group differences in sodium excretion. The acute depressor response to a 10 mg iv. bolus of arachidonic acid was blocked completely in dogs during COX-2 inhibition but there was no GI distress associated with chronic inhibitor treatment. This is the first study to report a chronic pressor response with hyperinsulinemia in dogs and it also suggests that the inability to detect this relationship previously was due to COX-2-mediated prostaglandin production.