Glucose Tolerance and Blood Pressure Are Improved in the Spontaneously Hypertensive Rat by Ethyl-2- (6-(4-chlorophenoxy)-hexyl)oxirane- 2-carboxylate (Etomoxir), an Inhibitor of Fatty Acid Oxidation

Abstract

We have demonstrated that glucose tolerance and insulin action are impaired in the spontaneously hypertensive rat (SHR), and that free fatty acids are elevated. Etomoxir, an inhibitor of fatty acid oxidation, has been shown to improve hyperglycemia in diabetic rats. We therefore performed oral glucose tolerance tests in SHR to assess glucose tolerance and insulin action in response to etomoxir. Because of the proposed relation between insulin action and hypertension, we examined the effect of etomoxir on blood pressure.

Thirteen-week-old male SHR were randomized into two groups. Food was withdrawn at 8 AM and at 11 AM, animals received etomoxir (50 mg/kg) or control vehicle by gavage. Oral glucose tolerance tests were started at 1 PM. In other studies, 21week-old male SHR were randomized into two groups. Animals were treated by gavage with etomoxir (50 mg/kg) or control vehicle, and blood pressure was measured noninvasively before and after treatment. Two weeks later, these experiments were repeated, but the treatments were reversed. In etomoxir-treated rats, the glucose response was significantly lower, whereas the insulin response was not significantly different. The combination of lowered glucose response, in the face of an unchanged insulin response, suggests an improvement in insulin action. However, fasting free fatty acids were higher, as was the free fatty acid response following etomoxir treatment. There was a dramatic decrease in blood pressure following etomoxir, with significant differences at 1.25, 3, 4.5, and 21 h after dosing.

In summary, etomoxir treatment improved glucose tolerance and insulin action in SHR, whereas free fatty acid values were higher. A comparable dose of etomoxir resulted in a prompt and sustained decrease in blood pressure. We conclude that inhibition of free fatty acid oxidation with etomoxir may lead to improved glucose tolerance, insulin action, and hypertension in SHR. This supports the notion that hypertension and insulin resistance are linked metabolically in SHR. Am J Hypertens 1994;7:739 – 744

Insulin resistance, hypertension, spontaneously hypertensive rat

© American Journal of Hypertension, Inc. 1994