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.
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 Food was withdrawn at 8 AM and at 11 AM, animals received etomoxir (50 mg/kg) or control vehicle by gavage.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, 21-week-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Swislocki
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Medical Service, VANCSC, Martinez, CA 94553.
Eason
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D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004852:Epoxy Compounds / Q000627:therapeutic use*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D010084:Oxidation-Reduction; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR
D001786:Blood Glucose; D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; C054207:etomoxir