S120

DIABETES, VOLUME 45, SUPPLEMENT 1, JANUARY 1996, PAGES S115-S119

Effects of Treatment of Spontaneously Hypertensive Rats With the Angiotensin-Converting Enzyme Inhibitor Trandolapril and the Calcium Antagonist Verapamil on the Sensitivity of Glucose Metabolism to Insulin in Rat Soleus Muscle In Vitro

Brendan Leighton, Alison L. Sanderson, Martin E. Young, George K. Radda, Ernest A. Boehm, and Joseph F. Clark

We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rats and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (1 mg/kg) and/or a second antihypertensive drug, the calcium antagonist verapamil, alone (100 mg/ kg) or as combination therapy (50 mg/kg). Treatment of SH rats with trandolapril or trandolapril in combination with verapamil for 6 weeks normalized the blood pressure. The estimated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., EC₅₀ values) was ~500 µU/ml for muscles from both WKY and SH rats. This value is five times higher than the value obtained from soleus muscle preparations isolated from insulin-sensitive Wistar rats. This indicates that glycogen synthesis is insensitive to insulin in SH and WKY rat soleus muscle. Treatment of SH rats with trandolapril with or without verapamil improved the sensitivity of glycogen synthesis to insulin in soleus muscle. Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metabolism. These results show that both trandolaprilat and bradykinin caused a small but significant increase in the rates of glucose metabolism. In conclusion, 1 ) SH and WKY rat skeletal muscle was insulin resistant, 2 ) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glycogen metabolism to insulin, and 3) bradykinin and trandolaprilat acutely caused a small but significant increase in the rate of glycogen synthesis to a submaximal physiological concentration of insulin. Diabetes 45 (Suppl. D:S120-S124, 1996

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