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 INRAT SOLENS MUSCLE IN-VITRO

We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rat s and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were t reated with the angiotensin-converting enzyme (ACE) inhibitor trandola pril (1 mg/kg) and/or a second antihypertensive drug, the calcium anta gonist verapamil, alone (100 mg/kg) or as combination therapy (50 mg/k g). Treatment of SEI rats with trandolapril or trandolapril in combina tion with verapamil for 6 weeks normalized the blood pressure. The est imated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., EC(50) values) was similar to 500 mu U/ml for muscles from both WKY and SH rats. This value is five times highe r than tile value obtained from soleus muscle preparations isolated fr om insulin-sensitive Wistar rats. This indicates that glycogen synthes is is insensitive to insulin in SH and WKY rat soleus muscle. Treatmen t 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-sens itive skeletal muscle with either trandolaprilat (the active metabolit e of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metab olism. These results show that both trandolaprilat and bradykinin caus ed a small but significant increase in the rates of glucose metabolism . In conclusion, 1) SH and WKY rat skeletal muscle was insulin resista nt, 2) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glyco gen metabolism to insulin, and 3) bradykinin and trandolaprilat acutel y caused a small but significant increase in the rate of glycogen synt hesis to a submaximal physiological concentration of insulin.