The importance of increased capillary density for the regulation of insulin sensitivity by transcapillary delivery of insulin to muscle cells in insulin-exposed rats was investigated by direct microdialysis measurements of interstitial (125I] insulin concentrations in the femoral muscle during an euglycaemic hyperinsulinaemic clamp. In insulin-exposed rats plasma insulin was approximately 25% (P < 0.05) higher than that in control animals during the first 100 min and reached their maximal concentrations after 100 min. After a nitroprusside infusion given at 100 min both groups had similar concentrations of insulin in plasma as well as in muscle interstitial fluid. However, mean glucose infusion rate during the first clamp hour was 20.5 +/- 2.3 and 12.6 +/- 5.2 mg kg-1 min-1 (P < 0.05) in insulin-exposed and control animals, respectively. During the second clamp hour the corresponding figures were 21.1 +/- 2.4 and 13.9 +/- 2.6 (P < 0.05). It may be concluded that capillarization and/or nitroprusside affected plasma insulin concentrations without altering either the interstitial insulin levels or the insulin effect on glucose consumption. The data suggest that the elevated insulin sensitivity after chronic insulin exposure is dependent on other than transcapillary transport events and demonstrate the different kinetics for insulin distribution in plasma and in the interstitial fluid.