Glucose homeostasis was studied in the spontaneously hypertensive rat (SHR). The fasting plasma glucose levels were similar in the SHR and normotensive Wistar-Kyoto (WKY) rat (102.7±2.4 vs. 107.4±4.2 mg/dl, P>0.01). One hour after glucose challenge, the plasma glucose level was slightly but insignificantly increased in both SHR and WKY rat (117±2.5 vs. 114.3±3.2 mg/dl, P>0.01). After N G -nitro-l-arginine methyl ester (l-NAME) 20 mg/kg per day was administered intraperitoneally (i.p.) for 4 days, the plasma glucose level was significantly increased in the rats (SHR 167.3±4.9; WKY rat 136.0±4.8 mg/dl); the increase was significantly more pronounced in the SHR. The fasting insulin levels were similar in the SHR and WKY rats (2.3±0.4 vs. 2.0±0.3 ng/ml, P>0.01). One hour after glucose challenge, the insulin level was significantly increased in the WKY rat (4.8±0.7 ng/ml) but not in the SHR (2.2±0.4 ng/ml). With l-NAME treatment, plasma insulin increase was noted in the WKY rat but not SHR (4.6±0.6 vs. 2.6±0.4 ng/ml, n=8, P<0.01). One hour after insulin 1 IU/kg was injected intramuscularly (i.m.), the plasma glucose level was significantly decreased in both the SHR (from 115.0±6.5 to 48.6±3.6 mg/dl, n=8) and WKY rat (from 108.3±3.8 to 52.6±4.2 mg/dl, n=8). No significant difference was noted between the decrease of the two groups (P>0.01). The present findings suggested that NO plays a role in the glucose homeostasis of rats. NO-synthase blockade resulted in an increase of plasma glucose level. The SHR maintains normal glucose level and tolerance in spite of a defective insulin release response. This is probably due the compensatory effect of a more prominent NO-dependent glucose homeostatic function.