The effect of endothelin-1 (ET-1) on production rates of glucose, lactate and cyclic adenosine monophosphate (cAMP) was studied in isolated rat livers perfused in a non-recirculating system. Continuous infusion of ET-1 (0.5 to 10 nmol/L) resulted in a dose-dependent increase in hepatic glucose production, reaching a maximum of 7.56 +/- 1.04 mumols.min-1.100 g bodyweight (BW)-1 at 10(-9) mol/L ET-1 versus 1.32 +/- 0.13 mumols.min-1.100 g BW-1 (P less than .01) after 60 minutes in control experiments. The integral ET-1-induced glucose release (37 +/- 20 mumols.g liver-1) was accompanied by a 15% decrease in hepatic glycogen content (basal, 116 +/- 12, after ET-1, 99 +/- 8 mumols glucose.g liver-1, P less than .05), while 10(-9) mol/L ET-1 affected neither hepatic lactate nor cAMP release versus control experiments. ET-1-induced glucose output was abolished during nominally Ca(2+)-free perfusions (-41.3 +/- 65.2 mumols.100 g BW-1, P less than .01), but was unaffected by 10(-6) mol/L verapamil and only slightly attenuated by 10(-6) mol/L nicardipine (376.3 +/- 101.4, NS, and 244.4 +/- 70.0 mumols.100 g BW-1, P less than .05, respectively). Dantrolene (10(-5) mol/L), an inhibitor of Ca2+ release from the endoplasmic reticulum, reduced glucose release elicited by 10(-9) mol/L ET-1 to 241.1 +/- 57.3 mumols.100 g BW-1 (P less than .05). Pharmacological concentrations of insulin (1 U/L) were required to inhibit ET-1-dependent glucose release by 59% (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)