We conducted cardiovascular interaction studies in conscious dogs to characterize the cyclic GMP and KATP channel opener (PCO)-dependent peripheral vasodilator components of nicorandil (NIC). Intravenously (i.v.) administered NIC (6-24 microg/kg/min for 6 h) reduced arterial blood pressure (BP) and increased heart rate (HR), and 15 mug/kg/min NIC was simulated by combining the cyclic GMP vasodilator nitroglycerin (NTG 1-5 microg/kg/min i.v.) with the PCO minoxidil (MNX 0.23 microg/kg i.v.). Tolerance to NTG-induced vasodilation was accelerated by oral isosorbide dinitrate (ISD 400 mg/2.5 days), and MNX was antagonized by the KATP blocker U-37883A (6 microg/kg/min i.v.). U-37883A attenuated NIC-induced hypotension with a mild tachycardia, whereas chronic ISD attenuated and delayed NIC-induced hypotension, with a pronounced tachycardia. Chronic ISD plus U-37883A completely blocked NIC-induced hypotension, although NIC-induced tachycardia persisted. These studies demonstrate that the cyclic GMP component of NIC induces a minimally tachycardiac acute vasodilation at lower drug concentrations resistant to K ATP blockade but cross-tolerant to ISD. Conversely, the PCO component of NIC induces a more tachycardiac vasodilation at higher concentrations free of ISD cross-tolerance but sensitive to KATP blockade. Therefore, low-dose NIC free of adjunctive nitrates should optimize its cyclic GMP vasodilator component for clinical indications.