Cardiovascular interactions characterizing the vasodilator components of nicorandil in conscious dogs.
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.
Humphrey
S J
SJ
Cardiovascular Pharmacology, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan, USA.
Schwende
F J
FJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin; D006152:Cyclic GMP