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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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.[1]


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