VASCULAR LEVELS AND CGMP-INCREASING EFFECTS OF NICORANDIL ADMINISTERED ORALLY TO RATS

We examined a relation between cyclic guanosine monophosphate (cGMP) p roduction in thoracic aorta, as an indicator probably reflecting the v ascular response, and the vascular as well as plasma levels of nicoran dil administered orally to rats. Nicorandil (3 mg/kg) given orally was rapidly absorbed, reaching the maximal plasma (similar to 2,600 ng/ml ) and vascular concentrations (similar to 176 ng/g) at 15 min after th e dosing and thereafter decreased rapidly. Even 2 h after the dosing, the level of the vascular cGMP formation in vivo remained significantl y higher (similar to 1,000 fmol/mg increase from the control level) in the nicorandil-treated group, compared with the vehicle-treated one, and was enough to develop pronounced muscle relaxation in in vitro aor tic preparations. However, it seems that the vascular cGMP increase in vivo was not always correlated to the plasma concentration of nicoran dil, because the plasma concentration (similar to 750 ng/ml correspond ing to 3.5 mu M) at 2 h after the dosing, caused only relatively low c GMP production (300-400 fmol/mg increase from the control level), when tested in in vitro aortic preparations. Our study may indicate, there fore, that the vascular cGMP elevation in vivo is due to the content o f nicorandil effectively remaining at its vascular targets of action a s well as the plasma nicorandil concentration.