CARDIOVASCULAR EFFECTS OF NICORANDIL AND NITROPRUSSIDE IN FUROSEMIDE PLUS DIGOXIN PRETREATED DOGS

In support of human congestive heart failure (CHF) trials, the cardiov ascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG ). In anesthetized control dogs, iv NP (2-19 mu g/kg/min) and NIC (24- 105 mu g/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) by 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DI G's plasma concentrations were unaffected by adjunctive NIC infused fo r 2.5 h at a mean 17 mu g/kg/min iv. No untoward interactions were see n with any combination. In conscious dogs, the hypotension and tachyca rdia seen with iv NP (2-20 mu g/kg/min) and NIC (20-160 mu g/kg/min) w ere also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0. 0125 mg/kg/ day), with no intolerance. Repeated oral NIC (7.5 mg/kg/da y x 3 days) in these chronic FURO + Die dogs was consistently hypotens ive but steadily more tachycardiac. This study offers a prototype of 3 -way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs. (C) 1994 Wiley-Liss, Inc.