Effects of ITF 296 on epicardial coronary artery diameter during acute and long-term treatment in the conscious dog

The action of the newly developed organic nitrate ITF 296 on large coronary arteries was investigated during acute and long-term treatment in the conscious dog, chronically instrumented for recording of large coronary artery diameter (CD), mean arterial blood pressure (MBP), and heart rate (HR). Short-term steady-state infusion of ITF 296 at doses of 0.1-30 micrograms/kg/min induced a dose-dependent increase in CD. Maximal coronary artery dilation (+11%) was reached at 10 micrograms/kg/min and no further increase was observed at 30 micrograms/kg/min. At the same doses no significant variations of MBP or HR were observed. Long-term administration (5-day infusion) of ITF 296 at 20 micrograms/kg/min resulted in a 10% increase in CD, and the effect was well maintained over the entire infusion period. MBP did not change significantly, whereas HR rose by 21% by the second day of infusion and remained elevated until the end of the treatment. These results confirm that ITF 296 is an effective dilator of large coronary arteries at doses devoid of peripheral hemodynamic effects. Moreover, the vasodilating effect on coronary arteries is well maintained during long-term administration, suggesting a reduced tolerance development.