NITROVASODILATORS ITF-296 AND ISOSORBIDE DINITRATE EXERT ANTIISCHEMICACTIVITY BY DILATING CORONARY PENETRATING ARTERIES

We examined the effect of the novel nitrovasodilator ITF 296 and isoso rbide dinitrate (ISDN) on myocardial blood flow (BF) distal to a coron ary artery stenosis. Eleven dogs with a Doppler velocity probe, hydrau lic occluder, and indwelling microcatheter in the left anterior descen ding coronary artery (LAD) were studied during treadmill exercise in t he presence of a coronary artery stenosis. On separate days, the effec ts of ITF 296 in doses of 4 and 20 mu g/kg/min i.v. or ISDN 20 mu g/kg /min i.v. were compared. Coronary pressure distal to the stenosis was maintained constant during the central period and after administration of either nitrovasodilator. Neither ITF 296 nor ISDN significantly al tered heart rate (HR), arterial blood pressure (BP), or left ventricul ar end-diastolic pressure (LVEDP). In the presence of a stenosis that decreased distal coronary pressure to 58 +/- 4 mm Hg, mean myocardial BF measured with microspheres was 0.91 +/- 0.08 ml/min/g in the LAD-de pendent region and 2.36 +/- 0.11 ml/min/g in the posterior control reg ion, respectively. With no change in distal coronary pressure, ITF 296 increased mean BF in the LAD region to 1.25 +/- 0.05 ml/min/g (4 mu g /kg/min i.v.) and 1.40 +/- 0.10 ml/min/g (20 mu g/kg/min i.v.), wherea s ISDN (20 mu g/kg/min i.v.) increased flow to 1.28 +/- 0.18 ml/min/g (each p < 0.05). The increase in BF occurred exclusively in the deeper layers, with no change in subepicardial BF. Consequently, the endocar dial/epicardial (endo/epi) BF ratio increased from 0.33 +/- 0.04 durin g control stenosis to 0.70 +/- 0.10 after ITF 296 (20 mu g/kg/min), an d to 0.56 +/- 0.08 after ISDN (each p < 0.05). Neither ITF 296 nor ISD N had an effect on myocardial BF in the normally perfused control regi on. Therefore, bath ITF 296 and ISDN improved BF to the deeper myocard ial layers distal to a coronary artery stenosis. This effect occurred without alterations in stenosis severity or diastolic intraventricular pressure, suggesting that these agents act by dilating the penetratin g arteries which deliver BF to the subendocardium.