Isosorbide dinitrate, a long-acting
vasodilator, has been tested in human
portal hypertension with conflicting results. In order to determine some of the factors that could affect the individual response to this
drug, we infused
isosorbide dinitrate at a low dose (10 to 25 micrograms per kg per min) and a high dose (100 micrograms per kg per min) to rats with portal vein
stenosis. Under
pentobarbital anesthesia, portal pressure was measured with an ileocolic vein
catheter while cardiac output and regional blood flows were measured with the
microsphere technique. At a dose that decreased arterial pressure by approximately 10%, cardiac output remained unchanged while portal vein inflow decreased significantly; portal pressure was not reduced (10.7 +/- 0.2 vs. 10.0 +/- 0.3 mm Hg), indicating a rise in portal vascular resistance. At a high dose of
isosorbide dinitrate, arterial pressure and cardiac output fell markedly; portal pressure decreased only modestly (11.3 +/- 0.3 vs. 9.8 +/- 0.6 mm Hg, p less than 0.05), but portal flow was unchanged, indicating a reduction in portal vascular resistance. In addition, portal hypertensive rats received a constant i.v. infusion of N-acetyl-
cysteine; the combination of the latter and
isosorbide dinitrate markedly potentiated the effects on arterial pressure. Thus, the dose of the
drug and the presence of
cysteine-containing compounds appear to modulate the hemodynamic response to
isosorbide dinitrate. Clinical testing with this
drug should be undertaken with consideration of these factors.