Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension.

Since it is well known that pharmacological tolerance may rapidly occur on continuous administration of organic nitrates, in this study we attempted to investigate whether isosorbide 5-mononitrate (Is-5-Mn), a long-acting vasodilator that decreases portal pressure in acute haemodynamic studies, causes a significant reduction in portal pressure following long-term oral administration. Eleven patients with cirrhosis and portal hypertension were studied prior to and following 3 months of continuous administration of Is-5-Mn, 40 mg b.i.d. The hepatic venous pressure gradient decreased significantly following long-term Is-5-Mn treatment (from 18.6 +/- 3.4 to 17.2 +/- 3.1 mmHg; p less than 0.01). This was associated with a moderate increase in hepatic blood flow. Azygos blood flow and portal blood flow did not change. There were significant decreases in mean arterial pressure (from 89.4 +/- 13.7 to 82.6 +/- 10.8 mmHg; p less than 0.05) and heart rate (from 77 +/- 10 to 73 +/- 10 b.p.m.; p less than 0.05). In contrast, there were no changes in portal pressure or hepatic and systemic haemodynamics in a control group of 17 patients receiving placebo. Repeated nitroglycerin cross-tolerance studies in five patients receiving Is-5-Mn indicated the development of a partial pharmacological tolerance (as shown by blunted haemodynamic response to nitroglycerin after long-term Is-5-Mn administration). This study shows that Is-5-Mn continues to cause a significant decrease in portal pressure during long-term therapy, with only partial pharmacological tolerance to this compound.