Counterregulatory Responses: Sustained-Release Isosorbide-5-Mononitrate Versus Transdermal Nitroglycerin

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Abstract
Therapy with nitroglycerin is associated with the development of counterregulatory responses. This investigation documents the counterregulatory responses to once daily sustained-release isosorbide-5-mononitrate, contrasting them with those observed during continuous transdermal nitroglycerin. Twenty male volunteers were studied in a single-blind, parallel comparison of sustained-release isosorbide-5-mononitrate versus continuous transdermal nitroglycerin. This was a 5-day in-hospital study. Standing systolic blood pressure, heart rate, hematocrit, plasma catecholamines, and plasma renin activity were assessed at baseline (day 1), during 3 days of nitrate therapy (days 2-4), and on day 5, when no therapy was given. The administration of both transdermal nitroglycerin and isosorbide-5-mononitrate was associated with a decrease in systolic blood pressure and an increase in heart rate. There was loss of the systolic blood pressure effects within 48 h in both groups. The effect on heart rate was maintained over time and was greater in the isosorbide-5-mononitrate group. Nitrate therapy caused no change in plasma catecholamine concentrations and only modest changes in plasma renin activity. In both groups, there was a decrease in hematocrit, indicating an increase in plasma volume, which was maintained until the end of day 5. Further investigation revealed that this decrease in hematocrit was not the result of venous sampling and that plasma volume expansion takes > 8 h to resolve after removal of transdermal nitroglycerin. Counterregulatory responses to isosorbide-5-mononitrate are similar to those observed with continuous transdermal nitroglycerin. Plasma volume expansion occurs and is sustained during repeated dosing, whereas neurohormonal activation is modest. The study also revealed new data concerning the time course of reversal of plasma volume expansion after removal of transdermal nitroglycerin.