Continuous therapy with nitroglycerin impairs endothelium-dependent vasodilation but does not cause tolerance in conductance arteries: a human in vivo study

We investigated in healthy humans whether continuous therapy with organic nitrates impairs conduit artery responses to nitroglycerin (GTN) as well as its effects on endothelium-dependent vasodilation. Sixteen young male volunteers were randomized to continuous treatment with either transdermal GTN (0.6 mg/h/24 hrs for 6 days) or no therapy. Endothelium-dependent (flow-mediated) dilatation (FMD) and endothelium-independent (GTN-mediated) dilatation (GMD) of the brachial artery were evaluated before randomization (session 1), after six days of transdermal GTN treatment (session 2), and three hours after withdrawal of transdermal GTN (session 3). In the GTN group, on session 1, 0.4 mg sublingual GTN increased resting brachial artery diameter from 0.40 +/- 0.03 to 0.45 +/- 0.03 cm (P < 0.01). At the time of session 2, this GTN-mediated vasodilation remained unchanged at baseline (0.47 +/- 0.04 cm), with no further significant dilatation in response to either stimulus. On session 3, three hours after patch removal, baseline brachial artery diameter and GMD returned to pretreatment values, but FMD remained blunted (session 1: 8.7 +/- 2.5; session 3: 4.1 +/- 1.7%, P < 0.05). There was no change in these variables in the control group. Our data demonstrate that continuous GTN therapy impairs endothelium-dependent vasodilation in conduit arteries yet does not induce nitrate tolerance.