RAPID DEVELOPMENT OF NITRATE TOLERANCE IN HEALTHY-VOLUNTEERS - ASSESSMENT USING SPECTRAL-ANALYSIS OF SHORT-TERM BLOOD-PRESSURE AND HEART-RATE-VARIABILITY

Nitrate tolerance is characterized by a loss of nitroglycerin (NTG) vasodilating and hypotensive effects during continuous administration, but is difficult to detect clinically. We hypothesized that the decrease in arterial blood pressure (BP) and the reflex sympathetic activation and tachycardia due to baroreflex deactivation associated with rapid intravenous (i.v.) infusion of NTG would be decreased during continuous NTG patch therapy as a result of tolerance to transdermal NTG. Sympathetic activation was measured as the change in amplitude of low-frequency (66-129 mHz) oscillations in BP and heart rate (HR) recorded by a noninvasive method. Eleven healthy male volunteers received rapid i.v. infusion of 0.45 mg NTG in 1 min on 3 consecutive days: before NTG patch, after 22.5 h of patch therapy, and 22.5 h after patch removal. The maximum decrease in systolic BP (SBP) and maximum reflex tachycardia as well as the sympathetic activation produced by i.v. NTG were compared during each of the three study periods. The maximum decrease in SBP was 38 +/- 8 mm Hg before NTG patch and 27 a 15 mm Hg during NTG patch (p < 0.05), with return to baseline values (37 +/- 13 mm Hg) after patch removal. There was no significant change in amplitude of reflex tachycardia among study periods. However, low-frequency oscillations in SBP increased by 40 +/- 31% in the absence of NTG patch and by only 9 +/- 35% after 22.5 h of patch therapy (p < 0.05). Patch removal resulted in a significant rebound increase in these oscillations (70 +/- 51%; p < 0.05 vs. baseline). Similar results were noted when sympathetic activation was assessed as the change in low-frequency oscillations in HR. We conclude that nitrate tolerance develops rapidly and can be assessed by the change in BP and HR oscillations produced by i.v. NTG administration.