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) va sodilating and hypotensive effects during continuous administration, b ut is difficult to detect clinically. We hypothesized that the decreas e in arterial blood pressure (BP) and the reflex sympathetic activatio n and tachycardia due to baroreflex deactivation associated with rapid intravenous (i.v.) infusion of NTG would be decreased during continuo us NTG patch therapy as a result of tolerance to transdermal NTG. Symp athetic activation was measured as the change in amplitude of low-freq uency (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 tachycard ia as well as the sympathetic activation produced by i.v. NTG were com pared 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 p atch (p < 0.05), with return to baseline values (37 +/- 13 mm Hg) afte r patch removal. There was no significant change in amplitude of refle x tachycardia among study periods. However, low-frequency oscillations in SBP increased by 40 +/- 31% in the absence of NTG patch and by onl y 9 +/- 35% after 22.5 h of patch therapy (p < 0.05). Patch removal re sulted in a significant rebound increase in these oscillations (70 +/- 51%; p < 0.05 vs. baseline). Similar results were noted when sympathe tic activation was assessed as the change in low-frequency oscillation s in HR. We conclude that nitrate tolerance develops rapidly and can b e assessed by the change in BP and HR oscillations produced by i.v. NT G administration.