Effects of nitroglycerin treatment on baroreflex sensitivity andshort-term heart rate variability in humans

Objectives We set out to determine the effect of sustained treatment with nitroglycerin (GTN) on neural modulation of heart rate in humans. Background Acutely, exogenous and endogenous nitric oxide reduces sympathetic, while increasing vagal, outflow. An animal study showed loss of these effects during nitrate tolerance. Methods A total of 29 healthy men (age range, 18 to 32 years) received transdermal GTN (0.6 mg/h/24 h) or no therapy for six days in a parallel controlled trial. The reflex regulation of heart rate was assessed with the spontaneous baroreflex sensitivity (BRS) method. Heart rate variability was calculated both in time (standard deviation of mean RR interval [RRSD]) and frequency domains (Fast Fourier Transformation) over 10-min intervals. Results Systolic blood pressure was unchanged after continuous GTN, whereas mean RR interval decreased significantly (from 839 to 781 ms, p < 0.05). Nitroglycerin blunted BRS (p < 0.05). When compared with untreated subjects, RRSD was significantly lower after GTN, whereas the ratio of low to high frequencies was increased (all p < 0.05). Conclusions Chronic GTN reduces tonic and reflex vagal heart rate modulation, resulting in greater relative sympathetic influence. Importantly, such changes in the regulation of chronotropic oscillations might have negative prognostic implications in both heart failure and coronary artery disease. Furthermore, because chronic GTN alters the blood pressure/heart rate relationship, our data suggest caution when using these variables as pharmacodynamic markers for the development of nitrate tolerance.