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CLINICAL STUDY

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

^a Division of Cardiology, Department of Medicine, Mount Sinai Hospital, and the University Health Network Hospitals, Toronto, Canada.

Manuscript received March 30, 2002; revised manuscript received August 9, 2002, accepted August 26, 2002.

^* Reprint requests and correspondence: Dr. John D. Parker, Division of Cardiology, Department of Medicine, Mount Sinai Hospital, Suite 1609, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5.
jdp{at}inforamp.net

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.

Abbreviations and Acronyms   ANCOVA   analysis of covariance   BRS   baroreflex sensitivity   GTN   nitroglycerin   HFnu   high-frequency components of spectral analysis (normalized units)   HRV   heart rate variability   LF   low-frequency components of spectral analysis   LF/HF   ratio of low- to high-frequency components   NO   nitric oxide   RRSD   standard deviation of RR intervals

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