Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and healthy subjects

Abstract

The objective is to study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural tachycardia syndrome (POTS) patients. Reduced neuronal NO function, which could contribute to a hyperadrenergic state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in POTS. In protocol 1, 13 healthy volunteers (33 ± 3 years) underwent autonomic blockade with trimethaphan and were administered equipressor doses of Nω-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor) and phenylephrine to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the effects of L-NMMA in 9 POTS patients (31 ± 3 years) and 14 healthy (32 ± 2 years) volunteers, during autonomic blockade. During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (27 ± 2 versus 27 ± 3 mm Hg). Phenylephrine produced only minimal heart rate changes, whereas L-NMMA produced a modest, but significant, bradycardia (-0.8 ± 0.4 versus -4.8 ± 1.2 bpm; P=0.011). There were no differences between POTS and healthy volunteers in the systolic blood pressure increase (22 ± 2 and 28 ± 5 mm Hg) or heart rate decrease (-6 ± 2 and -4 ± 1 bpm for POTS and controls, respectively) produced by L-NMMA. In the absence of baroreflex buffering, inhibition of endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role in POTS, it is through its interaction with the autonomic nervous system.

Trial registration: ClinicalTrials.gov NCT00770484.

Figure 1

Tonic positive chronotropic effect of nitric oxide (NO) in healthy volunteers. Intravenous doses of L-NMMA (white bars) and phenylephrine (Phe, gray bars) were titrated to produce similar increases in systolic blood pressure (right y-axis) in the presence of autonomic blockade with trimethaphan. Under these conditions, L-NMMA, but not phenylephrine, decreased heart rate, shown as an increase in RR interval (left y-axis).

Figure 2

Hemodynamic changes during autonomic blockade (Panel A) and NOS inhibition+autonomic blockade (Panel B) on heart rate (HR, left y-axis) and systolic blood pressure (SBP, right y-axis) in POTS patients (P, grey bars) and age- and gender-matched controls (C, black bars). Patients with POTS showed a trend toward a greater drop in systolic blood pressure during autonomic blockade (panel A). Similar increases in systolic blood pressure during NOS inhibition produced comparable changes in heart rate in POTS patients and healthy controls (panel B).

Figure 3