Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure

Abstract

Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N(G)-monomethyl-l-arginine, suggesting increased NO function rather than deficiency; a lower dose of N(G)-monomethyl-l-arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171+/-37 mg versus 512+/-81 mg, respectively; P=0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182+/-11 to 138+/-4 mm Hg in 8 AF patients with supine hypertension (P=0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N(G)-monomethyl-l-arginine (56+/-6 degrees versus 41+/-4 degrees with placebo; n=7; P=0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.

Trial registration: ClinicalTrials.gov NCT00178919.

Conflict of interest statement

Conflict(s) of Interest/Disclosure(s).- None

Figures

Figure 1. Autonomic failure patients required lower doses of L-NMMA to achieve similar increases in blood pressure compared to autonomically-blocked normal subjects

A shows individual values for systolic blood pressure (SBP) in patients with autonomic failure (AF, circles) and normal controls (NLS, triangles). At baseline, autonomic failure patients showed higher SBP values. They were subjected to graded head up tilt (Tilt) until a systolic blood pressure of about 110 mm Hg was reached, whereas autonomic blockade was induced in normal subjects with trimethaphan (TrMT). SBP were similar between groups after these interventions. The nitric oxide synthase inhibitor L-NMMA was then infused at increasing doses, individualized to reach a systolic blood pressure of 150 mm Hg. Panel B shows the cumulative total amount of L-NMMA required to increased systolic blood pressure to 150 mm Hg in autonomic failure patients (AF, gray bar) and normotensive controls (NLS, white bar).

Figure 2. NO inhibition with L-NMMA induces similar increases in systolic blood pressure in autonomic failure patients with or without supine hypertension

Panel A shows individual values for systolic blood pressure (SBP) in 9 patients with autonomic failure and supine hypertension (SupHTN) and 5 patients without supine hypertension (SupNTN), Baseline (Pre) SBP values were obviously greater in AF patients with supine hypertension (174±3.7 vs. 124±5.6 mm Hg in those without supine hypertension). Subjects were then gradually tilted head up (Tilt) to induce a SBP of ~110 mm Hg, and then the nitric oxide synthase inhibitor L-NMMA was infused at increasing doses individualized to reach a systolic blood pressure of 150 mm Hg. The changes in SBP induced by L-NMMA infusion were very similar in both groups (from 107±2.4 to 154±4.7 and from 111±1.6 to 148±4.9 in patients with and without supine hypertension respectively). Panel B shows that similar cumulative total amounts of L-NMMA were required to increased systolic blood pressure to 150 mm Hg in autonomic failure patients with supine hypertension (SupHTN, white bar) and without supine hypertension (SupNTN, white bar, p=0.438).

Figure 3. Potentiation of endogenous nitric oxide with sildenafil normalizes supine hypertension in autonomic failure

Effect of sildenafil 25 mg PO administered at 8 p.m. on nighttime systolic blood pressure (SBP) in 8 autonomic failure patients with supine hypertension.

Figure 4. Improvement of orthostatic tolerance after nitric oxide inhibition with L-NMMA in autonomic failure patients is similar to that achieved by a-stimulation with phenylephrine

Autonomic failure patients were subjected to graded uptight tilt to presyncope or systolic blood pressure