Decreased microvascular nitric oxide-dependent vasodilation in postural tachycardia syndrome

Abstract

Background: One variant of postural tachycardia syndrome (POTS), designated low-flow POTS, is associated with decreased peripheral blood flow related to impaired local vascular regulation.

Methods and results: To investigate the hypothesis that microvascular endothelial dysfunction produces decreased peripheral blood flow in low-flow POTS, we performed experiments using laser-Doppler flowmetry (LDF) combined with iontophoresis in 15 low-flow POTS patients, 17 normal-flow POTS patients, and 13 healthy reference volunteers varying in age from 14 to 22 years. We tested whether alpha-adrenergic vasoregulation was impaired using iontophoretic delivery of tyramine, phentolamine, and bretylium followed by a norepinephrine dose response. We tested endothelial-dependent and -independent receptor-mediated vasodilation by measuring acetylcholine and sodium nitroprusside dose responses. We tested whether nitric oxide-dependent vasodilation was different in these groups by testing the local thermal hyperemic response to saline used as a reference compared with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Adrenergic and receptor-dependent cutaneous vasoregulation was similar for low-flow POTS, normal-flow POTS, and reference subjects. Thermal hyperemia produced distinctly different findings: there was marked attenuation of the nitric oxide-sensitive plateau during prolonged heating, which was insensitive to L-NAME in low-flow POTS subjects. The pattern of thermal hyperemia response in low-flow POTS subjects during saline administration resembled the pattern in reference subjects during L-NAME administration and was minimally affected by L-NAME.

Conclusions: The data suggest that flow-dependent nitric oxide release is reduced in low-flow POTS. This may account for local flow regulation abnormalities.

Figures

Figure 1

Representative tracings of the response to local heating to 43°C. The tracing is biphasic. There is an initial peak, thought to be related to the neurogenic inflammatory response, followed by a higher plateau, which is believed to be related to flow-mediated NO-dependent vasodilation.

Figure 2

Dose response to norepinephrine iontophoresis after bretylium had been administered to the same site. There are no significant differences among POTS patients or reference subjects.

Figure 3

Response to additional α-adrenergic agonists and antagonists. Left panel shows the maximal LDF with bretylium; middle, maximum LDF response to phentolamine; right, response to preheating (dark bars) followed by tyramine (lighter bars). The only significant difference is a decrease in the pretyramine heating response in low-flow POTS. *P<0.05 difference from baseline for each group.

Figure 4

Responses to different doses of acetylcholine (AcCh), an endothelial-dependent vasodilator (left), and responses to sodium nitroprusside (SNP), an endothelial-independent vasodilator (right). There are no differences among the groups except that baseline low-flow POTS LDF is decreased in both panels.

Figure 5

Top, Saline or L-NAME administered to a representative reference subject by iontophoresis followed by local heating to 43°C. An initial peak occurs and is followed by a higher plateau. Iontophoretic administration of L-NAME slightly blunts the initial peak and markedly decreases the plateau phase. Bottom, Local heating followed by saline or L-NAME in a representative low-flow POTS patient. The initial peak is present, but there is marked attenuation of the NO-dependent plateau, even after saline administration, which resembles blunting by the NO inhibitor L-NAME. Iontophoretic administration of L-NAME minimally blunts the initial peak but has no additional effect on the plateau phase because of preexistent impairment of NO release.

Figure 6

Averaged data for local heating experiments. Data for saline administration (top) and L-NAME administration (bottom) are shown. The data indicate greater perfusion in heated saline reference subjects and normal-flow (Nl Flow) POTS patients. L-NAME results are similar for all groups and are not different from data obtained during saline administration in low-flow POTS patients.