Nitric Oxide is Decreased in Angiotensin-II dependent Low flow POTS but increased along with Splanchnic pooling Neuropathic POTS

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Low flow postural tachycardia syndrome (POTS), is associated with reduced nitric oxide (NO) activity assumed to be of endothelial origin.

We tested the hypothesis that cutaneous microvascular neuronal NO (nNO) is impaired rather than endothelial NO (eNO) in POTS. We performed three sets of experiments in subjects aged 22.5±2 years. We used laser Doppler flowmetry response to sequentially increase acetylcholine doses and to the local cutaneous heating response of the calf as bioassays for NO. First, during local heating we showed that when the selective neuronal nitric oxide synthase (NOS) inhibitor L-N^ω-Nitroarginine-2,4-L-diamino-butyric amide (N^ω, 10 mM) was delivered by intradermal microdialysis, cutaneous vascular conductance decreased by an amount equivalent to the largest reduction produced by the nonselective NOS inhibitor nitro-L-arginine (NLA 10mM). Second, we demonstrated that the response to acetylcholine was minimally attenuated by nNOS blockade using N^ω, but markedly attenuated by NLA, indicating that eNO largely comprises the receptor mediated NO release by acetylcholine. Third, we demonstrated that the acetylcholine dose-response was minimally reduced while local heat mediated NO-dependent responses were markedly reduced in POTS compared to control subjects. This is consistent with intact endothelial function and reduced NO of neuronal origin in POTS. The local heating response was highly attenuated in POTS (60±6 %CVC_max) compared to control (90±4 %CVC_max), but the plateau response decreased to the same level with nNOS inhibition (50±3 %CVC_max in POTS compared to 47±2 %CVC_max)  indicating reduced nNO bioavailability in POTS patients.

The data suggest that neuronal nitric oxide activity, but not endothelial nitric oxide activity, is reduced in low flow POTS.

 

Table 1 Dimensions and Supine Hemodynamics
	Control (N=13)	POTS (N=13)
Age (years)	22.2±1.1	23.9±.08
Weight (kg)	61±2	57±2
Height (cm)	170±2	168±3
Body Surface Area (m2)	1.75±.04	1.62±.03
Supine HR (beats/min)	68±2	88±3*
Supine Systolic BP (mmHg)	119±3	120±4
Diastolic Systolic BP (mmHg)	66±2	71±3
Pulse Pressure (mmHg)	58±2	46±3*
Venous Occlusion Calf Blood Flow (ml/100ml/min)	2.5±0.2	0.84±0.11*
Calf Arterial Resistance  (ml/100ml/min/mmHg)	34±4	88±7*
Maximum Laser Doppler Flow with Sodium Nitroprusside (pfu)	177±12	164±18
Resting Laser Doppler Flow (pfu)	19.8±1.0	13.4±2.2*
Resting %CVCmax	13.0±1.0	7.4±1.4*

The figure shows the local heating response in a healthy volunteer control subject. The response before the nNOS inhibitor N^ω is shown in black, while the response to local heating after N^ω is shown in gray. Similar response to nonselective NOS inhibition also occur.

The figure shows the local heating response at two separate microdialysis sites. The site shown in black is perfused for 30 minutes with NLA then heated to 42^oC. After the plateau is reached NLA is switched for N^ω and heating continued. The site shown in gray is perfused for 30 minutes with N^ω then heated to 42^oC. After the plateau is reached N^ω is switched for NLA and heating continued. There is similar blunting of the plateau phase at each site and with each NOS inhibitor.

The figure shows the dose response of volunteer control subjects to a step-wise increase in acetylcholine (Ach) at two separate microdialysis sites. Solid lines show the response to acetylcholine alone, short dashes the response to acetylcholine + N^ω, and long dashes the response to acetylcholine +NLA. There is a small but significant reduction in overall dose-response when N^ω is added. There is a much larger attenuation of the dose-response when NLA is added. *=P<.05 compared to acetylcholine alone. †=P<.05 compared to acetylcholine + N^ω.

The figure shows the dose response of control subjects (in black) and POTS patients (in red) to a step-wise increase in acetylcholine at two separate microdialysis sites. Both control subjects and POTS patients received acetylcholine alone and combined with NLA. There is no difference between POTS and control results.

The figure shows the local heat response of a representative control subject (in black) and a representative POTS patient (in gray). The plateau is decreased in the POTS patient. Administration of NLA once a stable plateau was achieved resulted in a decrease to a similar %CVCmax for both subjects.

Local heating response in a representative normal-flow (neuropathic splanchnic pooling) (POTS) patient (gray) and in a healthy volunteer control subject (black). Key points along the curve are marked. The heat response plateau, dependent on bioavailable nitric oxide (NO), is near maximum vasodilation in POTS patients, whereas the response in control subjects issignificantly smaller. %CVCmax, percent maximum cutaneous vascular conductance.

this indicates that cutaneous nitric oxide bioavailability is increased in neuropathic POTS

Local heating responses averaged over all POTS patients (gray) and all control subjects (black). Results are shown when the NO synthase (NOS) inhibitors nitro-L-arginine (NLA), L-N-nitroarginine-2,4-L-diamino-butyric amide (N), or aminoguanidine (AG) dissolved in Ringer solution are given and when only Ringer solution is given. The NO-dependent plateau is larger than control in POTS (top, left). The plateau response is equally inhibited by the nonisoform-specific NOS inhibitor NLA (top, right) and by the neuronal NOS-specific NOS inhibitor N (bottom, left). AG (bottom, right) has no effect on the heating response indicating no response of iNOS, and results are similar to those using Ringer solution alone.

The dose response to logarithmic increases in perfused acetylcholine averaged over all POTS patients (gray) and all control subjects (black). Acetylcholine is perfused in combination with Ringer solution only or in combination with Ringer solution containing dissolved NOS inhibitors NLA, N, or AG. Results for acetylcholine plus Ringer solution are shown as solid lines and are present in each panel for comparison with the NOS inhibitor results shown as dashed lines. POTS increases the response to acetylcholine compared with control (top, left). Both POTS and control responses are similarly blunted by the addition of NLA but by neither N nor AG. *P 0.05, significantly different from control; †P 0.05, significantly different from baseline.

Data indicate the involvement of eNOS in NO excess in neuropathic POTS.