Nitric oxide and prostaglandin inhibition during acetylcholine-mediated cutaneous vasodilation in humans.

Acetylcholine-induced endothelium-dependent vasodilation in conduit arteries primarily depends on nitric oxide (NO). However, the biochemical mediators in the microvasculature remain less well defined. We tested whether prostaglandins and NO are responsible for cutaneous acetylcholine-mediated vasodilation and if they interact to modulate vasodilation. We measured skin blood flow (SBF) using laser Doppler flow (LDF) with intradermal microdialysis in the calves of 23 healthy volunteers. We examined the response of SBF to different doses of acetylcholine (0.01-100 mM), the nonisoform-specific NO synthase inhibitor, nitro-L-arginine (NLA, 10 mM), the nonspecific cyclo-oxygenase (COX) inhibitor, ketorolac (Keto, 10 mM), and combined NLA + Keto. NLA had no effect on baseline SBF, while Keto increased baseline SBF by approximately 150%. The increase was blunted with combined NLA + Keto. SBF increased by approximately 700% with the highest acetylcholine concentration and reduced by approximately 60% by NLA. Ketorolac alone also reduced the response to acetylcholine, although the reduction varied between 10 and 20% at differing acetylcholine doses. NLA plus ketorolac reduced the responses to different doses of acetylcholine by some 30%, which was intermediate to NOS or COX inhibition alone. These data suggest that cutaneous acetylcholine-mediated endothelium-dependent vasodilation is highly NO-dependent and is also strongly related to the interactions of NO with prostaglandins.

Increased vasoconstriction predisposes to hyperpnea and postural faint.

Our prior studies indicated that postural fainting relates to splanchnic hypervolemia and thoracic hypovolemia during orthostasis. We hypothesized that thoracic hypovolemia causes excessive sympathetic activation, increased respiratory tidal volume, and fainting involving the pulmonary stretch reflex. We studied 18 patients 13-21 yr old, 11 who fainted within 10 min of upright tilt (fainters) and 7 healthy control subjects. We measured continuous blood pressure and heart rate, respiration by inductance plethysmography, end-tidal carbon dioxide (ET(CO(2))) by capnography, and regional blood flows and blood volumes using impedance plethysmography, and we calculated arterial resistance with patients supine and during 70 degrees upright tilt. Splanchnic resistance decreased until faint in fainters (44 +/- 8 to 21 +/- 2 mmHg.l(-1).min(-1)) but increased in control subjects (47 +/- 5 to 53 +/- 4 mmHg.l(-1).min(-1)). Percent change in splanchnic blood volume increased (7.5 +/- 1.0 vs. 3.0 +/- 11.5%, P < 0.05) after the onset of tilt. Upright tilt initially significantly increased thoracic, pelvic, and leg resistance in fainters, which subsequently decreased until faint. In fainters but not control subjects, normalized tidal volume (1 +/- 0.1 to 2.6 +/- 0.2, P < 0.05) and normalized minute ventilation increased throughout tilt (1 +/- 0.2 to 2.1 +/- 0.5, P < 0.05), whereas respiratory rate decreased (19 +/- 1 to 15 +/- 1 breaths/min, P < 0.05). Maximum tidal volume occurred just before fainting. The increase in minute ventilation was inversely proportionate to the decrease in ET(CO(2)). Our data suggest that excessive splanchnic pooling and thoracic hypovolemia result in increased peripheral resistance and hyperpnea in simple postural faint. Hyperpnea and pulmonary stretch may contribute to the sympathoinhibition that occurs at the time of faint.

Changes in regional blood volume and blood flow during static handgrip.

Increased blood pressure (BP) and heart rate during exercise characterizes the exercise pressor reflex. When evoked by static handgrip, mechanoreceptors and metaboreceptors produce regional changes in blood volume and blood flow, which are incompletely characterized in humans. We studied 16 healthy subjects aged 20-27 yr using segmental impedance plethysmography validated against dye dilution and venous occlusion plethysmography to noninvasively measure changes in regional blood volumes and blood flows. Static handgrip while in supine position was performed for 2 min without postexercise ischemia. Measurements of heart rate and BP variability and coherence analyses were used to examine baroreflex-mediated autonomic effects. During handgrip exercise, systolic BP increased from 120 +/- 10 to 148 +/- 14 mmHg, whereas heart rate increased from 60 +/- 8 to 82 +/- 12 beats/min. Heart rate variability decreased, whereas BP variability increased, and transfer function amplitude was reduced from 18 +/- 2 to 8 +/- 2 ms/mmHg at low frequencies of approximately 0.1 Hz. This was associated with marked reduction of coherence between BP and heart rate (from 0.76 +/- 0.10 to 0.26 +/- 0.05) indicative of uncoupling of heart rate regulation by the baroreflex. Cardiac output increased by approximately 18% with a 4.5% increase in central blood volume and an 8.5% increase in total peripheral resistance, suggesting increased cardiac preload and contractility. Splanchnic blood volume decreased reciprocally with smaller decreases in pelvic and leg volumes, increased splanchnic, pelvic and calf peripheral resistance, and evidence for splanchnic venoconstriction. We conclude that the exercise pressor reflex is associated with reduced baroreflex cardiovagal regulation and driven by increased cardiac output related to enhanced preload, cardiac contractility, and splanchnic blood mobilization.

Differential effects of lower body negative pressure and upright tilt on splanchnic blood volume.

Upright posture and lower body negative pressure (LBNP) both induce reductions in central blood volume. However, regional circulatory responses to postural changes and LBNP may differ. Therefore, we studied regional blood flow and blood volume changes in 10 healthy subjects undergoing graded lower-body negative pressure (-10 to -50 mmHg) and 8 subjects undergoing incremental head-up tilt (HUT; 20 degrees , 40 degrees , and 70 degrees ) on separate days. We continuously measured blood pressure (BP), heart rate, and regional blood volumes and blood flows in the thoracic, splanchnic, pelvic, and leg segments by impedance plethysmography and calculated regional arterial resistances. Neither LBNP nor HUT altered systolic BP, whereas pulse pressure decreased significantly. Blood flow decreased in all segments, whereas peripheral resistances uniformly and significantly increased with both HUT and LBNP. Thoracic volume decreased while pelvic and leg volumes increased with HUT and LBNP. However, splanchnic volume changes were directionally opposite with stepwise decreases in splanchnic volume with LBNP and stepwise increases in splanchnic volume during HUT. Splanchnic emptying in LBNP models regional vascular changes during hemorrhage. Splanchnic filling may limit the ability of the splanchnic bed to respond to thoracic hypovolemia during upright posture.

Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome.

Previous investigations have allowed for stratification of patients with postural tachycardia syndrome (POTS) on the basis of peripheral blood flow. One such subset, comprising "normal-flow POTS" patients, is characterized by normal peripheral resistance and blood volume in the supine position but thoracic hypovolemia and splanchnic blood pooling in the upright position. We studied 32 consecutive 14- to 22-yr-old POTS patients comprising 13 with low-flow POTS, 14 with normal-flow POTS, and 5 with high-flow POTS and 12 comparably aged healthy volunteers. We measured changes in impedance plethysmographic (IPG) indexes of blood volume and blood flow within thoracic, splanchnic, pelvic (upper leg), and lower leg regional circulations in the supine posture and during incremental tilt to 20 degrees, 35 degrees, and 70 degrees. We validated IPG measures of thoracic and splanchnic blood flow against indocyanine green dye-dilution measurements. We validated IPG leg blood flow against venous occlusion plethysmography. Control subjects developed progressive vasoconstriction with incremental tilt. Splanchnic blood flow was increased in the supine position in normal-flow POTS, despite marked peripheral vasoconstriction, and did not change during incremental tilt, producing progressive splanchnic hypervolemia. Absolute hypovolemia was present in low-flow POTS, all supine flows and volumes were reduced, there was no vasoconstriction with tilt in all segments, and segmental volumes tended to increase uniformly throughout tilt. Lower body (pelvic and leg) flows were increased in high-flow POTS at all angles, with consequent lower body hypervolemia during tilt. Our main finding is selective and maintained orthostatic splanchnic vasodilation in normal-flow POTS, despite marked peripheral vasoconstriction in these same patients. Local splanchnic vasoregulatory factors may counteract vasoconstriction and venoconstriction in these patients. Lower body vasoconstriction in high-flow POTS was abnormal, and vasoconstriction in low-flow POTS was sustained at initially elevated supine levels.

Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume.

POTS (postural tachycardia syndrome) is associated with low blood volume and reduced renin and aldosterone; however, the role of Ang (angiotensin) II has not been investigated. Previous studies have suggested that a subset of POTS patients with increased vasoconstriction related to decreased bioavailable NO (nitric oxide) have decreased blood volume. Ang II reduces bioavailable NO and is integral to the renin-Ang system. Thus, in the present study, we investigated the relationship between blood volume, Ang II, renin, aldosterone and peripheral blood flow in POTS patients. POTS was diagnosed by 70 degrees upright tilt, and supine calf blood flow, measured by venous occlusion plethysmography, was used to subgroup POTS patients. A total of 23 POTS patients were partitioned; ten with low blood flow, eight with normal flow and five with high flow. There were ten healthy volunteers. Blood volume was measured by dye dilution. All biochemical measurements were performed whilst supine. Blood volume was decreased in low-flow POTS (2.14 +/- 0.12 litres/m2) compared with controls (2.76 +/- 0.20 litres/m2), but not in the other subgroups. PRA (plasma renin activity) was decreased in low-flow POTS compared with controls (0.49 +/- 0.12 compared with 0.90 +/- 0.18 ng of Ang I.ml(-1).h(-1) respectively), whereas plasma Ang II was increased (89 +/- 20 compared with 32 +/- 4 ng/l), but not in the other subgroups. PRA correlated with aldosterone (r = +0.71) in all subjects. PRA correlated negatively with blood volume (r = -0.72) in normal- and high-flow POTS, but positively (r = +0.65) in low-flow POTS. PRA correlated positively with Ang II (r = +0.76) in normal- and high-flow POTS, but negatively (r = -0.83) in low-flow POTS. Blood volume was negatively correlated with Ang II (r = -0.66) in normal- and high-flow POTS and in five low-flow POTS patients. The remaining five low-flow POTS patients had reduced blood volume and increased Ang II which was not correlated with blood volume. The data suggest that plasma Ang II is increased in low-flow POTS patients with hypovolaemia, which may contribute to local blood flow dysregulation and reduced NO bioavailability.

Splanchnic hyperemia and hypervolemia during Valsalva maneuver in postural tachycardia syndrome.

Prior work demonstrated dependence of the change in blood pressure during the Valsalva maneuver (VM) on the extent of thoracic hypovolemia and splanchnic hypervolemia. Thoracic hypovolemia and splanchnic hypervolemia characterize certain patients with postural tachycardia syndrome (POTS) during orthostatic stress. These patients also experience abnormal phase II hypotension and phase IV hypertension during VM. We hypothesize that reduced splanchnic arterial resistance explains aberrant VM results in these patients. We studied 17 POTS patients aged 15-23 yr with normal resting peripheral blood flow by strain gauge plethysmography and 10 comparably aged healthy volunteers. All had normal blood volumes by dye dilution. We assessed changes in estimated thoracic, splanchnic, pelvic-thigh, and lower leg blood volume and blood flow by impedance plethysmography throughout VM performed in the supine position. Baseline splanchnic blood flow was increased and calculated arterial resistance was decreased in POTS compared with control subjects. Splanchnic resistance decreased and flow increased in POTS subjects, whereas splanchnic resistance increased and flow decreased in control subjects during stage II of VM. This was associated with increased splanchnic blood volume, decreased thoracic blood volume, increased heart rate, and decreased blood pressure in POTS. Pelvic and leg resistances were increased above control and remained so during stage IV of VM, accounting for the increased blood pressure overshoot in POTS. Thus splanchnic hyperemia and hypervolemia are related to excessive phase II blood pressure reduction in POTS despite intense peripheral vasoconstriction. Factors other than autonomic dysfunction may play a role in POTS.