Prostaglandin inhibition causes an increase in reactive hyperaemia after ischaemic exercise in human forearm

The hypothesis that prostaglandins contribute to the reactive hyperaemia after 5 min of ischaemia or 5 min of ischaemic exercise was investigated in six men by inhibiting prostaglandin production with ibuprofen (1800 mg) and indomethacin (225 mg) over 24 h before testing. Blood flow was measured continuously in the baseline and after ischaemia by combined pulsed and echo Doppler as the product of velocity and cross-sectional area. After 5 min of ischaemia, there were no differences in blood flow between placebo and the two drug conditions, except at 5 and 10 s when flow with indomethacin was greater than both placebo and ibuprofen. After 5 min of ischaemic exercise, blood flow was significantly greater as a consequence of increased vascular conductance in each of ibuprofen and indomethacin than placebo from 5 until 90 s of recovery. We conclude that prostaglandin inhibition had little or no effect on reactive hyperaemia after 5 min of circulatory occlusion alone, but that blood flow after ischaemic exercise was elevated due to increased vascular conductance when prostaglandin synthesis was inhibited.     

Effect of cigarette smoking on reactive hyperaemia in the human finger

Summary. The effect elicited by cigarette smoking on the reactive hyperaemia that develops following release of arterial occlusion in human skin was investigated, and compared to the corresponding effects elicited by oral administration of indomethacin (an inhibitor of the prostaglandin-forming enzyme cyclo-oxygenase) or nicotine, or by smoking of nicotine-free cigarettes. Finger blood flow was determined in human volunteers, using venous occlusion plethysmography, in the basal state and after 5 min of arterial occlusion. All subjects were studied before and after they had smoked two tobacco cigarettes, two herbal (nicotine-free) cigarettes, or chewed a nicotine chewing gum. The determinations before and after tobacco smoking were repeated after administration of indomethacin. In separate series, the effects of smoking on heart rate and systemic blood pressure were recorded. The basal finger blood flow was significantly (P< 0·05) diminished following cigarette smoking, by about 35%, and so was the reactive hyperaemia (P<0·05), by about 55%. The reactive hyperaemia after administration of indomethacin in combination with cigarette smoking did not differ from that obtained after cigarette smoking alone. The reactive hyperaemia was not affected by oral administration of nicotine, or by smoking of two herbal cigarettes. Cigarette smoking elicited increases in heart rate and systemic blood pressure that were of similar magnitude before and after indomethacin. From these data, we conclude that cigarette smoking elicits an inhibitory effect on the reactive hyperaemia in the human finger. This effect is probably not caused by nicotine, and seems to act via blockade of the vascular relaxation normally mediated by locally formed cyclo-oxygenase products.     

The influence of local skin heating and reactive hyperaemia on skin blood flow abnormalities in patients with reflex sympathetic dystrophy (RSD)

Abstract. Skin blood flow in reflex sympathetic dystrophy (RSD) patients has been reported to develop from an increase at an early stage to a decrease at later stages. So far, it remains unclear whether these abnormalities are solely of microcirculatory origin, and result from functional vasospasm or structural vessel wall changes. Eighty-seven RSD patients were categorized as follows: stage I in case of a stationary warmth sensation; stage II in case of an intermittent warmth and cold sensation; and stage III in case of a stationary cold sensation. Laser Doppler flowmetry (LDF) was used as a measure of total skin blood flow and transcutaneous oximetry (TCPO2) as a measure of vascular reactivity in the more superficial skin layers. Local skin heating and reactive hyperaemia were used to study the relative reserve capacity of skin microvessels. Finapres was used to assess digital arterial pressures. As compared to healthy volunteers ( n =16), LDF under control conditions demonstrated an increase in skin blood flow at stage I ( P <0.01). A decrease in skin blood flow under control conditions was seen at stages II ( P <0.05) and III ( P <0.05), but the relative flow reserve capacity, as measured with LDF, was not impaired at these stages. Regression analysis did not show a relation between LDF parameters and duration of the syndrome. TCPO2 revealed no differences between patient groups and controls. Regression analysis did not demonstrate a relation between TCPO2 parameters and duration of the syndrome. Digital systolic blood pressures were increased at stages II ( P <0.05) and III ( p <0.001). These findings indicate that abnormalities in skin blood flow, as observed in RSD patients, are of microcirculatory origin. The observed decrease in skin blood flow at stages II and III most likely results from functional vasospasm rather than from structural vessel wall changes.     

Prostanoids are not involved in postocclusive reactive hyperaemia in human skin

Several mediators contribute to postocclusive reactive hyperaemia (PORH) in the skin, including sensory nerves and endothelium‐derived hyperpolarizing factors. The main objective of this study was to investigate the specific involvement of prostanoids in human skin PORH. We tested the effect of the inhibition of cyclo‐oxygenases (COX) by 4 mm ketoprofen, infused through microdialysis fibers inserted into the healthy volunteers forearm skin, following 5 min brachial artery occlusion. Skin microvascular blood flux was recorded using two‐dimensional Laser Speckle Contrast Imaging. Maximal cutaneous vascular conductance (CVC_max) was obtained following the perfusion of 29 mm sodium nitroprusside. A systematic review of the effects of COX inhibitors on skin peak PORH was also performed. We observed no significant difference between ketoprofen and placebo for the PORH peak (78 ± 8 and 71 ± 19% CVC_max, respectively) and area under the curve (2951 ± 721 and 2490 ± 936% CVC_max.s). A meta‐analysis showed a substantial heterogeneity between studies, with overall a neutral effect of COX inhibition on peak PORH. Cyclo‐oxygenase inhibition does not alter skin PORH, suggesting no involvement of prostanoids in cutaneous postocclusive vasodilatation in healthy humans.     

Post-exercise cutaneous hyperaemia resulting from local exercise of an extremity

Large changes in skin blood flow occur after exercise. Most studies have concentrated on the systemic effects of vigorous exercise on skin blood flow. We were interested in the post-exercise response in the neighbourhood of focal exercise. We used a painless neuromuscular electronic stimulator to exercise the muscles of the forearm, producing flexion of the fingers. There was no change in blood pressure and only a small increase in heart rate during this exercise. We measured blood flow during a 5-min pre-exercise period and a 5-min post-exercise period at the forearm, at the dorsum of the index finger and on the pad of the index finger. We also measured values on the contralateral non-exercised extremity during exercise as well as during matched time periods in control experiments with no exercise. Exercise did elicit an increased blood flow in the post-exercise period at all three sites compared with the control experiments with no exercise and on the contralateral extremity. For example, the increase in blood flow at the finger dorsum was 2.1±0.1 ml (min 100 g)^?1 after exercise compared with ?0.08±0.09 ml min^?1 100 g^?1 during the control experiment and 0.1±0.1 ml (min 100 g)^?1 on the contralateral arm (all P<0.01). The local application of heat at the site of blood flow monitoring produced a substantial increase in the post-exercise response at the two finger locations [27.4±0.4 ml (min 100g)^?1 at the finger dorsum], but not at the arm. This is the first demonstration that highly focal exercise, unaccompanied by a systemic haemodynamic response, can elicit a post-exercise cutaneous hyperaemia. Local heating produced a large synergistic increase in the post-exercise hyperaemia at sites with arteriovenous microvascular perfusion but not at sites with primarily nutritive perfusion. These findings show that local vasoregulatory changes occur in response to exercise, even in the absence of whole-body haemodynamic and thermal change.     

Effects of dipyridamole and theophylline on reactive hyperaemia in subcutaneous adipose tissue in humans

Summary. The importance of adenosine for reactive hyperaemia in subcutaneous adipose tissue was studied in healthy volunteers, using the adenosine uptake inhibitor dipyridamole (bolus 0·1 mg/kg i.v. followed by infusion of 0·7 μg/kg/min) and the adenosine receptor antagonist theophylline (4 or 6 mg/kg i.v.). Basal blood flow, total blood flow and hyperaemia (total minus basal flow) after a 20-min arterial occlusion were measured in the distal femoral region by the ¹³³Xe washout technique with and without drug treatment. Basal blood flow (mean±SEM) was 2·4 ± 0·3 ml/min/100 g, while total post-occlusive flow and total reactive hyperaemia were 97·3 ±8·4 and 61·8 ± 6·5 ml/100 g, respectively, without drug treatment. Basal blood flow was unaffected by dipyridamole but the total flow and hyperaemia were enhanced by 49 ± 24 and 60 ± 31%, respectively (P<·005 for both). This enhancement was due to increases in both amplitude and duration of the hyperaemia. Neither basal blood flow, total post-occlusive flow nor hyperaemia were significantly altered by theophylline. The amplitude of the enhanced hyperaemia during dipyridamole was not significantly counteracted by simultaneous theophylline treatment (6 mg/kg) but the duration of hyperaemia was reduced from 13 ± 1 to 8 ± 1 min (P<0·01). The results suggest that endogenous adenosine does not regulate basal blood flow or reactive hyperaemia of limited duration in human adipose tissue. However, reactive hyperaemia may be enhanced by pharmacological elevation of endogenous adenosine levels.     

Determinants of post-ischaemic reactive hyperaemia in patients with diabetes mellitus type II

Dysfunction of resistance arteries is thought to be an early reversible stage in the development of atherosclerosis. Dynamics of post-ischaemic reactive hyperaemia are believed to constitute a useful tool for monitoring resistance vessel function. Patient characteristics influencing reactive hyperaemia, however, need to be defined more precisely. Since reactive hyperaemia is a dynamic process, yielding submaximal peak values after 5 min of ischaemia, this period was chosen to investigate the determinants of reactive hyperaemia in 100 type II diabetic patients as well as in 61 control subjects. Reactive hyperaemia was measured by venous-occlusion plethysmography; clinical and laboratory data were acquired by routine methods. Statistical comparison was performed with SYSTAT 5·0 for Apple Macintosh. Overall, no significant differences between diabetic patients and controls were observed by group comparison. In control subjects, only gender showed an influence on peak reactive hyperaemia (females 40·5 ± 15·3; males 51·8 ± 17·7 ml min^–1 100 ml^–1, P<0·01). In diabetic patients, in addition to gender, actual blood glucose (r=0·377, P<0·05) and meal intake (non-fasting 42·8 ± 19·2; fasting 51·2 ± 19·5 ml min^–1 100 ml^–1, P<0·05) were found to influence reactive hyperaemia. Further investigation revealed a loss of the correlation between peak reactive hyperaemia and actual blood glucose observed in the fasting state (P<0·001) in non-fasting diabetic patients, indicating an influence of meal intake on resistance vessel reactivity. Our results suggest that, in diabetic subjects, in addition to gender actual blood glucose and the postprandial situation impacts on peak reactive hyperaemia.     

Effects of local forearm skin heating on skin properties

This study investigated impacts of local skin heating on skin properties and tested whether skin changes depended on heat‐induced hyperaemia. It was reasoned that heat‐induced vasodilation impacts accompanying interstitial fluid changes. Forearm skin was locally heated from a baseline of 35°C to 40–42°C in 30 young adults (15 females, 15 males, 24.9 ± 2.1 years) and non‐heated in 10 others (5 females, 5 males, 25.2 ± 1.3 years. Skin blood flow (SBF) was continuously measured using a laser Doppler method and skin tissue dielectric constant (TDC), stratum corneum capacitance (SCC) and transepidermal water loss (TEWL) were measured before and after maintained heat for 12 min. TDC values were determined to effective measurement depths of 1.5 mm (TDC15) and 2.5 mm (TDC25). Results showed a large heat‐induced hyperaemia, with SBF increasing on average 8.8‐fold from its baseline of 35°C. Heating also caused significant increases in TDC, SCC and TEWL that, compared to preheating, increased approximately 1.1‐fold, 3.1‐fold and 4.5‐fold. None of these skin changes correlated with the magnitude of the SBF hyperaemic response. Absence of this correlation may indicate that in young healthy adults, increased capillary filtration due to heat‐induced arteriolar vasodilation is rapidly accommodated by postcapillary reabsorption, enhanced lymphatic activity and TEWL processes. An alternate explanation is that heating caused increased red cell oscillations that were detected as part of the laser Doppler increase without representing increased capillary flux. The major determinant of the Increases in TDC, SCC and TEWL is likely a consequence of heat‐induced eccrine gland activation. Studies of older persons or those with depressed function are warranted.     

Cutaneous reactive hyperaemia is unaltered by dietary nitrate supplementation in healthy humans

The purpose of this study was to determine whether nitrate supplementation augments cutaneous reactive hyperaemia. Seven participants were tested pre‐ and postnitrate supplementation (25 ml beetroot juice); participants consumed one shot per day for 3 days. Participants were instrumented with two microdialysis fibres: control (Ringer's solution) and NO synthase inhibition (20 mM L‐NAME). Skin blood flow was measured via laser‐Doppler flowmetry (LDF). A blood pressure cuff was placed on the experimental arm and inflated to 250 mmHg for 5 mins to occlude arterial inflow. The cuff was released, and the resultant reactive hyperaemia was measured. Blood pressure was continuously measured via plethysmography from a finger on the non‐experimental arm. Cutaneous vascular conductance was calculated (LDF/MAP) and normalized to maximal vasodilatation (%CVC_max). Only diastolic blood pressure was reduced following nitrate supplementation (71 ± 2 vs. 66 ± 1 mmHg; P<0·05). There was no effect of nitrate supplementation on peak reactive hyperaemia at control (Pre: 52 ± 3 vs. Post: 57 ± 2%CVC_max) or L‐NAME (Pre: 52 ± 2 vs. Post: 59 ± 4%CVC_max) sites. There was no effect of nitrate supplementation on total reactive hyperaemia at either control (Pre: 4197 ± 943 vs. Post: 4523 ± 1040%CVC_max * sec) or L‐NAME (Pre: 5108 ± 997 vs. Post: 5694 ± 1002%CVC_max * sec) sites. These data suggest cutaneous reactive hyperaemia is unaffected by dietary nitrate supplementation in healthy humans.     

Observation of skin thermal inertia distribution during reactive hyperaemia using a single-hood measurement system

An attempt was made to image the thermal inertia (defined as the square root of the product of thermal conductivity, specific heat and density) of the skin to observe the distribution of blood in the skin during post-occlusive reactive hyperaemia in normal healthy volunteers. The method was based on the ability to calculate thermal inertia by successive thermographic measurements of the skin after stepwise change in ambient radiation temperature surrounding the skin area. The stepwise change was achieved within 0.1 s through a single hood. Experimentation on the undisturbed volar forearm of normal subjects at the same site showed that the measurements thus achieved were reproducible. The thermal inertia values of forearm skin in normal subjects were scattered throughout the range 1.1 x 10(3) to 1.7 x 10(3) W s(1/2) m(-2) K(-1). Experiments on forearm skin subjected to arterial cuff occlusion indicated that thermal inertia can be detected at a low level of blood perfusion. A linear relationship was observed between thermal inertia and blood perfusion measured by laser Doppler imager before and during blood flow occlusion. During reactive hyperaemia, the thermal inertia image exhibited a non-uniform island-shaped pattern of distribution over the forearm, suggesting that, after release from occlusion, recovery of blood flow is non-uniform.     

Reproducibility of blood flow and post-occlusive reactive hyperaemia as measured by venous occlusion plethysmography

Venous occlusion plethysmography is commonly used as a tool to assess BF (blood flow) and VR (vascular resistance) at baseline and during PORH (post-occlusive reactive hyperaemia). However, little is known about the reproducibility of this method. The purpose of the present study was to investigate short- (hours) and medium (week)-term reproducibility of forearm, calf and thigh BF and VR at baseline and during PORH. Reproducibility was assessed by the CV (coefficient of variation). In eight subjects, baseline BF and VR of the forearm, calf and thigh were measured using venous occlusion plethysmography (50 mmHg). PORH and minimal VR were measured after 13 min of arterial occlusion (220 mmHg). Reproducibility of baseline forearm and calf BF was acceptable and in agreement with previous studies (CV, 12.9-21.2%). Short- and medium-term reproducibility of thigh BF was good (CV, 5.9% and 8.7% respectively). Baseline VR showed acceptable-to-good reproducibility for forearm, calf and thigh (8.3-22.5%). Forearm PORH showed a CV of 6.1% (short term) and 8.6% (medium term); this was 6.1% (short term) and 6.4% (medium term) for the calf and 6.4% (short term) and 8.0% (medium term) for the thigh. Minimal VR showed good-to-acceptable reproducibility (CV, 6.1-11.7%). In conclusion, forearm, calf and thigh BF and PORH measured by plethysmography have an acceptable-to-good short- and medium-term reproducibility. Short- and medium-term reproducibility of forearm and calf baseline BF are acceptable and thigh baseline BF has a good short- and medium-term reproducibility. Therefore plethysmography is a suitable low-cost tool to assess thigh baseline BF and PORH.     

The influence of age on reactive hyperaemia in the human calf: a study with strain gauge plethysmography

Postischaemic reactive hyperaemia in the calf was investigated by strain gauge plethysmography in four groups of ten subjects. The mean age of the different groups was 6, 13, 24 and 57 years respectively. Basal calf flow, repayment and recovery time in the 6-year-old children were greater than in the other groups, which may be related to a higher metabolic rate in young children. Maximal flow in the four groups was not significantly different, which indicates that the arteriolar response to circulatory arrest is not altered by increasing age. The cause of delay in maximal flow in the group of 6-year-olds is not clearly understood. Basal and postischaemic lowest peripheral resistance increased with age, which is probably caused by changes of the arterioles due to ageing and possibly inactivity. The fall in peripheral resistance induced by 3 min of ischaemia was positively correlated with mean blood pressure. This may be due to a greater net reduction in blood pressure during ischaemia, which brobably elicits a stronger myogenic response of the vessel wall. It is concluded that in clinical use of the reactive hyperaemia test in the calf, the influence of age is of minor importance, whereas postischaemic peripheral resistance is a more accurate measure of vasocilation for comparison of subjects with different blood pressure.     

Forelimb postischaemic reactive hyperaemia is impaired by hypotensive low body negative pressure in healthy subjects

Local metabolic conditions adapt blood supply to metabolic requirement by a direct effect on vascular smooth muscles and indirectly by modulating sympathetic vasoconstrictor effectiveness. During exercise, sympathetic nervous activity could in turn interfere on local metabolic control of vascular tone and restrain blood flow to active muscles. In order to investigate that interaction non-invasively, we measured postischaemic reactive hyperaemia (RH) in the forelimb of eight healthy young men (22.7 +/- 2.1 years) at rest and during two levels of sympathetic stimulation using low body negative pressure (LBNP -15 and -30 mmHg). During every stages, RH was measured after 40, 60, 90 and 180 s of arterial occlusion, respectively. In control conditions, RH rose with duration of ischaemia (18.9, 24.2, 30.4, 33.1 ml min(-1) per 100 ml(-1) for 40, 60, 90 and 180 s of ischaemia, respectively). During non-hypotensive LBNP (-15 mmHg) sympathetic activation was associated with decreased forelimb blood flow (6.4 +/- 0.9 versus 3.9 +/- 0.6 ml min(-1) per 100 ml(-1), P<0.01), but RH were not significantly different from control conditions. During hypotensive tachycardia LBNP (-30 mmHg), RH were significantly lower than under the previous LBNP stage. This fall in RH was greater after the shortest gap of ischaemia and tapered off as arterial occlusion gap increased (-22.3, -13.1, -10.5 and -8.7% for 40, 60, 90 and 180 s of ischaemia, respectively). These results suggested that vascular tone adaptation to local metabolic conditions was modified by sympathetic nervous activation. This was particularly marked when an hypotensive-mediated sympathetic stimulation was opposed to short gaps of ischaemia.     

Skin perfusion patterns (fluorescein perfusography) during reactive hyperaemia in peripheral arterial occlusive disease

From the pathophysiological point of view the regional distribution of blood flow is of special importance in ischaemic tissues. Within this study foot sole skin perfusion was investigated by means of fluorescein perfusography at rest and during reactive hyperaemia in patients with peripheral arterial occlusive disease confined to one limb (Fontaine stage 11). Ambient temperatures were maintained around 21°C. Mean fluorescein appearance times on the one side and their standard deviations (SD) and coefficients of variation (CV) on the other side were taken as measures of overall blood supply and homogeneity of flow, respectively. At rest no differences in these parameters could be detected between diseased legs and controls. After a 3-min supra-systolic circulatory arrest at the thigh, a significant reduction of fluorescein appearance times was observed for both groups but was statistically more pronounced in the controls. Furthermore, during reactive hyperaemia standard deviations as well as coefficients of variation decreased significantly only in normal limbs whereas they either remained constant (SD) or even increased (CV) in those with arterial obstructions. All effects associated with reactive hyperaemia showed statistically significant correlations with systolic ankle pressure indices. From these results it is concluded that haemodynamically effective arterial obstructions are followed by not only a restriction of overall hyperaemic blood supply but also a failure to homogenize microcirculatory perfusion in the case of increased flow requirements.