Forearm Skin Blood Flow Response Research Articles

A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study.

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans. Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler. CBD reduced resting systolic BP (-6 mmHg; P < 0.05) and stroke volume (-8 ml; P < 0.05), with increased heart rate (HR) and maintained cardiac output. Subjects who had taken CBD had lower BP (-5 mmHg; P < 0.05, especially before and after stress), increased HR (+10 bpm; P < 0.01), decreased stroke volume (-13 ml; P < 0.01), and a blunted forearm skin blood flow response to isometric exercise. In response to cold stress, subjects who had taken CBD had blunted BP (-6 mmHg; P < 0.01) and increased HR (+7 bpm; P < 0.05), with lower total peripheral resistance. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.

The shear stress of keeping cool: why being in the ‘hot seat’ might actually be good for your blood vessels

An automobile comes off the assembly line stuck with its particular structural and functional traits which may remain inadequate or even dysfunctional in responding to driving challenges, unless public outcry and media coverage demands a recall. Thankfully, biological organisms are capable of constantly modifying themselves to better deal with both external and internal stresses that challenge their structural and functional capacity to maintain homeostasis. How are these stresses coupled to biological structural and functional adaptation? This remains a quintessential question in integrative physiology. Reductionist approaches have done much to identify specifics of signalling pathways that translate a given challenge into adaptations in the functional and structural building blocks of organism response capacity. However, the resurgence of innovative, integrative human in vivo studies in recent years demonstrates the critical contribution this type of research can play in advancing new perspectives on the underpinnings of physiological adaptation. The recent Journal of Physiology study by Green et al. (2010) is a case in point. These investigators set out to test the hypothesis that it is shear stress which couples repeated bouts of local heating (challenge to temperature homeostasis) to improvements in microvascular structure and function (biological response adaptation). The notion that mechanical stresses of blood flow can be a stimulus for vascular adaptation is nothing new and a wealth of findings from reductionist studies demonstrate this (for review see Hudlicka & Brown, 2009). However, no human study designs have been able to demonstrate such a cause–effect in the microvasculature in vivo. Green et al. (2010) measured the forearm skin blood flow response to incremental local heating, which is largely nitric oxide dependent, both before and after 4 and 8 weeks of 30-min-3-times-per-week repeated bilateral forearm heating challenges via water immersion (heat ‘training’). The frequency and duration could be compared to a moderate exercise training intensity for aerobic fitness improvement in sedentary persons. A cuff around the elbow in one arm was inflated during heat training to minimize the increase in skin perfusion during the heating bouts, isolating the impact of skin microvascular hyperaemia and attendant shear stress elevation on microvascular adaptation. Heat training increased the skin blood flow response to incremental heating, but only in the arm which was allowed to experience normal elevations in microvascular perfusion. Some additional key observations should be noted. First, during the heat training challenges skin vasodilatation in the cuffed arm was not different from that in the non-cuffed arm. So, local heating was evoking the normal vasodilatory response even when perfusion was restricted. Yet, the coupling of local temperature change to improvements in microvascular dilatation response did not occur unless mechanical forces of blood flow increased. Second, while the cuff substantially attenuated the increase in skin blood flow with local heating, the increase was still ∼40% of that in the uncuffed arm (∼4-fold vs.∼7-fold), suggesting a threshold shear stress for adaptation. However, it should be acknowledged that shear increase would not be proportional to flow increase because non-shear-mediated dilatation of resistance vessels would attenuate the actual shear experienced. Therefore, it remains to be confirmed what the actual threshold shear for adaptation would be. So why does this study warrant our close attention? First, it has identified increased shear as a stimulus for improving microvascular function in humans, and thereby focuses attention on finding ways to target increased blood flow to vascular regions as part of vascular disease prevention and treatment. But this is not all! This experimental model will allow examination of microvascular adaptations via skin biopsy and microdialysis. An innovative review by Martinez-Lemus and Meininger (Martinez-Lemus et al. 2009) summarizes evidence for repositioning and alignment of vascular smooth muscle cells and cytoskeleton protein rearrangement that rapidly (within a few days) redesigns the mechanical and structural characteristics of the vessel wall to optimize vasoregulatory responsiveness to a new ‘normal’. The approach developed by Green et al. (2010) will allow us to answer the question ‘What is the impact of the type of heat training bouts on structural and functional adaptation and their respective timelines?’ and significantly advance the use of shear stress as a therapeutic approach for vascular health. Second, the lack of vascular adaptation to local heating alone is particularly intriguing. Local heating represents an externally imposed challenge to regulation of temperature. Increases in microvascular perfusion represent a biological response aimed at limiting hyperthermia. Yet, it is coincident shear stress and not heating per se that appears essential for improving microvascular responsiveness to an external heating challenge. So, what aspect(s) of a given challenge to homeostasis actually represent the stimulus for adaptation? This is a question that is sorely lacking answers across a wide range of physiological systems. Perhaps, when investigating this question, the answers will not be found in obvious places.

The pattern of physical activity in relation to health outcomes in boys

Spontaneous and transitory movement patterns are characteristic of children. The aim of this study was to explore the relationship between short, frequent activity bouts and children's health. Physical activity was recorded every 2 s by accelerometry (ActiGraph GT1M) for seven days in 47 boys (age 8-10 years). Summary activity measures and activity pattern characteristics (frequency, intensity and duration of > or = 4 s [short] and > or = 5 min [long] bouts of > or= light [> or = LIGHT], > or = moderate [> or = MOD], > or = vigorous [> or = VIG], and > or = hard [> or = HARD] intensity activity) were recorded. Microvascular function was assessed using laser Doppler perfusion imaging as the forearm skin blood flow response to the iontophoretic application of acetylcholine (endothelial dependent vasodilator) and sodium nitroprusside (endothelial independent vasodilator) at rest and following maximal exercise. Waist circumference, resting blood pressure and aerobic fitness (VO(2peak)) were measured. The intensity of short and long > or = LIGHT bouts and the frequency of short and long > or =MOD bouts were correlated with waist circumference (r = - 0.42 to -0.52, p < 0.01) and VO(2peak) (r = 0.42 to 0.47, p < 0.01), but not when scaled for lean body mass. The frequency of short and long > or =LIGHT bouts were associated with change in endothelial function from rest to post-exercise (r = 0.34 to 0.55, p < 0.05). No relationships were evident between blood pressure and activity. The relationship between the frequency of short bouts (> or =4 s) of activity and health was as strong as relationships identified between longer bouts (> or =5 min) and health. This is encouraging as sporadic intermittent activity is characteristic of children's activity pattern.

The association between serum urate levels and arterial stiffness/endothelial function in stroke survivors

There is increasing evidence that serum uric acid is an independent marker of cardiovascular risk. We have shown previously that high urate is associated with cardiac death in stroke survivors independently of conventional risk factors. We sought to determine in stroke survivors the association between high urate levels and arterial stiffness and endothelial function. One hundred and twenty stroke survivors were recruited. We assessed pulse wave velocity of the carotid artery using an echotracking ultrasound system. Endothelial function was assessed by measuring forearm skin blood flow responses, using laser Doppler imaging, to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Patients with high serum urate (0.42–0.71 mmol/l) had a greater pulse wave velocity ( P < 0.02) and a lower ACh response ( P = 0.001) than patients with lower urate (0.12–0.28 mmol/l). Pulse wave velocity significantly correlated with serum urate ( r = −0.358, P < 0.001), HDL cholesterol ( r = −0.22, P = 0.02), and male gender ( r = 0.26, P = 0.005). The ACh response significantly correlated with serum urate ( r = −0.30, P = 0.001), male gender ( r = −0.45, P < 0.001), HDL cholesterol ( r = 0.42, P < 0.001), and triglycerides ( r = −0.24, P = 0.01). Stepwise multiple regression showed that serum urate was significantly associated with pulse wave velocity ( β = 0.35, P < 0.001), independently of other risk variables. For the ACh response the significant determinants were male gender ( β = −0.38, P < 0.001) and HDL cholesterol ( β = 0.23, P = 0.018). We have shown for the first time that elevated serum urate is associated with increased arterial stiffness in stroke survivors, independently of other risk factors. A therapeutic intervention trial of lowering of serum urate is required to see whether this will impact positively on mortality and morbidity in patients with high-risk of strokes.

Vasoactive characteristics of bupivacaine and levobupivacaine with and without adjuvant epinephrine in peripheral human skin

Epinephrine is added to local anaesthetic preparations to prolong their action and reduce their systemic absorption. Bupivacaine and levobupivacaine cause vasodilatation at clinical doses, but lower doses appear to cause vasoconstriction. The aim of this study was to characterize fully the vasoactive effects of these anaesthetics, using an objective measure of blood flow, and to assess the influence of adding epinephrine. Laser Doppler imaging was used to measure the forearm skin blood flow responses to intradermal injection of eight doses of bupivacaine and levobupivacaine in 10 healthy male volunteers. The doses tested ranged from 0.008% to 0.75%, and the five highest doses were administered both with and without adjuvant epinephrine 2.5 microg ml(-1). The cumulative responses to the lower subclinical concentrations (0.008-0.0625%) of both anaesthetics were smaller than or similar to that produced by saline alone, indicating a net vasoconstrictive effect. Higher doses caused net vasodilatation, and the levobupivacaine responses were generally lower than the corresponding bupivacaine responses (P=0.022). Epinephrine 2.5 microg ml(-1) significantly reduced the responses to clinical doses of both drugs (P<0.001), producing net vasoconstriction. Bupivacaine and levobupivacaine have a biphasic vascular effect when injected intradermally, with subclinical doses causing net vasoconstriction. The addition of epinephrine 2.5 microg ml(-1) decreases these responses markedly.

Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes?

To investigate whether aerobic fitness is associated with skin microvascular function in healthy adults with an increased risk of developing Type 2 diabetes. Twenty-seven healthy normal glucose-tolerant humans with either a previous diagnosis of gestational diabetes or having two parents with Type 2 diabetes and 27 healthy adults who had no history of diabetes were recruited. Maximal oxygen uptake was assessed using an incremental exercise test to exhaustion. Skin microvascular function was assessed using laser Doppler techniques as the maximum skin hyperaemic response to a thermal stimulus (maximum hyperaemia) and the forearm skin blood flow response to the iontophoretic application of acetylcholine (ACh) and sodium nitroprusside. Maximal oxygen uptake was not significantly different in the 'at-risk' group compared with healthy controls. Maximum hyperaemia was reduced in those 'at risk' (1.29 +/- 0.30 vs. 1.46 +/- 0.33 V, P = 0.047); however, the peak response to acetylcholine or sodium nitroprusside did not differ in the two groups. A significant positive correlation was demonstrated between maximal oxygen uptake and maximum hyperaemia (r = 0.52, P = 0.006 l/min and r = 0.60, P = 0.001 ml/kg/min) and peak ACh response (r = 0.40, P = 0.04 l/min and r = 0.47, P = 0.013 ml/kg/min) in the 'at-risk' group when expressed in absolute (l/min) or body mass-related (ml/kg/min) terms. No significant correlations were found in the control group. In this 'at-risk' group with skin microvascular dysfunction maximal oxygen uptake was not reduced compared with healthy controls. However, in the 'at-risk' group alone, individuals with higher levels of aerobic fitness also had better microvascular and endothelial responsiveness.

Laser Doppler imager (LDI) scanner and intradermal injection for in vivo pharmacology in human skin microcirculation: responses to acetylcholine, endothelin‐1 and their repeatability

The purpose of this study was to evaluate the repeatability of forearm skin blood flow responses to intradermal injections of acetylcholine (ACh) and endothelin-1 (ET-1) using a double injection technique (DIT) and a laser Doppler imager (LDI) scanner in the human skin microcirculation. We used a laser Doppler imager (Moor LDI V3.01) to continuously monitor the change in skin blood flow during intradermal administration of physiological saline (0.9% NaCl), acetylcholine (ACh 10(-7), 10(-8), 10(-9) M) and endothelin-1 (ET-1 10(-14), 10(-16), 10(-18) M) in 10 healthy male subjects. Subjects were examined on 3 different days for assessment of interday and interobserver repeatability. Injections of either drug were randomly placed on different sites of the forearm. Laser Doppler images were collected before and after injection at 2.5 min intervals for 30 min. Data were analysed after the completion of each experiment using Moor Software V.3.01. Results are expressed as changes from baseline in arbitrary perfusion units (PU). ACh caused a significant vasodilation (P < 0.0001 anova, mean +/- SE: 766 +/- 152 PU, ACh 10(-9) M; 1868 +/- 360 PU, ACh 10(-8) M; 4188 +/- 848 PU, ACh 10(-7) M; mean of days 1 and 2, n = 10), and ET-1 induced a significant vasoconstrictive response (P < 0.0001 anova, -421 +/- 83 PU, ET-1 10(-18) M; -553 +/- 66 PU, ET-1 10(-16) M; -936 +/- 90 PU, ET-1 10(-14) M; mean of days 1 and 2, n = 10). There was no difference on the response to either drug on repeated days. Bland-Altman analyses showed a close agreement of responses between days with repeatability coefficients of 1625.4 PU for ACh, and 386.0 PU for ET-1 (95% CI: ACh, -1438 to 1747 PU, ET-1, -399 to 358 PU) and between observers with repeatability coefficients of 1057.2 PU for ACh and 255.8 PU for ET-1 (95% CI: ACh, -1024 to 1048 PU, ET-1, -252 to 249 PU). The variability between these responses was independent of average flux values for both ACh and ET-1. There was a significant correlation between responses measured in the same site, in the same individual on two different days by the same observer (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.90, P < 0.0006), and between responses measured by two different observers (ACh, r = 0.94, P < 0.0001; ET-1, r = 0.91, P < 0.0003). We have shown that interday and intraobserver responses to intradermal injections of ET-1 and ACh, assessed using the DIT in combination with an LDI scanner, exhibited good reproducibility and may be a useful tool for studying the skin microcirculation in vivo.

Acetylcholine-induced vasodilation and reactive hyperemia are not affected by acute cyclo-oxygenase inhibition in human skin.

To examine whether prostaglandins are involved in endothelium-dependent vasodilatory responses of the skin microcirculation. Twenty-three young male volunteers were studied on 2 different days 1-3 weeks apart. On each experimental day the forearm skin blood flow response to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) was determined with laser Doppler imaging following the intravenous administration of either the cyclo-oxygenase inhibitor lysine acetylsalicylate (L-AS), 900 mg, or the oral intake of indomethacin, 75 mg. Acetylcholine was iontophoresed both in presence and in absence of surface anesthesia. In some subjects, the effects of L-AS on skin reactive hyperemia were also assessed. Acute cyclo-oxygenase inhibition with either drug influenced neither the skin blood flow response to 4 different doses of Ach (0.28, 1.4, 7, and 14 mC/cm2) nor reactive hyperemia. The peak vasodilatory response to Ach was significantly increased by skin anesthesia, regardless of whether the subjects received the cyclo-oxygenase inhibitor or not. For example, the mean response (+/-SD) to the largest dose of Ach (tested in 6 subjects, expressed in perfusion units) were as follows: in absence of anesthesia: L-AS 339 +/- 105, placebo 344 +/- 68; with anesthesia: L-AS 453 +/- 76, placebo 452 +/- 65 (p <.01 for effect of anesthesia). These data give no support for a contribution of prostaglandins to acetylcholine-induced vasodilation or to reactive hyperemia in the skin microcirculation. In this vascular bed, local anesthesia seems to amplify acetylcholine-induced vasodilation via a prostaglandin-independent mechanism.

Vasoactive properties of lignocaine administered by iontophoresis in human skin

The vasoactivity of lignocaine has an important influence on its clinical efficacy and systemic vascular absorption. The aim of this study was to evaluate its vasoactive properties when administered by the non-invasive technique of iontophoresis. We used laser Doppler imaging to measure the forearm skin blood flow responses of seven healthy young males to iontophoretic delivery of two preparations of 20g/l of lignocaine hydrochloride, one containing the preservatives methylparaben and propylparaben and one without. The subjects were blind to the order of drug administration, and we assessed analgesia at the sites using a pinprick test. Delivery of both preparations of (positively charged) lignocaine under the anode caused demonstrable analgesia, but no change in skin blood flow. An increase in perfusion was measured, however, when the preservative-containing preparation was administered under the cathode. There was little or no response to the solution without preservatives, although the difference in response between the two preparations was not statistically significant (P = 0.063). Although there were no vasoactive effects of lignocaine at the relatively low dose used in the present study, our results suggest that the preservatives methylparaben and propylparaben are the most likely cause of the vasodilatation that we observed under the cathode, and may therefore have a significant influence on the vasoactivity of this preparation when administered by injection. Both are negatively charged in solution and have been reported to possess vasodilator properties. It might be worth considering the use of alternative, non-vasoactive preservatives in local anaesthetic preparations, or avoiding the use of additives altogether, when this is feasible.

Vasoactive properties of lignocaine administered by iontophoresis in human skin

The vasoactivity of lignocaine has an important influence on its clinical efficacy and systemic vascular absorption. The aim of this study was to evaluate its vasoactive properties when administered by the non-invasive technique of iontophoresis. We used laser Doppler imaging to measure the forearm skin blood flow responses of seven healthy young males to iontophoretic delivery of two preparations of 20 g/l of lignocaine hydrochloride, one containing the preservatives methylparaben and propylparaben and one without. The subjects were blind to the order of drug administration, and we assessed analgesia at the sites using a pinprick test. Delivery of both preparations of (positively charged) lignocaine under the anode caused demonstrable analgesia, but no change in skin blood flow. An increase in perfusion was measured, however, when the preservative-containing preparation was administered under the cathode. There was little or no response to the solution without preservatives, although the difference in response between the two preparations was not statistically significant (P =0.063). Although there were no vasoactive effects of lignocaine at the relatively low dose used in the present study, our results suggest that the preservatives methylparaben and propylparaben are the most likely cause of the vasodilatation that we observed under the cathode, and may therefore have a significant influence on the vasoactivity of this preparation when administered by injection. Both are negatively charged in solution and have been reported to possess vasodilator properties. It might be worth considering the use of alternative, non-vasoactive preservatives in local anaesthetic preparations, or avoiding the use of additives altogether, when this is feasible.

Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers

Objective The present study was undertaken to investigate whether chronic smoking alters the vasodilatory capacity in the microcirculation. Methods We assessed, in habitual cigarette smokers, the forearm skin blood flow response to iontophoretically applied acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside. Postocclusive forearm reactive hyperemia was also explored. The skin blood flow responses were determined with a laser-Doppler flowmeter that allowed us to scan the surface after acetylcholine and sodium nitroprusside application. Results Forty healthy male volunteers were included. Twenty subjects were aged 20 to 35 years and 20 subjects were aged 40 to 60 years. We studied the following 4 groups of 10 subjects each: group 1, younger smokers (mean of 7.2 pack-years); group 2, older smokers (mean of 30 pack-years); group 3, younger nonsmokers; and group 4, older nonsmokers. On the day of the experiment, the subjects of groups 1 and 2 were asked to smoke at least 15 cigarettes from the morning until the afternoon, when the experiments were performed. No significant difference in the studied parameters was observed between younger smokers and younger nonsmokers. In older smokers, however, both acetylcholine- and sodium nitroprusside-induced skin blood flow increases were significantly attenuated in comparison with nonsmokers. Heart rate also was significantly blunted by long-term cigarette smoking in older subjects. Conclusion These data show that the vasodilatory response of the skin microvasculature is impaired in subjects who have smoked cigarettes for many years. This abnormality involves both endothelium-dependent and endothelium-independent responses. (Am Heart J 2002;144:269-74.)

Augmented forearm vasoconstriction during dynamic exercise in healthy older men.

We tested the hypothesis that the nonactive limb vasoconstriction evoked during large-muscle dynamic exercise becomes augmented with aging in humans. Sixteen young control subjects (age, 26 +/- 1 year) and twelve older (65 +/- 1 year) healthy men with similar chronic physical activity levels were studied during supine leg cycling exercise. Both peak work load (1,100 +/- 60 versus 1,400 +/- 40 kpm/min) and peak O2 uptake (1.85 +/- 0.10 versus 2.38 +/- 0.07 l/min) were lower in the older men (p < 0.05). There were no differences in the two groups under conditions of quiet supine (basal) rest. During cycling for 5 minutes each at mild, moderate, and heavy submaximal intensities (approximately 45%, 65%, and 85% of peak O2 uptake), the increases in arterial blood pressure generally were similar in the young and older subjects; however, heart rate rose less in the older men (p < 0.05). Whole forearm blood flow (venous occlusion plethysmography) was lower and vascular resistance was higher (approximately 55-90%) in the older men at all loads (p < 0.05), but the steady-state forearm skin blood flow responses (laser Doppler velocimetry) were not different in the two groups. The increases in antecubital venous norepinephrine concentrations were greater in the older men at each work load (p < 0.05), although the plasma epinephrine responses were similar in the two groups. In other studies, 1) peak whole forearm reactive hyperemia and vascular conductance after sustained circulatory arrest (ischemia) were slightly (approximately 20%) but not significantly lower in the older men and 2) the forearm vasoconstrictor and plasma norepinephrine responses to a nonexercise sympathoexcitatory stimulus (limb immersion in ice water) tended to be blunted in the older men. During brief, submaximal, large-muscle dynamic exercise, healthy older men demonstrate augmented forearm vasoconstriction that is probably caused by greater constriction of skeletal muscle resistance vessels; this appears to be mediated, at least in part, by increased sympathetic outflow. These altered sympathetic vasoconstrictor adjustments do not represent a nonspecific hyperresponsiveness to acute stress with human aging. Finally, the regulation of arterial blood pressure appears to be normal in these healthy older men.