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Physical movement lasting any more than a few seconds (e.g., exercise), requires coordination of motor control with concomitant changes in the cardiovascular and respiratory support necessary to respond to the rapid increases in metabolic demand. Without such coordination, delivery of oxygen and removal of waste products become rate limiting and will restrict the duration, speed, and quality of movement. Fortunately, under healthy conditions, the central and peripheral nervous systems contribute importantly to this remarkable level of coordination via complex mechanisms that remain to be fully elucidated. The purposes of this review are to present the current state of knowledge regarding: (i) mechanisms by which the body maintains appropriate perfusion pressure to all organs during acute bouts of exercise, and (ii) alterations occurring in these mechanisms via central nervous system adaptations when exercise is performed or not performed on a regular basis (e.g., physically active versus sedentary lifestyle, respectively). Results from studies performed in humans and laboratory animals provide the reader a well-rounded knowledge base. They are intended to instill an appreciation of what is known, and not known, about how the brain regulates the cardiovascular system during acute bouts of exercise, and the adaptations that occur when individuals exercise regularly versus when chronically sedentary. Discussion of the latter is intended to provide novel mechanisms for the increased incidence of cardiovascular disease in sedentary individuals versus a reduced incidence in individuals who are regularly active. © 2018 American Physiological Society. Compr Physiol 8:103-151, 2018.

Key points Candesartan, an inverse agonist of the type 1 angiotensin II receptor (AT1 R), causes a concentration-dependent inhibition of pressure-dependent myogenic tone consistent with previous reports of mechanosensitivity of this G protein-coupled receptor. Mechanoactivation of the AT1 R occurs independently of local angiotensin II production and the type 2 angiotensin receptor. Mechanoactivation of the AT1 R stimulates actin polymerization by a protein kinase C-dependent mechanism, but independently of a change in intracellular Ca2+ . Using atomic force microscopy, changes in single vascular smooth muscle cell cortical actin are observed to remodel following mechanoactivation of the AT1 R. Abstract The Gq/11 protein-coupled angiotensin II type 1 receptor (AT1 R) has been shown to be activated by mechanical stimuli. In the vascular system, evidence supports the AT1 R being a mechanosensor that contributes to arteriolar myogenic constriction. The aim of this study was to determine if AT1 R mechanoactivation affects myogenic constriction in skeletal muscle arterioles and to determine underlying cellular mechanisms. Using pressure myography to study rat isolated first-order cremaster muscle arterioles the AT1 R inhibitor candesartan (10-7 -10-5 m) showed partial but concentration-dependent inhibition of myogenic reactivity. Inhibition was demonstrated by a rightward shift in the pressure-diameter relationship over the intraluminal pressure range, 30-110 mmHg. Pressure-induced changes in global vascular smooth muscle intracellular Ca2+ (using Fura-2) were similar in the absence or presence of candesartan, indicating that AT1 R-mediated myogenic constriction relies on Ca2+ -independent downstream signalling. The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) reversed the inhibitory effect of candesartan, while this rescue effect was prevented by the protein kinase C (PKC) inhibitor GF 109203X. Both candesartan and PKC inhibition caused increased G-actin levels, as determined by Western blotting of vessel lysates, supporting involvement of cytoskeletal remodelling. At the single vascular smooth muscle cell level, atomic force microscopy showed that cell swelling (stretch) with hypotonic buffer also caused thickening of cortical actin fibres and this was blocked by candesartan. Collectively, the present studies support growing evidence for novel modes of activation of the AT1 R in arterioles and suggest that mechanically activated AT1 R generates diacylglycerol, which in turn activates PKC which induces the actin cytoskeleton reorganization that is required for pressure-induced vasoconstriction.

Background Surgery followed by radiotherapy (RT) is indicated for patients with high-risk oral cavity cancer (OCC). Based on multi-institutional reports, we developed a guideline for postoperative RT for patients with OCC. Methods A multidisciplinary OCC team was recruited to develop a questionnaire concerning details of risk-factor categorization, target delineation, and dose specification. Thirty-one radiation oncologists from 18 institutions completed the questionnaire, and data were subjected to extensive review to establish the guideline by expert meeting. In this study, we also report the results for patients treated in accordance with the guideline at our institution between 2007 and 2011. Results Forty-one patients received RT compatible with this guideline with a median 26.8-month follow-up. Thirty-two patients (78%) remained disease-free, 6 (15%) developed locoregional recurrence (4 in-field, 1 marginal, and 1 out-field) and 4 (10%) developed distant metastasis. The overall 2-year survival rate was 86.7%. Conclusion This guideline is promising and should be validated and refined in further clinical practice. © 2014 Wiley Periodicals, Inc. Head Neck 37: 933–939, 2015

Background One hypothesis suggests that the differential response to ondansetron- and serotonin-specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5′-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5′-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5′-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching nontreatment-seeking alcohol-dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mismatching them assessing naturalistic and bar–laboratory alcohol drinking. Methods Seventy-seven AD individuals were randomized to 1 of 2 counterbalanced arms to receive sertraline 200 mg/d or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE) and then received placebo for 3 weeks followed by a second ASAE. Individuals then received the alternate drug for 3 weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in standard drinking units) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. Results Fifty-five participants completed the study. The genotype × order interaction was significant, F(1, 47) = 8.42, p = 0.006, for DDD. Three analyses of covariance were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first, F(1, 47) = 7.64, p = 0.008, but not the third ASAE. There was no difference in milliliters consumed during each ASAE. Conclusions This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast, there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in nontreatment-seeking individuals with the LL genotype.

Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P 0.05) and was intensity‐dependent (P

Correct species identification is critical when dipteran larvae are used for inference of the postmortem interval. To facilitate DNA-based identification of forensically important flies of the genus Lucilia in the continental United States, we develop a vouchered reference collection and DNA sequence database. A total of 122 specimens were collected for nine of the 10 species of Lucilia reported to occur in the continental United States. Using the polymerase chain reaction and DNA sequencing, data were obtained for an 1100-bp region of the mitochondrial gene encoding cytochrome oxidase I (COI). We consider a species suitable for DNA-based identification if it is exclusively monophyletic in >95% of bootstrap pseudoreplicate phylogenetic analyses. Seven of the nine species meet that criterion. Two species (Lucilia coeruleiviridis and Lucilia mexicana) share COI sequence and cannot be distinguished using our reference database. We conclude that DNA-based identification is likely to be successful for the other seven species.

Background. Recent studies have indicated hedgehog pathway plays a role in carcinogenesis of certain cancers. We investigated the clinical significance of its signal- ing components, including Sonic hedgehog (Shh), Patched (Ptch), and Gli-1, in oral squamous cell carcinoma (OSCC). Methods. By immunohistochemistry, we determined Shh, Ptch, and Gli-1 expression in surgical specimens from 40 patients with OSCC. The relationship between expression of these molecules and clinicopathologic variables were assessed by chi-square analysis. Statistical difference of sur- vival was compared using log-rank test. Results. Ptch overexpression was associated with lym- phatic metastasis (p ¼ .028). Nuclear Gli-1 overexpression cor- related with primary tumor size (p ¼ .001), lymphatic metastasis (p ¼ .011), and tumor recurrence (p ¼ .008). Over- expression of Ptch (p ¼ .020) or Gli-1 (p ¼ .002) in OSCC indi- cated poor prognosis in the univariate survival analysis. Conclusion. Our results suggest sonic hedgehog (Shh) pathway plays an important role in OSCC progression and should be considered a potential therapeutic target. V C 2012 Wiley Periodicals, Inc. Head Neck 00: 000-000, 2012

Please cite this paper as: Ella, Yang, Clifford, Gulia, Dora, Meininger, Davis and Hill (2010). Development of an Image-Based System for Measurement of Membrane Potential, Intracellular Ca2+ and Contraction in Arteriolar Smooth Muscle Cells. Microcirculation17(8), 629–640. Abstract Objective: Changes in smooth muscle cell (SMC) membrane potential (Em) are critical to vasomotor responses. As a fluorescent indicator approach would lessen limitations of glass electrodes in contracting preparations, we aimed to develop a Forster (or fluorescence) resonance energy transfer (FRET)-based measurement for Em. Methods: The FRET pair used in this study (donor CC2-DMPE [excitation 405 nm] and acceptor DisBAC4(3)) provide rapid measurements at a sensitivity not achievable with many ratiometric indicators. The method also combined measurement of changes in Ca2+i using fluo-4 and excitation at 490 nm. Results: After establishing loading conditions, a linear relationship was demonstrated between Em and fluorescence signal in FRET dye-loaded HEK cells held under voltage clamp. Over the voltage range from −70 to +30 mV, slope (of FRET signal vs. voltage, m) = 0.49 ± 0.07, r2 = 0.96 ± 0.025. Similar data were obtained in cerebral artery SMCs, slope (m) = 0.30 ± 0.02, r2 = 0.98 ± 0.02. Change in FRET emission ratio over the holding potential of −70 to +30 mV was 41.7 ± 4.9% for HEK cells and 30.0 ± 2.3% for arterial SMCs. The FRET signal was also shown to be modulated by KCl-induced depolarization in a concentration-dependent manner. Further, in isolated arterial SMCs, KCl-induced depolarization (60 mM) measurements occurred with increased fluo-4 fluorescence emission (62 ± 9%) and contraction (−27 ± 4.2%). Conclusions: The data support the FRET-based approach for measuring changes in Em in arterial SMCs. Further, image-based measurements of Em can be combined with analysis of temporal changes in Ca2+i and contraction.

The mechanism for exercise hyperaemia is a century old enigma. Much of the research on the topic has focused on the factors controlling skeletal muscle blood flow during steady-state dynamic exercise. It is likely that the factors which initiate the increase in blood flow are distinct from those which sustain the elevated blood flow. There is now convincing evidence that there is rapid vasodilatation following release of muscle contraction. Metabolic, neural and acetylcholine spillover mechanisms do not appear to explain the initial dilatation. Heretofore there has been only circumstantial evidence regarding the role of potassium released by skeletal muscle fibres. Studies which interrupt potassium-mediated dilatation are just emerging and are not conclusive. In addition, the latency of the vascular smooth muscle response to potassium makes it desirable to identify a mechanism that does not rely on diffusion of a vasoactive agent. Compression of the intramuscular arterioles during contraction could activate a mechanosensitive response by the vascular smooth muscle and/or endothelium. Recent in vitro and in vivo data support the notion that brief periods of mechanical compression elicit rapid vasodilatation. Thus, vascular compression could represent a feedforward mechanism for initiating skeletal muscle vasodilatation at the onset of exercise.

To date, no satisfactory explanation has been provided for the immediate increase in blood flow to skeletal muscles at the onset of exercise. We hypothesized that rapid vasodilatation is a consequence of release of a vasoactive substance from the endothelium owing to mechanical deformation of the vasculature during contraction. Rat soleus feed arteries were isolated, removed and mounted on micropipettes in a sealed chamber. Arteries were pressurized to 68 mmHg, and luminal diameter was measured using an inverted microscope. Pressure pulses of 600 mmHg were delivered for 1 s, 5 s, and as a series of five repeated 1 s pulses with 1 s between pulses. During application of external pressure the lumen of the artery was completely closed, but immediately following release of pressure the diameter was significantly increased. In intact arteries (series 1, n= 6) for the 1 s pulse, 5 s pulse and series of five 1 s pulses, the peak increases in diameter were, respectively, (mean ±s.e.m.) 16 ± 2, 14 ± 2 and 27 ± 3%, with respective times from release of pressure to peak diameter of 4.1 ± 0.3, 4.6 ± 0.7 and 2.8 ± 0.4 s. In series 2 (n= 9) the arteries increased diameter by 15 ± 2, 15 ± 2 and 30 ± 3% before and by 8 ± 1, 8 ± 1 and 21 ± 2% after removal of the endothelium with air. The important new finding in these experiments is that mechanical compression caused dilatation of skeletal muscle feed arteries with a time course similar to the change in blood flow after a brief muscle contraction. The magnitude of dilatation was not affected by increasing the duration of compression but was enhanced by increasing the number of compressions. Since removal of the endothelium reduced but did not abolish the dilatation in response to mechanical compression, it appears that the dilatation is mediated by both endothelium-dependent and -independent signalling pathways.

We performed a cross-sectional study of Hispanic and non-Hispanic parents of children with acne using a survey designed to determine their level of awareness of acne and its treatment; 82% of Hispanic parents and 40% of non-Hispanic parents agreed that a health care provider should treat mild acne (p < 0.001). Hispanic parents of adolescents with acne agreed more frequently than non-Hispanic parents that children with mild and moderate acne should be taken to a health care provider for treatment, but they tended not to visit health care providers. Future studies should aim to determine the reasons for this discrepancy, after which culturally sensitive educational programs can be developed to address this disparity.

During dynamic exercise, there is reduced responsiveness to alpha(1)- and alpha(2)-adrenergic receptor agonists in skeletal muscle vasculature. However, it is desirable to examine the sympathetic responsiveness to endogenous release of neurotransmitter, since exogenous sympathomimetic agents are dependent upon their ability to reach the abluminal receptor. Therefore, to further our understanding of sympathetic control of vasomotor tone during exercise, we employed a technique that would elicit the release of endogenous noradrenaline (norepinephrine) during dynamic exercise. Mongrel dogs (n = 8, 19-24 kg) were instrumented chronically with transit time ultrasound flow probes on both external iliac arteries. A catheter was placed in a side branch of the femoral artery for intra-arterial administration of tyramine, an agent which displaces noradrenaline from the nerve terminal. Doses of 0.5, 1.0 and 3.0 microg ml(-1) min(-1) of iliac blood flow were infused for 1 min at rest and during graded intensities of exercise. Dose-related decreases in iliac vascular conductance were achieved with these concentrations of tyramine. The reductions in iliac vascular conductance (means +/- S.E.M.) were 45 +/- 6 %, 30 +/- 4 %, 26 +/- 3 % and 17 +/- 2 %, for the 1.0 microg ml(-1) min(-1) dose at rest, 3.0 miles h(-1), 6.0 miles h(-1) and 6.0 miles h(-1), 10 % gradient, respectively. At all doses, the magnitude of vasoconstriction caused by administration of tyramine was inversely related to workload. We conclude that there is a reduced vascular responsiveness to sympathoactivation in dynamically exercising skeletal muscle.

BACKGROUND The primary objective of the current study was to determine the response rate of paclitaxel in patients with recurrent malignant glioma by using different doses dependent on the concomitant use of anticonvulsants. Secondary objectives were to determine the time period to treatment failure, to evaluate toxicities, and to obtain pharmacokinetic data. METHODS Adult patients who had recurrent malignant glioma were treated with paclitaxel. Patients were treated at different doses depending on the concomitant use of anticonvulsants known to induce the p450 hepatic enzyme system. Patients on such agents were treated at a dose of 330mg/m2, whereas those not on these anticonvulsants were treated at a dose of 210 mg/m2. Tumor response was assessed at 6-week intervals. Treatment was continued until documented tumor progression or unacceptable toxicity occurred, or a total of 12 paclitaxel infusions was completed. RESULTS From January 1997 to June 1997, 23 patients were treated with paclitaxel. Four patients were ineligible for the current study. Of the 19 eligible patients, there were no responses seen. Four (21%) had stabilization of disease. Median time to treatment failure was 1 month (95% confidence interval [CI], 1–2 mos) and median survival was 7 months (95% CI, 6–10mos). Three patients were removed from the current study because they had toxicity. Pharmacokinetic studies demonstrated that drug levels and clearance values were consistent with previously reported findings. CONCLUSION Even though higher doses were administered to patients who had recurrent malignant glioma and who were on concomitant anticonvulsants, there were no objective responses to paclitaxel. Time to tumor progression was 1 month. Further testing of paclitaxel at this dose schedule does not appear to be warranted in this patient population. Cancer 2001;91:417–22. © 2001 American Cancer Society.

BACKGROUND Primary leptomeningeal melanomas are rare tumors that originate in the leptomeninges and are associated with a poor prognosis and no response to radiation and chemotherapy. These tumors rarely metastasize outside the central nervous system. Recombinant interleukin-2 (rIL-2) is a cytokine that activates natural killer cells and lymphokine-activated killer cells, augments their antitumor effects, and recruits and activates cytotoxic T lymphocytes. We hypothesized that rIL-2 may prolong disease free survival in a patient with primary leptomeningeal melanoma. METHODS The patient was treated with intrathecal rIL-2 via lumbar puncture daily for 5 days, then weekly for 5 weeks. To investigate whether rIL-2 induced a favorable clinical response, the following parameters were monitored: survival, neurologic status, cerebrospinal fluid (CSF) analysis, visual fields, and magnetic resonance imaging (MRI) of the lumbosacral spine. RESULTS The patient is still alive and disease free 15 months after receiving rIL-2, and his neurologic status remains unchanged. The CSF glucose concentration, undetectable prior to therapy, has become normal. Repeated cytologic examinations of CSF were negative for malignant cells. The visual field examinations have remained unchanged. MRI scans of the lumbosacral spine have shown the development of arachnoiditis, but no recurrence of the mass lesion. CONCLUSIONS The tumor response in this patient, as measured by remarkable disease free survival and normalization of the CSF glucose concentration, illustrates the potential benefits of intrathecal rIL-2 in the treatment of patients with this otherwise rapidly fatal disease. Cancer 1996; 77:1544-50.

We conducted a dose escalation trial of cyclophosphamide plus Sargramostim in the therapy of patients with newly diagnosed or recurrent central nervous system tumors. Cyclophosphamide was administered at doses ranging between 1.0 and 2.5 g/m2 daily for two doses. Sargramostim was administered at a fixed dose of 250 μg/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the absolute neutrophil count (ANC) was >1,000 cells/μl for two consecutive days. The MTD for patients who had not received any prior chemotherapy and who had received either no radiotherapy or radiotherapy confined to the cranium was 2.0 g/m2 daily for two doses. The MTD for patients previously treated with chemotherapy or neuraxis radiotherapy was also 2.0 g/m2 daily for two doses. Responses were seen in patients with medulloblastoma (8/9), glioblastoma multiforme (2/13), germinoma (1/1), and pineoblastoma (1/2). © 1995 Wi1ey-Liss Inc.

Background. In human brain tumors, sensitivity to procarbazine as measured by sensitivity in a xenograft tumor model correlated inversely with amounts of the DNA repair enzyme O6-alkylguanine DNA alkyltransferase(AT). Methods. To test the hypothesis that mutations of the p53 tumor suppressor gene in human tumors also can correlate with the response to chemotherapy, p53 mutations were identified in primary human malignant brain tumors and cell lines in which AT activity and procarbazine sensitivity in a xenograft model was ascertained. Results. Mutations were identified in 7 of 21 (33%) specimens tested. Specimens containing p53 mutations tended to exhibit an increased growth delay in procarbazine-treated xenografts and lower amounts of AT. Conclusions. p53 mutations in brain tumors may contribute to procarbazine sensitivity by failing to induce arrest at the G1/S cell-cycle checkpoint, thereby preventing the repair of procarbazine-induced genetic alterations. Cancer 1995;75:1339-42.

Pigeon serum (PS) is one of the most common causes of hypersensitivity pneumonitis (HP). PS-induced HP was examined in a dog model. The dogs (n = 6) were immunized by i.m. injections of PS, followed by insufflation with aerosolized PS, while all control dogs (n = 3) received saline only. All animals insufflated with PS developed tachypnea 2-4 h after PS inhalation. After PS insufflation, a significant decrease in arterial oxygen tension (PaO2) was detected in sensitized dogs. No change in PaO2 was detected in sensitized dogs after saline or in the controls after PS insufflation. In intradermal skin tests with PS antigen, a positive skin reaction was found in 3/6 dogs in 30 min, and in 5/6 dogs in 6 and 48 h after the PS injections. Sensitized dogs showed a significant increase in PS-specific IgG in serum and lavage fluid (LF). In LF of sensitized dogs, an increase in the percentage of lymphocytes, eosinophils, and neutrophils was detected. Sensitized dogs developed chronic interstitial inflammation with lymphocytes, macrophages, plasma cells, and eosinophils in lungs. Granulomas with lymphocytes, histiocytes, and giant cells were detected in both the interstitium and the bronchiolar wall in the lungs of sensitized dogs. PaO2 was lowest in dogs showing the most severe interstitial inflammation in the lungs. The results indicate that dogs can be successfully used in immunologic and physiologic studies of PS-induced HP.

Background. Although pilocytic astrocytomas (PA) generally are considered benign, a subset of patients with PA have disease progression despite standard treatment with surgery and radiation therapy. The authors report their experience with chemotherapy in this patient group. Methods. The authors treated 11 patients (4 males and 7 females; median age at diagnosis, 8 years) with pathologically confirmed PA with chemotherapy. In eight patients, tumor progression or recurrence despite prior surgery and radiation therapy led to chemotherapy treatment. In three children younger than 5 years, chemotherapy was given in lieu of radiation therapy immediately after diagnosis (in one patient) or at the time of disease progression after surgery (in two patients). The authors used ten different chemotherapy regimens to treat the 11 patients. Results. Chemotherapy produced clinical and radiographic improvement (R/R) in four (36%) patients, clinical stabilization and radiographic improvement (SD/R) in 1 (9%), clinical and radiographic stabilization (SD/SD) in 3 (27%), and was associated with clinical and radiographic progression (PD/PD) in 3 (27%). Three of the five patients with radiographic improvement had a greater than 75% reduction of maximal cross-sectional tumor area. Hematologic toxicity resulted in dose reductions in 43 of 110 (39%) total courses of chemotherapy. There were three hospital admissions for fever and neutropenia and one chemotherapy-related death. Conclusions. The authors conclude that chemotherapy may benefit those with progressive inoperable PA. Chemotherapy may delay the need for radiation therapy in young patients with unresectable PA requiring treatment. PA may be a chemosensitive primary brain tumor.

Several studies have reported a greater blood flow response to contractions when the limb is in the dependent compared to the independent position. These results have been interpreted as evidence f...

The influence of muscular compression on the blood flow in skeletal muscle has been pondered for many years. Anrep & von Saalfeld (1935) first showed that arterial inflow is reduced during contraction due to compression of the intramuscular vessels, an effect later confirmed by Wesche (1986) in humans. Compression of the veins aids venous return to the heart (Guyton et al. 1962) and has been postulated to increase skeletal muscle perfusion by reducing the downstream venous pressure during relaxation, i.e. the muscle pump effect. Evidence in support of this notion is scanty, but the absence of contraction-induced hyperaemia when vascular smooth muscle relaxation is impaired implies that immediate increases in blood flow are attributable to rapid vasodilatation rather than a muscle pump effect (Hamann et al. 2004). Indeed, there is definitive evidence of rapid vasodilation at the onset of contractions in the rat spinotrapezius muscle (Marshall & Tandon, 1984), hamster cremaster muscle (Mihok & Murrant, 2004), and the hamster retractor muscle (VanTeeffelen & Segal, 2006). An additional way that compression could influence blood flow is through activation of a myogenic-like response. This idea was first put to the test by Mohrman & Sparks (1974) who showed that inflation of a cuff placed around isolated canine gastrocnemius muscle could cause vasodilatation. In addition, they observed that changes in vascular conductance following contraction were related to intramuscular pressure. More recent data demonstrated that brief periods of mechanical compression elicit dilatation in isolated soleus feed arteries (Clifford et al. 2006). The time course of the vasodilatation was remarkably similar to that for the change in blood flow after a brief muscle contraction. In addition, multiple pressure pulses evoked a greater magnitude of dilatation than a singe pressure pulse. On the basis of these results it was suggested that compression of the intramuscular vasculature could provide a mechanism for rapid vasodilatation following contraction. The study by Kirby et al. (2007) in this issue of The Journal of Physiology represents another important landmark in this story. The clever manipulations employed by this group are a superb example of how to study integrative human physiology. Moreover, the results show quite clearly that mechanical compression can elicit hyperaemia in the human forearm. The existence of a dose–response relationship over a range of cuff pressures between 25 and 100 mmHg provides the potential to produce graded vasodilatation in response to graded compression of the vasculature. Importantly, the observation of a temporal dissociation between the peak response to compression and that elicited by contractions argues that mechanical influences do not completely explain contraction-induced vasodilatation. In considering these results, one must keep in mind that it cannot be determined whether the forearm cuff faithfully mimics the compression elicited by forceful muscular contraction. One issue that remains to be resolved is whether this mechanism is operative in all types of muscle under all conditions. Berg et al. (1997) and vanTeeffelen & Segal (2006) maintain that vessel compression is not a factor in thin muscle in situ preparations. However, it must be emphasized that complete collapse of the vessel is not required to evoke this response. In fact, subjects in the study of Kirby et al. with a mean arterial pressure of 89 mmHg exhibited significant dilatation when external pressure was applied at only 50 mmHg. In the in vitro model (Clifford et al. 2006), high extravascular pressures were employed to simulate intramuscular pressures during maximal contraction. More recent experiments (unpublished observations Clifford & Jasperse) reveal that compression-induced dilatation can occur with little discernible reduction in vessel diameter. Substantial dilatation was observed when a brief pressure pulse matching intraluminal pressure was applied to the outside of the vessel. We speculate that contraction of muscle fibres may evoke sufficient vascular compression to elicit dilatation in the in situ muscle preparations. There has been considerable discussion of redundant factors being involved in complex physiological responses such as exercise hyperaemia. The present findings suggest a scenario where there may be temporally distinct phases of vasodilatation. Mechanically induced feed forward vasodilatation could occur with the initial contraction. Vasodilatation could then continue as potassium rapidly accumulates in the interstitium. After sufficient time to allow production and diffusion of metabolites from skeletal muscle, the blood flow could be adjusted by feedback mechanisms to match blood flow with oxygen consumption. A critical challenge for physiologists interested in this topic will be to begin teasing out the time course over which each of these overlapping mechanisms may act. The paper by Kirby et al. (2007) makes a key contribution by demonstrating that mechanically induced vasodilatation is most important in the very initial phase of hyperaemia. Until recently, little consideration has been given to a mechanical mechanism to explain vasodilatation during exercise. Kirby and colleagues have provided the impetus for further study of this mechanism. It seems clear that the influence of mechanical factors must be incorporated into our models for the overall picture of exercise hyperaemia.