Differences In Vascular Reactivity Research Articles

Abstract P1-02-07: Real-Time Functional Imaging of Tumor Vascular Normalization by Anti-Angiogenic Agents

Abstract Background: We describe here new technology that enables non-invasive imaging of normalization of tumor blood vessels by anti-angiogenic agents in real time. Materials and Methods: Variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography were used to visualize vessel normalization. Results: Morphological changes in the same vessel prior to and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was demonstrated by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense750, was retained in tumors after both anti-VEGF antibody and rapamycin treatment as visualized by noninvasive fluorescence tomography. The anti-angiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of Paclitaxel due to increased drug penetration throughout the tumor. Discussion: The optical imaging technology described here is thus a powerful real-tool imaging tool of functional and morphological tumor vessel normalization and its therapeutic consequences. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-07.

Different Patterns of Vascular Response Between Patients With or Without Diabetes Mellitus After Drug-Eluting Stent Implantation: Optical Coherence Tomographic Analysis

We performed this study to investigate with optical coherence tomography (OCT) the vascular response after sirolimus-eluting stent (SES) implantation between patients with and those without diabetes mellitus (DM). The difference in vascular response after SES implantation between patients with and those without DM has not been fully evaluated with OCT. Optical coherence tomography was performed to examine 74 nonrestenotic SES implanted in 63 patients (32 with DM and 31 without DM) at 9 months after SES implantation. For struts showing neointimal coverage, the neointimal thickness on the luminal side of each strut section was measured, and neointimal characteristics were classified into high, low, and layered signal pattern. Baseline patient characteristics and lesion and procedural characteristics data were similar between the 2 groups. In total, 11,422 struts were analyzed. High signal neointima was observed in 90.2 ± 13.9%, low signal neointima in 7.3 ± 10.0%, and layered neointima in 2.7 ± 5.8%/stents. There was higher incidence of low signal neointima (10.5 ± 10.3% vs. 4.5 ± 5.6%, p = 0.003), neointimal thickness was larger (median: 106.8 μm, interquartile range: 79.3 to 130.4 μm vs. median: 83.5 μm, interquartile range: 62.3 to 89.3 μm; p < 0.0001), and neointimal coverage of stent struts was higher (92.1 ± 6.2% vs. 87.2 ± 11.9%; p = 0.03) in DM patients. High signal neointimal pattern was predominantly observed, and low or layered signal pattern was observed in some cases. In DM patients, low signal neointima was observed with high frequency. Neointimal coverage and neointimal thickness was also higher in DM patients as compared with non-DM patients.

Robustly measuring vascular reactivity differences with breath-hold: Normalising stimulus-evoked and resting state BOLD fMRI data

Inter-subject differences in local cerebral blood flow (CBF) and cerebral blood volume (CBV) contribute to differences in BOLD signal reactivity and, therefore, unmodelled variance in group level fMRI analyses. A simple way of elevating blood CO2 concentrations to characterise subject differences in vascular reactivity is through breath-holds but two aspects of this measure are often neglected: (1) breath-holds are usually modelled as blocks even though CO2 accumulates over time and (2) increases in CO2 differ between subjects. This study demonstrates that the BOLD breath-hold response is best modelled by convolving the end-tidal CO2 trace with a standard haemodynamic response function and including its temporal derivative. Inclusion of the BOLD breath-hold response as a voxel-dependent covariate in a group level analysis increases the spatial extent of activation in stimulus evoked and resting state datasets. By expressing the BOLD breath-hold response as a percentage signal increase with respect to an absolute change in the partial pressure of CO2 (expressed in mmHg), the spatial extent of stimulus-evoked activation is further improved. This demonstrates that individual end-tidal CO2 increases to breath-hold should be accounted for to provide an accurate measure of vascular reactivity resulting in more statistically active voxels in group level analyses.

Genetic variance in CYP2C8 and increased risk of myocardial infarction

Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI. This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders. During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22-1.95). There was a significant gene-sex interaction with a relative excess risk of 1.40 (95% CI: 0.33-2.47) for men. SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.

Abstract 386: Real-time noninvasive optical imaging of angiogenesis and vasculogenesis inhibition and normalization

Abstract We have developed and optimized non-invasive in vivo imaging to continuously visualize and characterize tumor angiogenesis and vascular response to anticancer therapies in real time in live mice. Tumor vessels could be monitored longitudinally undergoing vasculogenesis and angiogenesis the same mouse. Morphometric changes of the same vessel prior to and after drug treatment were captured with high resolution. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were imaged. The multi-channel imaging capability of the OV100 small animal imaging system (Olympus) enabled visualization of the functional integrity (permeability) of tumor vessels before and after anti-angiogenic therapies using the near-infrared blood pool reagent Angiosense750. We observed real-time tumor vessel normalization as demonstrated by significantly reduced leakiness and subsequent improved delivery of BODPY-Paclitaxel upon administration of low-dose and short-term anti-angiogenic therapy. Further, alterations in Angiosense750 tumor retention in response to different treatments were confirmed and quantified using noninvasive fluorescent molecular tomography (VisEN FMT). Histological, and immunofluorescence staining (CD31, lectin, SMA, NG2) along with confocal microscopy, confirmed the in vivo imaging observations. Thus, imaging is a powerful tool for investigating tumor angiogenic progression and for preclinical drug screening of anti-angiogenic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 386.

Effects of sex and estrogen on chicken ductus arteriosus reactivity

Sex hormones have an important influence on cardiovascular physiology and pathophysiology and sex differences in vascular reactivity have been widely demonstrated. In the present study we hypothesized 1) the presence of sexual dimorphism in chicken ductus arteriosus (DA) responsiveness to contractile and relaxant stimuli and 2) that estrogens are vasoactive in the chicken DA. In vitro contractions (assessed with a wire myograph) induced by normoxia, KCl, 4-aminopyridine, norepinephrine, phenylephrine, U46619, or endothelin-1, as well as relaxations induced by ACh, sodium nitroprusside, BAY 41-2272, PGE(2), isoproterenol, forskolin,Y-27632, and hydroxyfasudil were not significantly different between males and females. The estrogen 17beta-estradiol elicited concentration-dependent relaxation of KCl-, phenylephrine-, and oxygen-induced active tone in male and female chicken DA. The stereoisomer 17alpha-estradiol showed lesser relaxant effects, and the selective estrogen receptor (ER) agonists 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl)tris-phenol (ERalpha) and 2,3-bis(4-hydroxyphenyl)-propionitrile (ERbeta) did not show any effect. There were no sex differences in the responses to estrogen. Endothelium removal or the presence of the soluble guanylate cyclase inhibitor ODQ, the K(+) channel blockers tetraethylammonium, glibenclamide, and charybdotoxin, or the ER antagonist fulvestrant did not modify 17beta-estradiol-induced relaxation. CaCl(2) (30 muM-10 mM) induced concentration-dependent contraction in DA rings depolarized by 62.5 mM KCl or stimulated with 21% O(2) in Ca(2+)-free medium. Preincubation with 17beta-estradiol or the L-type Ca(2+) channel blocker nifedipine produced an inhibition of CaCl(2)-induced contractions. In conclusion, there are no sex-related differences in chicken DA reactivity. The estrogen 17beta-estradiol induces an endothelium-independent relaxation of chicken DA that is not mediated by ER activation. This relaxant effect is, at least partially, due to inhibition of Ca(2+) entry from extracellular space.

Gender Differences in Vascular Reactivity of Aortas from Streptozotocin-Induced Diabetic Mice

The aim of the present study was to assess gender differences in diabetes-related vascular reactivity in murine aortas. Diabetes is a risk factor for ischemic heart disease, cerebral ischemia, and atherosclerosis, conditions in which endothelial dysfunction plays a pathogenetic role. We examined vascular responses in aortas isolated from streptozotocin (STZ)-induced type 1 diabetic mice and age-matched control mice, and looked for gender differences in the diabetes-induced changes in these responses. For each gender, the plasma adiponectin levels were lower in diabetic mice than in the controls, and they were significantly higher in females than in males. The acetylcholine (ACh)-induced endothelium-dependent relaxation of aortic rings was impaired (vs. that in the age-matched controls) in diabetic male mice, but not in diabetic female mice. The sodium nitroprusside-induced endothelium-independent aortic relaxation was not altered by diabetes in either male or female mice. The norepinephrine-induced aortic contraction was enhanced (vs. that in the control group) in diabetic female mice, but not in diabetic male mice, whereas in the presence of N(G)-nitro-L-arginine neither gender exhibited a significant diabetes-induced change in this contraction. The clonidine-induced and insulin-induced endothelium-dependent aortic relaxations were impaired only in the diabetic female group (vs. the age-matched controls). These results suggest that: a) in male diabetic mice, which exhibited low adiponectin levels, these were impairments of both the aortic relaxation and nitric oxide (NO) production induced by ACh, whereas b) in female diabetic mice, there were impairments of the aortic relaxations induced by both insulin and clonidine.

Monitoring interstitial m‐THPC‐PDT in vivo using fluorescence and reflectance spectroscopy

In order to understand the mechanisms of photodynamic therapy (PDT) it is important to monitor parameters during illumination that yield information on deposited PDT dose. The aim of this study is to investigate the possibility of monitoring implicit parameters, such as photobleaching, in addition to monitoring explicit parameters (fluence (rate), oxygenation, photosensitizer concentration) directly or indirectly. These parameters are monitored during PDT without interrupting the therapeutic illumination. Rats were injected with 0.3 mg kg(-1) m-THPC. Sixteen hours after administration the abdominal muscle in rats was irradiated for 1,500 seconds using clinically relevant fluence rates of 50, 100, and 250 mW cm(-1) of diffuser length at 652 nm. In addition to the linear diffuser for delivering treatment light, isotropic fiber-optic probes and fiber-optic probes for differential path-length spectroscopy (DPS) were placed on both sides of the muscle to monitor tissue physiological parameters, fluence rate, and fluorescence. The m-THPC treatment groups show a decrease in fluence rate throughout PDT of 16%, 19%, and 27% for the 50, 100, and 250 mW cm(-1) groups, respectively. Both during and post-PDT differences in vascular response between treatment groups and animals within the same treatment group are observed. Furthermore we show fluence rate dependent bleaching of m-THPC up to a measured fluence rate of 100 mW cm(-1). The data presented in this study show the possibility of simultaneously monitoring fluence (rate), fluorescence, hemoglobin oxygen saturation, and blood volume during PDT without interruptions to the therapeutic illumination. Differences in saturation profiles between animals and treatment groups indicate differences in vascular response during illumination. Furthermore, the relationship between fluence rate and m-THPC fluorescence photobleaching is complex in an interstitial environment.

Vascular Function Changes Following An Acute Bout Of Resistance Exercise In Obese And Non-obese Males

One of the earliest sub-clinical stages associated with atherosclerosis is endothelial dysfunction, which has been shown to predict future cardiovascular events. Chronic exercise is thought to improve vascular function (VF); however, few studies have evaluated the effects of acute resistance exercise (RE) on VF. In addition, there are no studies to date that have compared VF responses in obese and non-obese individuals following acute RE. PURPOSE: The purpose of this study was to evaluate VF, as determined by the assessment of forearm blood flow (FBF) and vascular reactivity (VR) before and after a single bout of RE in obese and non-obese males. METHODS: Seven non-obese (21.4 ± 2.1 yrs; 22.5 ± 1.2 kg/m2) and seven obese (23.8 ± 2.9 yrs; 36.3 ± 2.4 kg/m2) males volunteered to participate. FBF was assessed prior to (PRE) and immediately after (POST) 3 sets of arm curls to fatigue (70% of 1-RM) using strain-gauge plethysmography before and after 5 min of upper arm occlusion and subsequent reactive hyperemia. Total excess flow, calculated as the difference between baseline FBF and FBF during reactive hyperemia, was used as an indicator of VR. A One-Way ANOVA was performed to determine differences within each group. A multivariate ANOVA was used to test between-subject factors. RESULTS: In non-obese males, FBF was significantly increased in response to reactive hyperemia during the PRE (P = 0.021) and POST (P = 0.007) trials. However, this increase was not observed in obese males (PRE, P = 0.147; POST, P = 0.341). There was no significant difference observed in VR for both non-obese and obese males PRE and POST. Between-subject analysis revealed that only POST FBF (ml 100 ml-1 min-1 · s) was significantly different between non-obese and obese subjects at baseline (1782.7 ± 169.6 vs. 1272.1 ± 92.6, P = 0.021) and during reactive hyperemia (2796.4 ± 265.8 vs. 1503.5 ± 214.4, P = 0.003). Additionally, a significant difference in VR was observed between non-obese and obese males POST (1013.7 ± 208.5 vs. 231.4 ± 220.4, P =.024). CONCLUSIONS: VR was increased during reactive hyperemia following a single bout of RE in non-obese, but not obese males. The different responses suggest that adiposity may have a detrimental effect on VF during acute exercise. Future studies that investigate the effects of obesity on cardiovascular health are warranted.

Gender differences in vascular reactivity to endothelin-1 (1-31) in mesenteric arteries from diabetic mice

Endothelin-1 (1-31) [ET-1 (1-31)], a novel member of the ET family, comprises 31 amino acids and is derived from the selective hydrolysis of big ET-1 by chymase. Although ET-1 (1-31) reportedly exerts biological effects by direct or indirect [via its conversion to ET-1 (1-21)] mechanisms, it is unclear whether in diabetes the vascular effects of ET-1 (1-31) display gender differences. We investigated this question by exposing mesenteric artery rings to ET-1 (1-31), using arteries from mice in the early or chronic phase of diabetes. In the early stage of diabetes, the ET-1 (1-31)-induced contraction was similar between age- and sex-matched control and streptozotocin (STZ)-induced diabetic mice. In the chronic stage of diabetes, the ET-1 (1-31)-induced contraction was enhanced in diabetic female mice, but not in diabetic male mice (vs. both age-matched control and early-stage diabetic mice). This enhancement was largely prevented by Y27632 (Rho kinase inhibitor), PD98059 [inhibitor of extracellular signal related kinases 1 and 2 (ERK1/2)], or SP600125 [C-jun terminal kinase (JNK) inhibitor]. These data indicate that the ET-1 (1-31)-induced vasoconstriction in the mesenteric artery may be specifically enhanced in established diabetic female mice, and that this enhancement may be due to alterations in the activities of Rho/Rho kinase or mitogen-activated protein kinase.

Intermedin/adrenomedullin‐2 (IMD/AM2) relaxes rat pulmonary arterial rings via protein kinase G (PKG) and BKCa channel dependent pathway: The effect of chronic hypoxia induced pulmonary hypertension

Our previous results showed that when rat pulmonary arterial (PA) rings were precontracted with U‐46619 IMD relaxes PA rings in a nitric oxide and endothelial dependent manner. In this study the pulmonary vasorelaxant response (PVR) to IMD in PA was inhibited by cholera toxin, Rp‐8‐Br‐PET‐cGMPs and iberitoksin whereas rolipram, KT5720 and apamin were without effect. PVR to IMD was potentialized in the presence of sildenafile. In PA rings isolated from rats with pulmonary hypertension induced by chronic hypoxia (PHCH), PVR to both IMD and ACh response were diminished. In contrast, in the isolated, buffer‐perfused rat lungs with PHCH, the pulmonary vasodilator responses to IMD and ACh were not altered. In PA rings from rats with PHCH, the PVR to NS1619 decreased when compared to control rats. The present data suggest that cGMP‐induced PKG activation and promotion of hyperpolarization through BKCa is the major pathway for rIMD induced vasorelaxation in PA rings. CH may induce downregulation of BKCa channels in pulmonary arterial conductance segments whereas pulmonary resistance arterial segments may not be susceptible to similar changes by PHCH, it is possible other mechanisms such as selective upregulation of eNOS or downregulation in phosphodiesterase activity in response to CH in resistance arteries may explain the difference in vascular responsiveness.

Cardiovascular function in normotensive offspring of persons with essential hypertension and black race.

Prior investigations have shown impaired endothelial function in hypertensive blacks when compared with whites. It is not clear, however, whether the difference in vascular responsiveness predates or follows the development of hypertension. Thirty-nine young black adults with a family history of essential hypertension and 41 control participants were studied for brachial artery reactivity and carotid intima-media thickness via ultrasonography, cardiac muscle mass and diastolic function by echocardiography, and biochemical analysis. There was no significant difference in brachial artery reactivity between the study groups, although women had greater reactivity than men (P=.05). Carotid intima-media thickness, left ventricular geometry, and biomarkers were equivalent between the study groups (P=not significant). Vascular imaging and biomarkers were unable to identify early evidence of endothelial dysfunction in offspring of African Americans with essential hypertension. These same studies demonstrated some early changes in vascular function based on sex.

Retinal Arteriolar Diameter, Blood Velocity, and Blood Flow Response to an Isocapnic Hyperoxic Provocation in Early Sight-Threatening Diabetic Retinopathy

To quantify the magnitude of retinal arteriolar vascular reactivity in diabetic patients stratified by severity of retinopathy and in age-matched control subjects. The sample comprised 21 nondiabetic control subjects (group 1), 19 patients with no clinically visible DR (group 2), 19 patients with mild-to-moderate nonproliferative DR and without clinically evident diabetic macular edema (DME) (group 3), and 17 patients with DME (group 4). methods Subjects initially breathed air, followed by oxygen, while isocapnia was maintained. Retinal arteriolar diameter and blood velocity measurements were acquired simultaneously. Changes in blood velocity and wall shear rate (WSR) were significantly less in groups 3 and 4 (P < 0.0001 and P = 0.0002, respectively) than in groups 1 and 2. Change in blood flow was significantly less in group 4 (P < 0.004) than in groups 1 and 2. The change in maximum-to-minimum (max:min) ratio was significantly less in groups 2 and 4 than in group 1 (P = 0.001). There was a significant relationship between baseline objective edema indices and vascular reactivity. The magnitude of vascular reactivity in response to isocapnic hyperoxia was reduced in those individuals with clinically evident DR relative to subjects without diabetes. The differences in vascular reactivity occurred in the absence of any difference in baseline hemodynamic values. Vascular reactivity is impaired in early sight-threatening DR, and this impairment is related to the objectively defined magnitude of retinal edema.

The influence of obesity on calf blood flow and vascular reactivity in older adults.

ObjectiveTo determine whether differences in vascular reactivity existed among normal weight, overweight, and obese older men and women, and to examine the association between abdominal fat distribution and vascular reactivity.MethodsEighty-seven individuals who were 60 years of age or older (age = 69 ± 7 yrs; mean ± SD) were grouped into normal weight (BMI < 25; n = 30), overweight (BMI ≥ 25 and < 30; n = 28), or obese (BMI ≥ 30; n = 29) categories. Calf blood flow (BF) was assessed by venous occlusion strain-gauge plethysmography at rest and post-occlusive reactive hyperemia.ResultsPost-occlusive reactive hyperemia BF was lower (p = 0.038) in the obese group (5.55 ± 4.67 %/min) than in the normal weight group (8.34 ± 3.89 %/min). Additionally, change in BF from rest to post-occlusion in the obese group (1.93 ± 2.58 %/min) was lower (p = 0.001) than in the normal weight group (5.21 ± 3.59 %/min), as well as the percentage change (75 ± 98 % vs. 202 ± 190 %, p = 0.006, respectively). After adjusting for age, prevalence in hypertension and calf skinfold thickness, change in BF values remained lower (p < 0.05) in obese subjects compared to the normal weight subjects. Lastly, the absolute and percentage change in BF were significantly related to BMI (r = -0.44, p < 0.001, and r = -0.37, p < 0.001, respectively) and to waist circumference (r = -0.36, p = 0.001, and r = -0.32, p = 0.002).ConclusionObesity and abdominal adiposity impair vascular reactivity in older men and women, and these deleterious effects on vascular reactivity are independent of conventional risk factors.

Effects of Dietary Arachidonic Acid Supplementation on Age-Related Changes in Endothelium-Dependent Vascular Responses

The purpose of the present study was to examine the effects of dietary supplementation of arachidonic acid (ARA) on age-related changes in endothelium-dependent vascular responses. Young male Fisher-344 rats (2-mo-old) and aged rats of the same strain (22-mo-old) were randomly separated into a control diet group (young control, YC; old control, OC) and an ARA-containing diet group (young ARA, YA; old ARA, OA). After a 2-mo feeding period, vascular responses were evaluated using both endothelium-intact and -denuded aortic rings. Phenylephrine (alpha1-adrenoceptor agonist)-induced vasoconstrictor responses in endothelium-intact rings from group OC tended to be augmented compared with those of rings from groups YC and YA, although this augmentation was significantly suppressed by dietary supplementation of ARA. There were no significant differences in vascular responses to phenylephrine in endothelium-denuded rings among groups YC, YA, OC, and OA. Acetylcholine (Ach)-induced, endothelium-dependent vasorelaxation was attenuated in groups OC and OA compared with that in groups YC and YA. ARA supplementation induced slight enhancement of Ach-induced vasorelaxation in aged rats. Ach-induced vasorelaxation correlated very well with aortic ARA concentration in aged rats, but not in young rats. There were no significant differences in endothelium-independent vasodilator responses to sodium nitroprusside in endothelium-denuded rings among groups YC, YA, OC, and OA. These findings suggest that dietary ARA supplementation improves the age-related endothelial dysfunction that leads to various cardiovascular diseases.

Differences in Vascular Reactivity Between Men and Women

The purpose of this study was to compare the gender and age-related differences in vascular reactivity in healthy men and women across a wide age range. Fifty-seven men and 61 women between 20 and 89 years of age, free of cardiovascular disease and risk factors, were categorized into younger (20-39 years), middle-aged (40-59 years), and older (60-89 years) age groups. Subjects were characterized on body weight and height, body mass index (BMI), and calf blood flow under resting, postocclusive reactive hyperemic (PORH), and maximal hyperemic conditions in the lower extremity with use of venous occlusion mercury strain-gauge plethysmography. Similar baseline characteristics were observed among age groups, whereas men had greater body weight (p<0.05), higher BMI values (p<0.05), and a trend toward higher ankle-brachial index (ABI) values (p=0.054) than women. While calf blood flow measurements were similar for men and women at rest and at maximal hyperemic conditions, women had a greater percentage change in calf blood flow from rest to PORH than men (p=0.046). After adjusting for body weight, BMI, and ABI, the percentage change in calf blood flow from rest to PORH was no longer significantly higher in the women (p>0.05). Furthermore, the percentage change in calf blood flow from rest to PORH was negatively related to body weight (r = -0.30, p<0.01) and to BMI (r = -0.26, p<0.01) in the men and women. No differences (p>0.05) in the calf blood flow measures were observed among the age groups. In a healthy cohort free of cardiovascular disease, increased BMI accounted for poorer vascular reactivity in men compared to women regardless of age.

Regional differences in vascular responsiveness of nasal mucosae isolated from naive guinea pigs

Objective In the present study, the contractile response to norepinephrine (NE) and relaxing response to histamine and leukotriene D 4 (LTD 4) were compared among the nasal mucosae of septa (S) and lateral (L) and medial turbinates (M) isolated from naive male Hartley guinea pigs. Methods The isometrical tension of the isolated nasal mucosae of the above regions was measured at a resting tension of 0.5 g by using a standard organ-bath technique. Results In each mucosal strip, NE induced a contraction in a concentration-dependent manner. A significant difference in efficacy (maximal response) of NE was found (L > M > S). In mucosal strips precontracted with NE (3 × 10 −5 M), both histamine and LTD 4 induced relaxing responses. The efficacy of histamine in S was significantly greater than those in L and M. The potency order of LTD 4 was L > M > S; a significant difference was observed between L and S. Conclusion In conclusion, the present study demonstrated a distinct regional difference in the response to contractile and relaxant agonists of isolated nasal mucosae of guinea pigs.

Is There a Difference in Vascular Reactivity of the Arms and Legs?

The arterial vessels within the arms and legs are exposed to different hydrostatic pressures and blood-flow demands during the course of daily life. There is compelling indirect evidence that arterial reactivity differs in the arms and legs of humans; greater blood-flow responses to physiological vasodilator stimuli are generally reported in the arms of healthy younger subjects, whereas greater sympathetically mediated vasoconstrictor responsiveness is generally observed in the legs. Limb blood-flow responses to local arterial infusions of vasoactive agents reveal a similar pattern of heterogeneity in human arms versus legs. The advantages and assumptions of these pharmacological approaches for evaluating limb arterial reactivity are discussed, and methodological issues pertaining to the normalization and interpretation of vascular responses in the human arm and leg are critically examined. The article concludes with recent data from our laboratory indicating that limb-specific variation in arterial function may be age-, sex-, and physical activity dependent.

Regional differences in nitric oxide‐mediated vasorelaxation in porcine pulmonary arteries

Several previous investigations have shown improved oxygenation when ventilator-treated patients with acute lung injury are turned prone. In a previous human study, we demonstrated higher Ca(2+)-dependent nitric oxide synthase (NOS) activity in dorsal than in ventral parts of the lung. The current investigation was designed to determine whether Ca(2+)-dependent NOS activity was different in dorsal and ventral porcine lung regions. In addition, possible differences in vascular responses to nitroprusside or secondary to acetylcholine- or bradykinin-stimulated NO production were studied in dorsal and ventral pulmonary arteries. In the study, 20 pigs were used. Lung biopsies and pulmonary arterial rings were harvested from ventral and dorsal lung regions. NOS activity was determined by citrulline assay in the presence and absence of the calcium chelator ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EDTA) to discriminate between Ca(2+)-dependent and Ca(2+)-independent NOS activity. In organ baths, in submaximally contracted arterial rings, vasorelaxation induced by acetylcholine, bradykinin and nitroprusside was measured. Ca(2+)-dependent NOS activity was higher in dorsal parts (87.2 +/- 9.1 citrulline units) than in ventral parts (62.2 +/- 10.1 citrulline units, P < 0.05) of porcine lung. There was a greater relaxation in dorsal than in ventral pulmonary arterial rings induced by both acetylcholine and bradykinin. Nitroprusside relaxed both sites equally. Our results show that endothelial-derived NO is an important factor influencing the differences between dorsal and ventral lung regions in vasorelaxing activity in porcine pulmonary arteries. This finding provides an explanation for the improved oxygenation when patients with severe acute lung insufficiency are turned prone.

Different vascular responses in glabrous and nonglabrous skin with increasing core temperature during exercise

To elucidate the characteristics of vasomotor control in glabrous and nonglabrous skin during dynamic exercise, we compared the vascular responses in both areas to increasing core temperature during the cycle exercise for 30 min at different intensities in the range 20-60% of peak oxygen consumption (VO(2peak)) in a total of 13 male and four female subjects in two experimental protocols. Skin blood flow was monitored using laser Doppler flowmetry. In protocol 1, the slope of the relationship between esophageal temperature (T (es)) and cutaneous vascular conductance (CVC) in the early phase of the exercise decreased (P < 0.05) with increasing exercise intensity at glabrous sites (palm) but not nonglabrous sites (dorsal hand). In protocol 2, to examine whether a difference in vascular responses in the two areas is due to the adrenergic vasoconstrictor system, the release of norepinephrine from adrenergic nerves in forearm and palmar skin was blocked locally by iontophoresis of bretylium tosylate (BT). The administration of BT diminished completely the change of CVC in the palm during the exercise but did not alter the response in the forearm compared with the untreated site. In the two areas, neither the T (es) threshold for vasodilation nor the change in CVC above the threshold in the middle and late phase of the exercise was influenced by the intensity of the exercise. These results suggest that, in the early phase of the exercise, light-to-moderate exercise reduces in an intensity-dependent manner the thermal sensitivity for vasodilation in glabrous skin but not nonglabrous skin via an adrenergic vasoconstrictor pathway.