Reduction In Peripheral Blood Flow Research Articles

C64 REDUCTION IN EJECTION AND PRE–EJECTION PERIODS ARE PREDICTIVE OF MORTALITY IN AL AND ATTR HEART AMYLOIDOSIS

Abstract Background Amyloidosis is a systemic disease caused by fibrillary misfolded protein deposition in several organs including the heart. Cardiac deposition is the leading cause of death in these patients. Echocardiography is the imaging technique mostly used to study cardiac amyloidosis. Many studies tried to identify earlier markers to stratify the mortality risk. Heart stiffness is the main issue leading the heart dysfunction. However, few data are available on the possible role of connection between heart and possible vessels alterations. Purpose: Aim of this study was to evaluate heart stiffness using Ventricular–arterial coupling (VAC) for relationship between heart and vessel tree. Methods We studied 58 patients (22 F and 36 M, aged 67.14± 12.49) with AL or ATTR amyloidosis and heart involvement. They were 42 AL and 16 ATTR patients. All patients were evaluated before treatment with a complete history, physical exam, serum markers of disease, and echocardiogram. The abdominal fat biopsy to confirm amyloid deposition was performed before treatment. Among all patients, 18 died with a mean OS of 12 months [IQR 1–24 months]. Results At baseline, VAC was increased in died patients (alive 1.53 ± 0.43 vs died 2.06 ± 1.73, p=0.09) but was ineffective to predict the risk of mortality (ROC analysis AUC 0.54, p=0.57). By analysing ejection and pre–ejection periods we found that they were both increased in alive patients (p=0.0016 and p=0.0072, respectively). Moreover, these periods were effective in prediction of the death risk (ejection time AUC 0.81, cut–off 239 msec, sensitivity 61.54% and specificity 88.24%; pre–ejection time AUC 0.75, cut–off 82 msec, sensitivity 84.62% and specificity 58.82%). No difference in VAC, ejection time or pre–ejection time were found comparing AL to ATTR, nor both parameters had a predictive role. Conclusion Amyloidosis induces an increase in heart stiffness and reduces heart contractility. This causes a reduction of peripheral blood flow and a worsening in heart failure. We demonstrated that this mechanism affects the capacity to pump blood in vessels due the reduction in time for loading during the systole. These results may predict the mortality with a significant sensitivity and specificity, regardless of the type of amyloidosis.

Effect of obesity on the vascular response to sympathetic activation during hypoxia in female participants

Background: Activation of the sympathetic nervous system causes vasoconstriction and an acute reduction in peripheral blood flow. However, during hypoxia, sympathetically-mediated vasoconstriction is attenuated in young females without obesity. Given sustained increases in sympathetic activity associated with obesity may create a greater propensity to vasoconstrict in response to sympathetic activation, we sought to examine the effect of obesity on the vascular response to sympathetic activation during hypoxia. We hypothesized sympathetically-mediated vasoconstriction during hypoxia would be greater in premenopausal female adults with obesity when compared to females without obesity. Methods: Blood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in premenopausal female adults with obesity (n=5, 25±3 yrs, 37±1 kg/m2, 48±1% body fat) and without obesity [n=19, 23±1 yrs, 23±1 kg/m2, (33±2% body fat, n=8)]. Data were combined from two cohorts (IRB #2022525, 2011312) to test present hypotheses. Participants completed two trials consisting of a 2-min cold pressor test (CPT) during baseline normoxia (98±1% SpO2) and following 3-5 min of steady-state hypoxia (0.10±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC) and a change in FVC during the last 1-min of CPT was calculated (ΔFVC). The main effect of group (obese, non-obese), condition (normoxia, hypoxia) and the interaction of group and condition were compared using a two-way repeated measures ANOVA. Results: In female participants without obesity, ΔFVC during normoxia was attenuated during hypoxia (-0.57±0.19 vs +0.36±0.34 mL/dL/100mmHg/min; p=0.009). Conversely, in female participants with obesity, ΔFVC during normoxia did not differ from the response during hypoxia (-0.31±0.46 vs -0.87±0.34 mL/dL/100mmHg/min; p=0.382). Group differences in ΔFVC were not observed during normoxia (p=0.657), but were present during hypoxia (p=0.039). Conclusion: Sympathetically-mediated vasoconstriction is attenuated during steady-state hypoxia in premenopausal females without obesity, whereas this response is not observed in female adults with obesity. These preliminary data advance our understanding of the impact of obesity on hypoxic vascular control in premenopausal female participants and have implications for conditions in which hypoxia and sympathetic activation are observed ( e.g., sleep apnea, heart failure, COVID-19). NIH HL130339 (JKL), NIH HL153523 (JKL), AHA 909014 (DWJ) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of hyperglycemia on tbx5a and nppa gene expression and its correlation to structural and functional changes in developing zebrafish heart.

The objective of the current study is to analyze the effects of gestational diabetes on structural and functional changes in correlation with these two essential regulators of developing hearts in vivo using zebrafish embryos. We employed fertilized zebrafish embryos exposed to a hyperglycemic condition of 25 mM glucose for 96 h postfertilization. The embryos were subjected to various structural and functional analyses in a time-course manner. The data showed that exposure to high glucose significantly affected the embryo's size, heart length, heart rate, and looping of the heart compared to the control. Further, we observed an increased incidence of ventricular standstill and valvular regurgitation with a marked reduction of peripheral blood flow in the high glucose-exposed group compared to the control. In addition, the histological data showed that the high-glucose exposure markedly reduced the thickness of the wall and the number of cardiomyocytes in both atrium and ventricles. We also observed striking alterations in the pericardium like edema, increase in diameter with thinning of the wall compared to the control group. Interestingly, the expression of tbx5a and nppa was increased in the early development and found to be repressed in the later stage of development in the hyperglycemic group compared to the control. In conclusion, the developing heart is more susceptible to hyperglycemia in the womb, thereby showing various developmental defects possibly by altering the expression of crucial gene regulators such as tbx5a and nppa.

Sex differences in the vascular response to sympathetic activation during acute hypoxaemia.

What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control comes from predominantly male cohorts. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not? What is the main finding and its importance? Sympathetically mediated vasoconstriction is preserved or even enhanced during steady-state hypoxia in young men, and the peripheral vascular response to sympathetic activation during hypoxaemia is attenuated in young women. These data advance our understanding of sex-related differences in hypoxic vascular control. Activation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. Sympathetically mediated vasoconstriction may be attenuated during systemic hypoxia to maintain oxygen delivery; however, in predominantly male participants sympathetically mediated vasoconstriction is preserved or even enhanced during hypoxaemia. Given the potential for sex-specific differences in hypoxic vascular control, prior results are limited in application. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not. Healthy young men (n=13, 25±4years) and women (n=11, 24±4years) completed two trials consisting of a 2-min cold pressor test (CPT, a well-established sympathoexcitatory stimulus) during baseline normoxia and steady-state hypoxaemia. Beat-to-beat blood pressure (finger photoplethysmography) and forearm blood flow (venous occlusion plethysmography) were measured continuously. Total and forearm vascular conductance (TVC and FVC, respectfully) were calculated. A change (Δ) in TVC and FVC from steady-state during the last 1min of CPT was calculated and differences between normoxia and systemic hypoxia were assessed. In men, the reduction in TVC during CPT was greater during hypoxia compared to normoxia (ΔTVC, P=0.02), whereas ΔTVC did not differ between conditions in women (P=0.49). In men, ΔFVC did not differ between normoxia and hypoxia (P=0.92). In women, the reduction in FVC during CPT was attenuated during hypoxia (ΔFVC, P<0.01). We confirm sympathetically mediated vasoconstriction is preserved or enhanced during hypoxaemia in young men, whereas peripheral vascular responsiveness to sympathetic activation during hypoxaemia is attenuated in young women. The results advance our understanding of sex-related differences in hypoxic vascular control.

S‑1‑Propenylcysteine, a sulfur compound in aged garlic extract, alleviates cold‑induced reduction in peripheral blood flow in rat via activation of the AMPK/eNOS/NO pathway

Aged garlic extract (AGE) has been shown to improve peripheral circulatory disturbances in both clinical trials and experimental animal models. To investigate the effect of S-1-propenylcysteine (S1PC), a characteristic sulfur compound in AGE, on cold-induced reduction in tail blood flow of rat, Wistar rats were individually placed in a restraint cage and given the treatment with cold water (15˚C) after the oral administration of AGE or its constituents S1PC, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC). After the cold-treatment the tail blood flow of rats was measured at the indicated times. The pretreatment with AGE (2 g/kg BW) and S1PC (6.5 mg/kg BW) significantly alleviated the reduction of rat tail blood flow induced by cold treatment. The effect of S1PC was dose-dependent and maximal at the dose of 6.5 mg/kg BW, whereas SAC and SAMC were ineffective. To gain insight into the mechanism of S1PC action, the concentration of nitrogen oxide metabolites (NOx) in the plasma and the levels of phosphorylated endothelial nitric oxide synthase (eNOS) and 5'-AMP-activated protein kinase (AMPK) in the aorta were measured. The pretreatment with S1PC significantly increased the plasma concentration of NOx as well as the level of phosphorylated form of AMPK and eNOS in the aorta after cold-treatment. The present findings suggest that S1PC is a major constituent responsible for the effect of AGE to alleviate the cold-induced reduction of peripheral blood flow in rat by acting on the AMPK/eNOS/NO pathway in the aorta.

Sex Differences in Response to Acute Sympathetic Activation During Steady State Hypoxia

BackgroundActivation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. This sympathetically‐mediated vasoconstriction may be attenuated during hypoxia to maintain oxygen delivery – termed sympatholysis. However, hypoxic sympatholysis was previously shown to be absent in humans. A limitation of prior work was the failure to directly examine this response in women. Given young women exhibit an increase in blood flow during hypoxia, we hypothesized hypoxic sympatholysis would be present in young women but absent in young men.MethodsBlood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in healthy young men (n=9, 26±1 yrs) and women (n=10, 24±1 yrs). Subjects completed two trials consisting of a 2‐min cold pressor test (CPT) during baseline normoxia (0.21 FiO2, 98±0% SpO2) and following 3 min of steady‐state hypoxia (0.11±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC). A change in FVC from steady‐state during the last 1‐min of CPT was calculated (ΔFVC). The difference in ΔFVC between normoxia and hypoxia trials was used as an index of hypoxic sympatholysis.ResultsIn men, ΔFVC did not differ between normoxia and hypoxia (ΔFVC Normoxia: −0.30±0.45, Hypoxia: −0.77±0.41 mL/dL/100mmHg/min; p=0.46). In contrast, in women ΔFVC during normoxia (−0.70±0.27 mL/dL/100mmHg/min) was attenuated during hypoxia (+0.48±0.46 mL/dL/100mmHg/min; p=0.04) – indicating sympatholysis. The magnitude of hypoxic sympatholysis was greater in women than in men (Men: −0.46±0.38, Women: +1.18±0.39 mL/dL/100mmHg/min; p&lt;0.01).ConclusionYoung women attenuate sympathetically‐mediated vasoconstriction during steadystate hypoxia, whereas men do not. In other words, hypoxic sympatholysis is present in young women, but absent in young men. These data advance our understanding of sex‐related differences in hypoxic vascular control.Support or Funding InformationFundingNIH HL130339

Differential vasomotor responses to isocapnic hyperoxia: cerebral versus peripheral circulation.

Isocapnic hyperoxia (IH) evokes cerebral and peripheral hypoperfusion via both disturbance of redox homeostasis and reduction in nitric oxide (NO) bioavailability. However, it is not clear whether the magnitude of the vasomotor responses depends on the vessel network exposed to IH. To test the hypothesis that the magnitude of IH-induced reduction in peripheral blood flow (BF) may differ from the hypoperfusion response observed in the cerebral vascular network under oxygen-enriched conditions, nine healthy men (25 ± 3 yr, mean ± SD) underwent 10 min of IH during either saline or vitamin C (3 g) infusion, separately. Femoral artery (FA), internal carotid artery (ICA), and vertebral artery (VA) BF (Doppler ultrasound), as well as arterial oxidant (8-isoprostane), antioxidant [ascorbic acid (AA)], and NO bioavailability (nitrite) markers were simultaneously measured. IH increased 8-isoprostane levels and reduced nitrite levels; these responses were followed by a reduction in both FA BF and ICA BF, whereas VA BF did not change. Absolute and relative reductions in FA BF were greater than IH-induced changes in ICA and VA perfusion. Vitamin C infusion increased arterial AA levels and abolished the IH-induced increase in 8-isoprostane levels and reduction in nitrite levels. Whereas ICA and VA BF did not change during the vitamin C-IH trial, FA perfusion increased and reached similar levels to those observed during normoxia with saline infusion. Therefore, the magnitude of IH-induced reduction in femoral blood flow is greater than that observed in the vessel network of the brain, which might involve the determinant contribution that NO has in the regulation of peripheral vascular perfusion.

Therapeutic effects of physostigmine during systemic inflammation.

IntroductionUsually, physostigmine is used as antidote for anticholinergic poisons in order to improve hemodynamics and cardiac output. In addition, it causes beneficial effects during sepsis when added timely. Here, we studied whether physostigmine improves hemodynamics when treatment during systemic inflammation was delayed.MethodsTwo series of randomized studies with overall 44 rats were conducted. Systemic inflammation was induced by lipopolysaccharide (LPS) infusion (0.5 mg LPS/kg×h). Physostigmine (PHY) was intravenously applied after an LPS infusion period of 90 minutes (50 µg PHY/kg within 10 minutes) with (series 1) and without (series 2) additional volume loading. Hemodynamic parameters, blood gases, and parameters for tissue damage were periodically determined for up to 180 minutes.ResultsEven though volume was additionally administered (series 1), LPS caused a reduction of peripheral blood flow. Treatment with PHY improved hemodynamics in macrocirculation (mean arterial blood pressure) and microcirculation (peripheral blood flow). PHY neither affected alterations in blood gases, electrolyte homeostasis, and glucose metabolism nor prevented intestinal damage induced by LPS. In series 2, without any additional volume loading, PHY likewise resulted in an improvement of the LPS-induced alterations in macro- and microcirculation, but finally worsened the LPS-mediated effects on plasma parameters for tissue damage such as creatine kinase, probably due to the lack of volume and a further damage to the heart.ConclusionThe present results demonstrated that hemodynamic responses to PHY may not only be visible in patients with anticholinergic drug overdose but also be visible in septic patients, provided that fluid intake of these patients is adequate.

Retention of finger blood flow against postural change as an indicator of successful sympathetic block in the upper limb.

BackgroundSympathetic block in the upper limb has diagnostic, therapeutic and prognostic utility for disorders in the upper extremity that are associated with sympathetic disturbances. Increased skin temperature and decreased sweating are used to identify the adequacy of sympathetic block in the upper limb after stellate ganglion block (SGB). Baroreflexes elicited by postural change induce a reduction in peripheral blood flow by causing sympathetic vasoconstriction. We hypothesized that sympathetic block in the upper limb reduces the decrease in finger blood flow caused by baroreflexes stimulated by postural change from the supine to long sitting position. This study evaluated if sympathetic block of the upper limb affects the change in finger blood flow resulting from postural change. If change in finger blood flow would be kept against postural changes, it has a potential to be a new indicator of sympathetic blockade in the upper limb.MethodsSubjects were adult patients who had a check-up at the Department of Pain Management in our university hospital over 2 years and 9 months from May 2012. We executed a total of 91 SGBs in nine patients (N=9), which included those requiring treatment for pain associated with herpes zoster in seven of the patients, tinnitus in one patient and upper limb pain in one patient. We checked for the following four signs after performing SGB: Horner’s sign, brachial nerve blockade, finger blood flow measured by a laser blood flow meter and skin temperature of the thumb measured by thermography, before and after SGB in the supine position and immediately after adopting the long sitting position.ResultsWe executed a total of 91 SGBs in nine patients. Two SGBs were excluded from the analysis due to the absence of Horner’s sign. We divided 89 procedures into two groups according to elevation in skin temperature of the thumb: by over 1°C (sympathetic block group, n=62) and by <1°C (nonsympathetic block group, n=27). Finger blood flow decreased significantly just after a change in posture from the supine to long sitting position after SGB in both groups. In the sympathetic block group, the ratio of finger blood flow in the long sitting position/supine position with a change in posture significantly increased after SGB compared with before SGB (before SGB: range 0.09–0.94, median 0.53; after SGB: range 0.33–1.2, median 0.89, p<0.0001).ConclusionOur study shows that with sympathetic block in the upper limb, the ratio of finger blood flow significantly increases despite baroreflexes stimulated by postural change from the supine to long sitting position. Retention of finger blood flow against postural changes may be an indicator of sympathetic block in the upper limb after SGB or brachial plexus block.

Retention of Finger Blood Flow against Postural Change Has the Potential to Become a New Indicator of Sympathetic Block in the Upper Limb - A Preliminary Study

Introduction: Increased skin temperature and decreased sweating are used to identify the adequacy of sympathetic block in the upper limb. This, however, requires a thermography device to precisely evaluate skin temperature and a diaphoremeter to measure sweating. Baroreflexes elicited by postural change induce a reduction in peripheral blood flow to sustain systemic blood pressure and cerebral blood flow. We hypothesized that sympathetic blockade in the upper limb results in minimal changes in finger skin blood flow against postural change from the supine to sitting position. The aim of this study was to evaluate whether retention of finger blood flow against postural change can be used as a new indicator of sympathetic block in the upper limb. Methods: We tested for the following three signs after performing stellate ganglion block (SGB): Horner’s sign, brachial nerve blockade and finger blood flow, which was measured by a laser blood flow meter before and after SGB in the supine and immediately after adopting the sitting position. The criterion for determining effective sympathetic blockade in the upper limb was defined as follows: (Blood flow in the sitting position) / (Blood flow in the supine position) > 90%. Results: We executed a total of 80 SGBs in 7 patients. Two SGBs were excluded from analysis due to the absence of Horner’s sign. Brachial nerve blockade after SGB was absent in all patients. The criterion of (Blood flow in the sitting position) / (Blood flow in the supine position) > 90% was observed significantly more often on the SGB (45 cases) than non-SGB side (3 cases).

Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure.

Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, sex, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress, and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Furthermore, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice.

Sirtuin1 single nucleotide polymorphism (A2191G) is a diagnostic marker for vibration-induced white finger disease

BackgroundVibration-induced white finger disease (VWF), also known as hand-arm vibration syndrome, is a secondary form of Raynaud’s disease, affecting the blood vessels and nerves. So far, little is known about the pathogenesisof the disease. VWF is associated with an episodic reduction in peripheral blood flow. Sirtuin 1, a class III histone deacetylase, has been described to regulate the endothelium dependent vasodilation by targeting endothelial nitric oxide synthase. We assessed Sirt1single nucleotide polymorphisms in patients with VWF to further elucidate the role of sirtuin 1 in the pathogenesis of VWF.MethodsPeripheral blood samples were obtained from 74 patients with VWF (male 93.2%, female 6.8%, median age 53 years) and from 317 healthy volunteers (gender equally distributed, below 30 years of age). Genomic DNA was extracted from peripheral blood mononuclear cells and screened for potential Sirt1single nucleotide polymorphisms. Four putative genetic polymorphisms out of 113 within the Sirt1 genomic region (NCBI Gene Reference: NM_012238.3) were assessed. Allelic discrimination was performed by TaqMan-polymerasechainreaction-based allele-specific genotyping single nucleotide polymorphism assays.ResultsSirt1single nucleotide polymorphism A2191G (Assay C_25611590_10, rs35224060) was identified within Sirt1 exon 9 (amino acid position 731, Ile → Val), with differing allelic frequencies in the VWF population (A/A: 70.5%, A/G: 29.5%, G/G: 0%) and the control population (A/A: 99.7%, A/G: 0.3%, G/G: 0.5%), with significance levels of P < 0.001 (Mann–Whitney U test (two-tailed) P <0.001; F-exact t-test and Chi-square test with Yates correction (all two-tailed): P <0.0001). The heterogeneous A/G genotype in base pair position 2191 is significantly overrepresented in the VWF patient population when compared with healthy controls.ConclusionWe identified theSirt1A2191Gsingle nucleotide polymorphism as a diagnostic marker for VWF.

Hyperventilation and finger exercise increase venous-arterial P co2 and pH differences

Introduction Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. Methods We measured venous-arterial P co 2 difference ((v-a)P co 2) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. Results In healthy volunteers, both (v-a)P co 2 and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)P co 2 and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. Conclusions It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.

Experimental Model of Lower Limb Ischemia in Rats and the Effect of YM466, an Oral Direct Factor Xa Inhibitor

A simple, quantitative, and reproducible model of lower limb ischemia was developed. Vascular injury was induced by ferric chloride (FeCl(3)) solution to the rat iliac artery, after which blood flow in all of the lower limbs were continuously monitored using a scanning laser Doppler blood flowmeter. After FeCl(3) injury, a distinct decrease in blood flow in the ischemic lower limb was observed and blood flow did not recover during the 30 min after vascular injury. YM466, an oral direct factor Xa inhibitor, dose-dependently inhibited the reduction of peripheral blood flow. The area under the blood flow-time curve during 30 min after vascular injury improved dose-dependently, with significance at doses of 3 and 10 mg/kg. These results suggest that factor Xa inhibitors are effective in patients with peripheral arterial disease, and that this vascular injury model is a useful tool for the screening and evaluation of the efficacy of new antithrombotic agents.

Aryl hydrocarbon receptor 2 mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish.

In order to use the zebrafish as a model vertebrate to investigate the developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), it is essential to know whether one or both forms of the zebrafish aryl hydrocarbon receptor (AHR), zfAHR1 or zfAHR2, mediate toxicity. To determine the role of zfAHR2, an antisense morpholino approach was used to knock down translation of the protein. No effect of the zfahr2 morpholino (zfahr2-MO) was seen on normal development in embryos not treated with TCDD. Injection of embryos at the 1-2 cell stage with zfahr2-MO decreased TCDD-induced transcription of zfCYP1A mRNA until 96 h post fertilization (hpf), and immuno-histochemical detection of zfCYP1A protein in embryos at 72 hpf revealed a dramatic decrease in expression. The zfahr2-MO completely protected embryos from TCDD-induced edema and anemia and provided protection against TCDD-induced reductions in peripheral blood flow initially; however, a slight reduction in blood flow was observed at later times when the morpholino was no longer effective. Due to persistence of TCDD and decreasing effectiveness of the zfahr2-MO over time, the morpholino provided only transient protection against TCDD-induced inhibition of chondrogenesis of the lower jaw, and no protection against an effect of TCDD that was initiated late in development, blockade of swimbladder inflation. The zfahr2-MO did not protect embryos from TCDD-induced mortality but did produce a 48 h delay in its onset. Endpoints of TCDD developmental toxicity manifested in zfahr2 morphants at late stages of development, beyond 144 hpf, were clearly different from TCDD-exposed embryos injected with a control morpholino. Most strikingly, zfahr2 morphants exposed to TCDD never developed edema. Taken together, these results demonstrate that zfAHR2 mediates several endpoints of TCDD developmental toxicity in zebrafish.

皮膚温度および食塩の塩味に及ぼす天然にがりの影響

The results of this study clarify the physiological significance of the variation in skin temperature at the shoulder. The skin temperature was found to be reduced by shoulder stiffness, indicating that this decrease in the skin temperature might have been caused by disturbance of the peripheral blood flow. In addition to the effect from shoulder stiffness, ingesting miso soup called “asage” also reduced the skin temperature at shoulder. The addition of bittern prepared at Indonesia to the miso soup accelerated the reduction of skin temperature, suggesting that the salty taste of the miso soup might have been responsible for this reduction. Experiments were conducted to clarify whether or not the bittern increased the salty taste of the miso soup to indicate that the reduction in skin temperature might have been induced by the salty taste. The experimental results clearly indicated that the bittern increased the salty taste of NaCl solution and show that MgCl2 in the bittern was the active principle. These results collectively suggest that reduction in skin temperature associated with shoulder stiffness might have been induced by the reduction of peripheral blood flow and that the addition of the bittern to the miso soup accelerated this reduction in skin temperature.

Carotid hemodynamic alterations in hypertensive patients with insulin resistance

Background Insulin resistance (IR) is implicated in the pathogenesis of atherosclerosis. One mechanism is thought to be the impaired vasodilation, which can lead to a reduction in peripheral blood flow. Hypertensive patients with IR have greater intima–media thickness (IMT) in the common carotid artery (CCA) than those without IR. However, the relationship between IR and hemodynamic alterations of the CCA has not been clarified. Methods Seventy patients with essential hypertension (EHT) and 11 normotensive controls (NT) participated in this study. The IMT, number of plaques, and internal dimensions of the CCA were evaluated by ultrasound imaging. Mean diastolic (Vd) and systolic (Vs) velocity were determined by the Doppler flow method, and other parameters such as Vd/Vs and the cross-sectional distensibility coefficient (CSDC) were further calculated. When the homeostasis model assessment (HOMA) index exceeded 2.0, the subject was considered to have IR. Results: The IMT was positively correlated with the HOMA index in all subjects. The Vd/Vs and CSDC were significantly decreased in EHT patients with IR compared to NT and EHT patients without IR. The Vd/Vs and CSDC were negatively correlated with the HOMA index. A stepwise regression analysis revealed that age, HDL-cholesterol, and the HOMA index were independently associated with IMT in patients with EHT. Age, the HOMA index, and mean blood pressure (MBP) were independently associated with CSDC, and the first two factors were independently associated with Vd/Vs. Conclusions Decreased distensibility of the arterial wall and ensuing low diastolic perfusion are possible mechanisms of atherosclerotic changes in the CCA in EHT patients with IR.

Effects of 9 Kampo medicines clinically used in hypertension on hemodynamic changes induced by theophylline in rats.

We examined the effects of 9 kinds of Kampo medicines, which are clinically used for the treatment of hypertension, on anesthetized rats with increases in arterial blood pressure, heart rate and peripheral blood flow induced by theophylline (5 mg/kg, i.v.) that were partially or completely mediated by endogenous catecholamines. Each Kampo medicine (1 g/kg) was intraduodenaly administered. Shinbu-to caused a severe disturbance of the arterial blood pressure. Saiko-ka-ryukotsu-borei-to, Oren-gedoku-to, San'o-shashin-to and Dai-jyoki-to had hypotensive effects, while Hachimi-jio-gan, Gosha-jinki-gan, Dai-saiko-to and Choto-san did not have such an effect. Moreover, Saiko-ka-ryukotsu-borei-to attenuated the heart rate. In Oren-gedoku-to, San'o-shashin-to and Dai-jyoki-to, a reduction in peripheral blood flow was observed. These results suggest that Saiko-ka-ryukotsuborei-to, Oren-gedoku-to, San'o-shashin-to and Dai-jyoki-to are ameliorative to the hypertension in sympathetic system dominance and Shinbu-to is occasionally dangerous to it.

901-74 Delayed and Incomplete Reversal of Impaired Metabolic Vasodilation in Patients with Heart Failure During Long-term Circulatory Support with a Left Ventricular Assist Device

Impaired vasodilation in response to metabolic stimuli in the peripheral circulation is an important determinant of exercise intolerance in patients with congestive heart failure (CHF). The pathogenesis of impaired metabolic vasodilation in patients with CHF is uncertain but may be related in part to chronic reductions in peripheral blood flow in patients with low cardiac output (CO). A left ventricular assist device (LVAD) is an implantable mechanical pump that provides a non-pharmacologic means to markedly Increase CO in patients with severe CHF for long periods of time. Whether long-term mechanical restoration of normal resting CO with an LVAD enhances metabolic vasodilation in the peripheral circulation of patients with CHF is unknown. Accordingly, peak forearm blood flow (FBF, ml/min/l00 ml) after 5 minutes of brachial artery occlusion (a maximal metabolic vasodilation stimulus) was measured with venous occlusion plethysmography in 8 patients with NYHA Class IV CHF (mean age 52 yrs, mean EF 22%) before, and 1 and 8 weeks (wks) after continuous LVAD support and in 8 normal subjects. Mean arterial pressure (MAP, mmHg) was measured during each FBF measurement in the contralateral arm by cuff method. MAP, peak FBF, and maximum vascular conductance (calculated in arbitrary units as FBF/MAP) after arterial occlusion were as follows:Empty CellBefore LVAD1wk post8 wks postNormalsMAP65 ± 493 ± 6*92 ± 5*89 ± 9Peak FBF5.9 ± 1.69.5 ± 4.816.4 ± 2.8*31.5 ± 2.7†Conductance0.10 ± 0.030.10 ± 0.050.18 ± 0.03*0.36 ± 0.05†*indicates p &lt; 0.05 vs. Before LVAD†indicates p &lt; 005 vs. 8 wks post-LVAD indicates p &lt; 0.05 vs. Before LVAD indicates p &lt; 005 vs. 8 wks post-LVAD Mean CO increased from 2.3 l/min before LVAD to 5.4 l/min 1 and 8 wks during LVAD support. Despite early normalization of CO and MAP within 1 week after LVAD, the maximum vascular conductance after brachial artery occlusion did not change after 1week, and remained less than that observed in normal subjects after 8 weeks of LVAD support. The delayed and incomplete reversal of abnormal metabolic vasodilation during long-term continuous LVAD support suggests that mechanisms in addition to reduced CO contribute to decreased metabolic vasodilation in patients with CHF.

The hemodynamic effects of adrenergic blocking agents.

The various antihypertensive agents reduce blood pressure by different mechanisms. Alpha-1 receptor blockers reduce vascular resistance and maintain cardiac output. Chronic treatment with beta blockers without intrinsic sympathomimetic activity produces a fall in blood pressure which is associated with a fall in cardiac index and heart rate. Beta blockers with strong intrinsic sympathomimetic activity showed reduced heart rate during exercise. Labetalol reduces cardiac output and peripheral vascular resistance with little or no reduction in peripheral blood flow. Alpha-1 blockers are suitable for patients with active life-styles, with peripheral vascular disorders, or with high blood-cholesterol levels. Beta blockers are useful in patients who have tachycardia, palpitation problems, or angina pectoris, or who have survived a heart attack. They should not be used in patients with bronchial asthma, reduced peripheral blood flow, or heart failure. Labetalol reduces blood pressure in a somewhat larger fraction of patients than the pure alpha- or beta-blocking agents. It is hoped that its long-term results will include regression of cardiovascular damage, improved quality of life, and increased life expectancy.