Sumio Hoka

Limited maximal vasodilator capacity of forearm resistance vessels in normotensive young men with a familial predisposition to hypertension.

The study was performed to determine whether there is a structural vascular abnormality in normotensive subjects with hypertensive relatives. We examined maximal vasodilator capacity of forearm resistance vessels in 23 normotensive young men (mean blood pressure 94 ± 0.4 mm Hg, mean ± SE) with hypertensive relatives (age 24 ± 0.1 years) and in 17 normotensive subjects (mean blood pressure 85 ± 0.4 mm Hg) with no family history of hypertension (age 24 ± 0.1 years). Maximal vasodilator capacity was examined by measuring minimal vascular resistance during peak reactive hyperemia after release from 10 minutes of arterial occlusion. Minimal forearm vascular resistance after release from 10 minutes of arterial occlusion was 25% higher (P < 0.02) in subjects with hypertensive relatives (2.0 ± 0.02 units) than that in subjects with no family history (1.5 ± 0.01 units). We confirmed the previous findings that increasing metabolic vasodilator stimulus by performing intermittent handgrip exercise during 10 minutes of arterial occlusion did not augment peak dilation. This suggests that 10 minutes of arterial occlusion produced maximal vasodilation. Forearm vascular responses to ice on the forehead was greater in subjects with hypertensive relatives than those in subjects with no family history. These results suggest that there may be a structural abnormality in the forearm resistance vessels in normotensive subjects with family history of hypertension.

Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral neuronal systems and exhibits numerous biological activities in mammals. We examined in the present study whether or not endogenous CGRP released from neuronal systems facilitates neovascularization indispensable to wound healing. In CGRP knockout mice (CGRP-/-), wound-induced angiogenesis and wound closure were significantly suppressed compared with those in wild-type mice. The suppressed healing in CGRP-/- was accompanied by reduction in expressions of vascular endothelial growth factor (VEGF) in the wound granulation tissues. A CGRP antagonist, CGRP8-37 when infused with mini-osmotic pumps subcutaneously blocked the wound healing processes and reduced the expressions of CD31 and VEGF expression in the wound granulation tissues. Wound healing process was significantly delayed in neuropeptide-depleted mice pretreated with capsaicin, compared with vehicle-treated mice. These results indicate that CGRP derived from neuronal systems may facilitate wound healing and angiogenesis. Targeting of CGRP may be promising in controlling angiogenesis related to pathophysiological conditions.

Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide

A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in neuronal systems and exhibits numerous biological activities. Using CGRP-knockout mice (CGRP−/−), we examined whether or not endogenous CGRP facilitates angiogenesis indispensable to tumor growth. CGRP increased tube formation by endothelial cells in vitro and enhanced sponge-induced angiogenesis in vivo. Tumor growth and tumor-associated angiogenesis in CGRP−/− implanted with Lewis lung carcinoma (LLC) cells were significantly reduced compared with those in wild-type (WT) mice. A CGRP antagonist, CGRP8-37 or denervation of sciatic nerves (L1–5) suppressed LLC growth in the sites of denervation compared with vehicle infusion or sham operation. CGRP precursor mRNA levels in the dorsal root ganglion in LLC-bearing WT were increased compared with those in non-LLC-bearing mice. This increase was abolished by denervation. The expression of VEGF in tumor stroma was down-regulated in CGRP−/−. These results indicate that endogenous CGRP facilitates tumor-associated angiogenesis and tumor growth and suggest that relevant CGRP may be derived from neuronal systems including primary sensory neurons and may become a therapeutic target for cancers.

Impaired acquisition of skilled behavior in rotarod task by moderate depletion of striatal dopamine in a pre-symptomatic stage model of Parkinson's disease

In view of recent findings that suggest that the nigrostriatal dopamine (DA) system plays a role in motor control and the acquisition of habits and skills, we hypothesized that the striatum-based function underlying the acquisition of skilled behaviors might be more vulnerable to dopamine depletion than the motor control. To test this hypothesis, we investigated whether impaired acquisition of skilled behaviors occurs in a pre-symptomatic stage model of Parkinsons disease (PD). By using the microdialysis method and the 6-OHDA-technique to destroy dopamine neurons, we confirmed that rats with unilateral partial lesions of the nigral dopamine cells by 6-OHDA are suitable for a pre-symptomatic stage model of Parkinsons disease. The rats in this model exhibited moderate disruption of striatal dopamine release function and relatively intact motor functions. In a rotarod test, the impaired acquisition of skilled behavior occurred in rats with bilateral partial lesions of the nigral dopamine cells by 6-OHDA. These rats displayed intact general motor functions, such as locomotor activity, adjusting steps, equilibrium function and muscle strength. Based on these results, we concluded that the striatum-based function underlying the acquisition of skilled behaviors or sensorimotor learning may be more vulnerable to dopamine depletion than the motor control.

Propofol-induced Increase in Vascular Capacitance Is Due to Inhibition of Sympathetic Vasoconstrictive Activity

Background Venodilation is thought to be one of the mechanisms underlying propofol‐induced hypotension. The purpose of this study is to test two hypotheses: (1) propofol increases systemic vascular capacitance, and (2) the capacitance change produced by propofol is a result of an inhibition of sympathetic vasoconstrictor activity. Methods In 33 Wistar rats previously anesthetized with urethane and ketamine, vascular capacitance was examined before and after propofol infusion by measuring mean circulatory filling pressure (Pmcf). The P (mcf) was measured during a brief period of circulatory arrest produced by inflating an indwelling balloon in the right atrium. Rats were assigned into four groups: an intact group, a sympathetic nervous system (SNS)‐block group produced by hexamethonium infusion, a SNS‐block + noradrenaline (NA) group, and a hypovolemic group. The Pmcf was measured at a control state and 2 min after a bolus administration of 2, 10, and 20 mg/kg of propofol. Results The mean arterial pressure (MAP) was decreased by propofol dose‐dependently in intact, hypovolemic, and SNS‐block groups, but the decrease in MAP was less in the SNS‐block group (‐25%) than in the intact (‐50%) and hypovolemic (‐61%) groups. In the SNS‐block + NA group, MAP decreased only at 20 mg/kg of propofol (‐18%). The Pmcf decreased in intact and hypovolemic groups in a dose‐dependent fashion but was unchanged in the SNS‐block and SNS‐block + NA groups. Conclusions The results have provided two principal findings: (1) propofol decreases Pmcf dose‐dependently, and (2) the decrease in Pmcf by propofol is elicited only when the sympathetic nervous system is intact, suggesting that propofol increases systemic vascular capacitance as a result of an inhibition of sympathetic nervous system.

Low-concentration lidocaine rapidly inhibits axonal transport in cultured mouse dorsal root ganglion neurons.

BackgroundAxonal transport plays a critical role in supplying materials for a variety of neuronal functions such as morphogenetic plasticity, synaptic transmission, and cell survival. In the current study, the authors investigated the effects of the analgesic agent lidocaine on axonal transport in neurites of cultured mouse dorsal root ganglion neurons. In relation to their effects, the effects of lidocaine on the growth rate of the neurite were also examined. MethodsIsolated mouse dorsal root ganglion cells were cultured for 48 h until full growth of neurites. Video-enhanced microscopy was used to observe particles transported within neurites and to measure the neurite growth during control conditions and in the presence of lidocaine. ResultsApplication of 30 &mgr;m lidocaine immediately reduced the number of particles transported in anterograde and retrograde axonal directions. These effects were persistently observed during the application (26 min) and were reversed by lidocaine washout. The inhibitory effect was dose-dependent at concentrations from 0.1 to 1,000 &mgr;m (IC50= 10 &mgr;m). In Ca2+-free extracellular medium, lidocaine failed to inhibit axonal transport. Calcium ionophore A23187 (0.1 &mgr;m) reduced axonal transport in both directions. The inhibitory effects of lidocaine and A23187 were abrogated by 10 &mgr;m KN-62, a Ca2+–calmodulin-dependent protein kinase II inhibitor. Application of such low-concentration lidocaine (30 &mgr;m) for 30 min reduced the growth rate of neurites, and this effect was also blocked by KN-62. ConclusionsLow-concentration lidocaine rapidly inhibits axonal transport and neurite growth via activation of calmodulin-dependent protein kinase II.

Alteration of blood flow distribution and vascular capacitance during induced hypotension in deafferented dogs

The effects of three hypotensive agents, sodium nitroprusside (SNP), nitroglycerin (NTG), and adenosine triphosphate (ATP), on blood flow distribution and vascular capacitance were examined in dogs anesthetized with sodium pentobarbital. To eliminate the modification by the baroreflex, carotid sinus was denervated and aortic and cardiopulmonary vagal fibers were sectioned. Total systemic circulation was divided into two parallel compartments, splanchnic (SP) and extra-splanchnic (ESP) vascular beds. Alteration of vascular capacitance was assessed by a change in systemic blood volume with constant cardiac output and constant venous pressure using a total heart-lung bypass. SNP- and ATP-induced hypotension caused blood flow redistribution from the SP to ESP beds, and this redistribution is greater (P less than 0.01) with ATP than that with SNP. In contrast, NTG-induced hypotension did not significantly cause redistribution. Systemic blood volume was increased during NTG- (10.4 +/- 2.2 ml/kg), and SNP-induced (4.8 +/- 1.1 ml/kg) hypotension. The increase by NTG was significantly greater (P less than 0.05) than that by SNP. In contrast, ATP-induced hypotension did not significantly change systemic blood volume. Since redistribution can result in a passive change in vascular capacitance, the differences in capacitance among SNP, NTG, and ATP can be explained in part by differences in redistribution of blood flow. Redistribution of blood flow from SP to ESP beds can increase venous return due to increasing the slope of the venous return curve. The results suggest that redistribution should be taken into consideration in evaluating the hemodynamic changes during induced hypotension.

Neurotoxicity of intrathecally administered bupivacaine involves the posterior roots/posterior white matter and is milder than lidocaine in rats

Background and Objectives Clinical and laboratory studies suggest that lidocaine is more neurotoxic than bupivacaine. However, histological evidence of their comparative neurotoxicity is sparse. We thus pathologically and functionally compared the intrathecal neurotoxicity of these agents. Methods Rats received 0.12 μL/g body weight lidocaine (0%, 2%, 10%, or 20%) or bupivacaine (0%, 0.5%, 2.5%, or 5%) in distilled water via an intrathecal catheter. The influence of high osmolarity was also examined using 5% bupivacaine in 20% glucose solution (5% BG) and a control 25% glucose solution. The L3 spinal cord, the posterior and anterior roots, and the cauda equina were examined by light and electron microscopy. Walking behavior and sensory threshold were investigated as neurofunctional tests. Results The posterior root and posterior white matter showed axonal degeneration in rats treated with 10% and 20% lidocaine and 5% bupivacaine in distilled water (5% BDW) and in 5% BG, but not in rats treated with 2% lidocaine, 0.5% and 2.5% bupivacaine, distilled water, or 25% glucose solution. The histological damages were more severe in 20% lidocaine-treated rats than in 5% bupivacaine-treated rats. The damage of posterior white matter was observed only when the posterior root was severely injured. No significant difference of histological findings was observed between 5% BDW and 5% BG. Functional abnormalities were found only in rats treated with 20% lidocaine. Conclusions The neurotoxic lesions caused by bupivacaine and lidocaine were indistinguishable in the primary site and the extending pattern, such as axonal degeneration originating from the posterior roots and extending to the posterior white matter. The intrathecal neurotoxicity is greater in lidocaine than in bupivacaine.

Clinical characteristics of perioperative coronary spasm : reviews of 115 case reports in Japan

AbstractPurpose. Factors affecting perioperative development of coronary spasm have not been elucidated. A number of case reports describing perioperative coronary spasm have appeared in Japanese anesthesia journals, mostly published in Japanese. The purpose of this study was to investigate the contributing factors affecting perioperative coronary artery spasm by reviewing the published articles. Methods. Reports were identified by using Medline database (1968–1998) or by manually searching nonindexed Japanese journals. The clinical characteristics of perioperative coronary spasm were analyzed in 115 patients who developed coronary artery spasm during the perioperative period. Results. The mean age of the patients was 64 ± 9 years (range, 36 to 87 years). There were 97 men (84%) and 18 women (16%). Preoperative risk factors included hypertension (27%), angina pectoris (27%), cigarette smoking (13%), and diabetes mellitus (11%). The attack was related to inadequate depth of general anesthesia (23%), use of vasopressors (22%), vagal reflex (19%), administration of drugs other than vasopressors (17%), and epidural block (15%). About 85% of patients showed no ischemic abnormality on the preoperative electrocardiogram, whereas 56% had significant coronary stenosis on postoperative coronary arteriography. Coronary spasm tended to occur in patients under inhalation anesthesia combined with epidural block. Nitrates alleviated the episode in the majority of cases, whereas defibrillation and cardiac massage were required in 19% of patients. No deaths were reported. Conclusion. Perioperative coronary spasm is prevalent in elderly male patients with coronary risk factors who undergo abdominal or thoracic surgery under inhalational anesthesia combined with epidural anesthesia. Instability of the autonomic nervous system and/or vascular hyperreactivity may be the underlying pathogenic mechanisms of perioperative coronary spasm.

Chemokine (C-C motif) Receptor 5 Is an Important Pathological Regulator in the Development and Maintenance of Neuropathic Pain

Background:The chemokine family has been revealed to be involved in the pathogenesis of neuropathic pain. In this study, the authors investigated the role of chemokine (C-C motif) ligand 3 and its receptors chemokine (C-C motif) receptor 1 and chemokine (C-C motif) receptor (CCR) 5 in neuropathic pain. Methods:A spinal nerve injury model was established in adult male Wistar rats. The von Frey test and hot plate test were performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry were performed to understand the molecular mechanisms. Results:The expression levels of chemokine (C-C motif) ligand 3 and CCR5 messenger RNA in the spinal cord were up-regulated after nerve injury, which was possibly due to CD11b-positive microglia. Single intrathecal administration of recombinant chemokine (C-C motif) ligand 3 produced biphasic tactile allodynia; each phase of pain behavior was induced by different receptors. Intrathecal injection of CCR5 antagonist suppressed the development of tactile allodynia (12.81 ± 1.33 g vs. 3.52 ± 0.41 g [mean ± SEM, drug vs. control in paw-withdrawal threshold]; P < 0.05, n = 6 each) and could reverse established tactile allodynia (10.87 ± 0.91 g vs. 3.43 ± 0.28 g; P < 0.05, n = 8 and 7). Furthermore, Oral administration of CCR5 antagonist could reverse established tactile allodynia (8.20 ± 1.27 g vs. 3.18 ± 0.46 g; P < 0.05, n = 4 each). Conclusions:Pharmacological blockade of CCR5 was effective in the treatment of the development and maintenance phases of neuropathic pain. Thus, CCR5 antagonists may be potential new drugs for the treatment of neuropathic pain.