Motoyasu Takenaka

Mechanisms Underlying Cerebrovascular Effects of Cigarette Smoking in Rats In Vivo

BACKGROUND AND PURPOSE The effects of acute smoking on cerebral circulation are controversial. This study was designed (1) to clarify any differences between the effects of cigarette smoking and nicotine infusion and between the effects of single- and multiple-cigarette smoking on cerebral vessels and (2) to probe the mechanism(s) underlying the vascular responses. METHODS In pentobarbital-anesthetized, mechanically ventilated Sprague-Dawley rats, pial vessel diameters were measured with the use of a cranial window preparation. We studied the effects of (1) 60 puffs per minute of mainstream cigarette smoke from cigarettes having 2 nicotine levels (0.1 and 1 mg per cigarette), (2) administration of nicotine (0.05 mg per body IV), and (3) repeated smoking (four 1 mg nicotine-containing cigarettes at 30-minute intervals) (n=6 each). RESULTS Inhalation of smoke from a 0.1 or 1 mg nicotine-containing cigarette for 1 minute caused pial arterioles to constrict at 30 seconds (7.2% and 7.3%, respectively) and then to dilate (peak at 5 to 10 minutes; 4.6% and 17.9%, respectively). Nicotine infusion caused pial vasodilation (35.7%) without an initial vasoconstriction. Repeated smoking suppressed the pial vasodilation but not the initial vasoconstriction. The vasodilation induced by a single cigarette was greatly inhibited by pretreatment with mecamylamine or glibenclamide and attenuated by propranolol or Nomega-nitro-L-arginine methyl ester; the initial vasoconstriction was inhibited by seratrodast, a thromboxane A2 receptor antagonist (n=6 in each case). CONCLUSIONS Single-cigarette smoking had a significant biphasic effect on cerebral arteriolar tone. The vasodilation was attenuated by repeated smoking. The vasodilation is most likely an effect of nicotine, at least in part mediated via sympathetic activation, NO production, and K+ channel activation. The vasoconstriction is partially due to thromboxane A2 induced by cigarette smoke.

Spinal conduction block by intrathecal ketamine in dogs

In addition to its use for intravenous (IV) anesthesia, ketamine can provide pain relief in humans when administered spinally.To elucidate the mechanisms of intrathecal (IT) ketamine analgesia, we observed differences in the effects of IV and IT ketamine on intraspinal evoked potentials (ISEPs) in 28 dogs anesthetized with pentobarbital. Bipolar extradural electrodes were inserted at the cervical and lumbar regions of the spinal cord for recording descending ISEPs represented by the two negative deflections, Waves I and II. IV ketamine 2 and 10 mg/kg did not affect the amplitude and latency of Wave I, whereas the large dose (10 mg/kg) significantly decreased the amplitude but not the latency of Wave II. IT ketamine 1 and 5 mg/kg caused significant dose-dependent decreases in both Wave I and II amplitudes and prolongations of both Wave I and II latencies. These IT effects on ISEPs are consistent with previous in vitro observations that ketamine blocks axonal conduction. We conclude that axonal conduction block may contribute to the analgesic mechanism of IT ketamine. (Anesth Analg 1997;85:106-10)

Rho-kinase inhibitor and nicotinamide adenine dinucleotide phosphate oxidase inhibitor prevent impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats.

Introduction. We previously reported that acute cigarette smoking can cause a dysfunction of endothelium-dependent vasodilation in cerebral vessels, and that blocking the angiotensin II (Ang II) type 1 (AT1) receptor with valsartan prevented this impairment. Our aim was to investigate the effects of a Rho-kinase inhibitor (fasudil) and a Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase inhibitor (apocynin) on smoking-induced endothelial dysfunction in cerebral arterioles. Method. In Sprague—Dawley rats, we used a closed cranial window preparation to measure changes in pial vessel diameters following topical acetylcholine (ACh) before smoking. After one-minute smoking, we again examined the arteriolar responses to ACh. Finally, after intravenous fasudil or apocynin pre-treatment we re-examined the vasodilator responses to topical ACh (before and after cigarette smoking). Results. Under control conditions, cerebral arterioles were dose-dependently dilated by topical ACh (10-6 M and 10-5 M). One hour after a one-minute smoking (1 mg-nicotine cigarette), 10-5 M ACh constricted cerebral arterioles. However, one hour after a one-minute smoking, 10-5 M ACh dilated cerebral pial arteries both in the fasudil pre-treatment and the apocynin pre-treatment groups, responses that were significantly different from those obtained without fasudil or apocynin pre-treatment. Conclusion. Thus, inhibition of Rho-kinase and NADPH oxidase activities may prevent the above smoking-induced impairment of endothelium-dependent vasodilation.

Successful treatment by adding duloxetine to pregabalin for peripheral neuropathy induced by paclitaxel.

Although paclitaxel is a commonly used anticancer drug, peripheral neuropathy may develop as a side effect. Worsening of the symptoms with time may cause patients who receive paclitaxel to give up their chemotherapy. Duloxetine, a serotonin- and norepinephrine-reuptake inhibitor, has been used to treat peripheral neuropathic pain. We report the case of a 68-year-old man with gastric cancer, who underwent gastrectomy and then received 8 cycles of chemotherapy involving weekly administrations of paclitaxel. Under this paclitaxel treatment, he complained of severe peripheral neuropathy, leading to a diminished quality of life. Following treatment with a combination of duloxetine and pregabalin, a remission of his symptoms was achieved. Duloxetine plus pregabalin therapy may be useful for the peripheral neuropathy induced by paclitaxel.

Intrathecal Dexmedetomidine Attenuates Hypercapnic but Not Hypoxic Cerebral Vasodilation in Anesthetized Rabbits

Background Systemic dexmedetomidine (DXM) attenuates the cerebral vasodilation induced by hypercapnia and decreases the cerebral blood flow response to hypoxia. We determined whether lumbar intrathecal DXM affected the cerebrovascular reactivity to hypercapnia and hypoxia. Methods Rabbits (n = 55) anesthetized with pentobarbital were prepared for measurement of pial vessel diameters using a closed cranial window preparation. The first study evaluated the response to hypercapnia after intrathecal administration of DXM (2 &mgr;g/kg; n = 7) or normal saline (n = 8). The second evaluated the response to hypercapnia after intrathecal DXM in the presence of yohimbine (20 &mgr;g/kg followed by DXM 2 &mgr;g/kg; n = 7). The third evaluated the response to mild or moderate hypoxia after intrathecal DXM (2 &mgr;g/kg; n = 7) or normal saline (n = 7). The hypercapnic responses were also examined in the presence of systemic DXM (2, 10 &mgr;g/kg; n = 6), topical DXM (10−8 m, 10−6 m; n = 6) and of intrathecal clonidine (2 &mgr;g/kg; n = 7). Results The pial arteriolar dilator response to hypercapnia was significantly attenuated after intrathecal administration of DXM. Pretreatment with yohimbine completely blocked the decreased reactivity to hypercapnia. Intrathecal clonidine, although less than DXM, also attenuate the hypercapnic response. Intrathecal DXM did not affect the vasodilation of pial arterioles induced by mild or moderate hypoxia. The systemic DXM 10 &mgr;g/kg and topical DXM 10−6 m, but not systemic 2 &mgr;g/kg and topical 10−8 m, attenuated hypercapnic vasodilation of pial arterioles. Conclusions The presence of &agr;2-adrenoceptor agonist administered intrathecally into the lumbar spinal region attenuates hypercapnic but not hypoxic cerebral vasodilation, probably via a stimulation of central &agr;2-adrenergic receptors of the central nervous system.

The effects of alpha-human atrial natriuretic peptide and milrinone on pial vessels during blood-brain barrier disruption in rabbits

The effects of &agr;-human atrial natriuretic peptide (HANP) and milrinone on cerebral pial vessels, especially during blood-brain barrier (BBB) disruption, are not clear. We studied topical HANP (10−14, 10−12, and 10−10 M) or milrinone (10−7, 10−5, and 10−3 M), and IV HANP (0.1, 0.2, and 1.0 &mgr;g · kg−1 · min−1) or milrinone (0.5, 5.0, and 20.0 &mgr;g · kg−1 · min−1) with or without hyperosmolar BBB disruption, using a rabbit cranial window preparation. At 10−12 and 10−10 M topical HANP produced significant arteriolar (16%, 20%, respectively), but no venular dilation. Topical milrinone (10−3 M) produced significant arteriolar and venular dilation (21%, 8%, respectively). IV HANP produced no arteriolar or venular changes at any dose except during BBB disruption, when it caused a significant arteriolar (16%, 16%, and 17%, respectively), but no venular dilation. In contrast, IV milrinone caused small but significant arteriolar and venular dilation without BBB disruption (arterioles, 6%, 7% and 8%, respectively; venules, 6% at 20.0 &mgr;g · kg−1 · min−1). During BBB disruption, these responses to milrinone were similar. Although HANP and milrinone each have a direct vasodilator effect on arterioles, their systemic administration at clinical doses could induce different effects. BBB disruptive conditions could increase the response of pial vessels to systemically administered HANP.

Both milrinone and colforsin daropate attenuate the sustained pial arteriolar constriction seen after unclamping of an abdominal aortic cross-clamp in rabbits.

We previously reported that unclamping of an abdominal aortic cross-clamp causes initial dilation of pial arteries followed by sustained constriction. Both milrinone and colforsin daropate have a vasodilator action, and both have been used in such critical conditions as abdominal aortic aneurysmectomy. We measured cerebral pial arteriolar diameters using a rabbit closed cranial window preparation before (baseline) and 15 min after the start of an IV infusion of 0.9% saline (control group), milrinone, or colforsin daropate (0.05 and 0.5 &mgr;g · /kg−1 · min−1) (pre-clamp), just after aortic clamping, 20 min after clamping, and at 0 to 60 min after unclamping. In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum, −15% for large and −26% for small arterioles versus baseline). These values were significantly smaller after both doses of milrinone and the larger dose of colforsin daropate (−5% and −8%, 10% and 12%, and −2% and −5%, respectively vs baseline, at 60 min). In a second experiment, changes in regional cerebral blood flow and tissue oxygen tension reflected changes in vascular variables. Thus, sustained cerebral pial arteriolar constriction induced by aortic unclamping can be attenuated by IV milrinone or colforsin daropate.

Effect of Postoperative Administration of Pregabalin for Post-thoracotomy Pain: A Randomized Study

OBJECTIVE The present study was performed to evaluate the effect of postoperative administration of pregabalin in patients who reported moderate-to-severe pain after epidural analgesia following thoracotomy. DESIGN An open-label, randomized, controlled, parallel-group study. SETTING A single center in Japan. PARTICIPANTS Consecutive patients (aged≥20 years) who reported moderate-to-severe pain after effectual 2-day epidural analgesia post-thoracotomy for lung cancer from February 2012 to March 2013. INTERVENTIONS Patients were assigned to 2 groups: control (control treatment: acetaminophen, 400 mg, and codeine phosphate powder, 20 mg) or pregabalin (pregabalin, 75 mg, plus control treatment). The 12-week study period included 2-week study treatment and 10-week follow-up. MEASUREMENTS AND MAIN RESULTS For efficacy, the primary endpoint was the visual analog scale (VAS) scores for pain at rest and with coughing at week 2, and secondary endpoints were the VAS scores for pain and the neuropathic pain questionnaire at week 12. Fifty patients were randomized (25 per group). At week 2, the VAS scores for pain at rest (mean [SD]) were 29.5 (21.9) in the control group and 16.3 (15) in the pregabalin group (p = 0.02); for pain with coughing, the scores were 45.2 (20.9) and 28.8 (25.9), respectively (p = 0.02). VAS scores improved more in the pregabalin group than in the control group over the 12 weeks. Patients free from possible neuropathic pain were 48% of the control group and 88% of the pregabalin group, respectively (p = 0.001). CONCLUSIONS Postoperative administration of pregabalin effectively reduced post-thoracotomy pain.

Preliminary Study of the Efficacy of Radiofrequency Lesions of Stellate Ganglion in Chronic Pain Patients

Dear Editor, The technique of stellate ganglion block (SGB) by means of local anesthetics has long been well known among pain specialists as an effective treatment for chronic facial or upper limb pain, although repeated blocks are required for patients in whom the effective period is short [1]. Radiofrequency (RF) thermocoagulation of the SG that induces nerve degeneration by RF-induced heat energy might be expected to have a more prolonged effect [2,3]. We evaluated the efficacy of RF lesions of the SG (RF-SG) in patients with chronic painful conditions that could be temporarily relieved by SGB using local anesthetics. Twenty patients with facial or upper limb pain were enrolled for the RF procedure. Following SGB using mepivacaine, all had experienced 2–3 hours pain relief of at least 50% on the visual analog scale (VAS). All participants gave their informed consent, and the study was approved by the local Ethics Committee. In the RF-SG study, pain relief was assessed using VAS at the following time-points: before RF-SG, the next day, 1 week later, 1 month later, and 3 months later. Differences in VAS values among the various time-points were analyzed using Wilcoxon signed-rank test. Associated signs, symptoms, and complications were also observed. The procedure for RF-SG blockade was carried out as follows. …

Nicorandil protects pial arterioles from endothelial dysfunction induced by smoking in rats.

Background: Our aims are to investigate the effect of nicorandil, which is used for angina prevention and treatment, on the endothelial dysfunction induced by acute smoking and to clarify the underlying mechanism. Materials and Methods: A closed cranial window preparation was used to measure changes in pial vessel diameters in Sprague-Dawley rats. The responses of arterioles were examined to an endothelium-dependent vasodilator acetylcholine (ACh) before smoking. After intravenous nicorandil (200 &mgr;g/kg bolus infusion and then 60 &mgr;g/kg/min continuous infusion; n=6) or saline (control; n=6) pretreatment, the pial vasodilator response to topical 10−5 M ACh infusion was reexamined both before and 1 hour after 1-minute cigarette smoking. Thereafter, either glibenclamide or N-&ohgr;-nitro-L-arginine methyl ester (L-NAME) was infused 20 minutes before nicorandil infusion. In the glibenclamide (n=6) or L-NAME; n=6 pretreatment group, the pial vasodilator response to topical ACh was examined before and after smoking. Percentage changes in pial vessel diameters were used for the statistical analysis. Results: Cerebral arterioles were dilated during topical ACh infusion. After smoking, 10−5 M ACh constricted cerebral arterioles (−7.7±1.8%). After smoking, in the nicorandil-pretreatment group, 10−5 M ACh dilated cerebral pial arterioles by 10.5±3.0%. When given before nicorandil infusion, glibenclamide, but not L-NAME, abolished the preventive effects of nicorandil against smoking-induced endothelial dysfunction in pial vessels. Conclusions: Acute cigarette smoking causes dysfunction of endothelium-dependent pial vasodilatation, and nicorandil prevents this effect of smoking. The mechanism underlying this protective effect may depend mainly on adenosine triphosphate–sensitive potassium-channel activation.