Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation.
1. The aim of the present study was to analyse the cardiovascular actions of the synthetic CB1/CB2 cannabinoid receptor agonist WIN55212-2, and specifically to determine its sites of action on sympathetic cardiovascular regulation. 2. Pithed rabbits in which the sympathetic outflow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular effects, respectively. For studying effects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular effects of the cannabinoid were studied in conscious rabbits with intravenous drug administration. 3. In pithed rabbits in which the sympathetic outflow was continuously electrically stimulated, intravenous injection of WIN55212-2 (5, 50 and 500 microg kg(-1)) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these effects were antagonized by the CB1 cannabinoid receptor-selective antagonist SR141716A. The hypotensive and the sympathoinhibitory effect of WIN55212-2 was shared by CP55940, another mixed CB1/CB2 cannabinoid receptor agonist, but not by WIN55212-3, the enantiomer of WIN55212-2, which lacks affinity for cannabinoid binding sites. WIN55212-2 had no effect on vascular tone established by infusion of noradrenaline in pithed rabbits. 4. Intracisternal application of WIN55212-2 (0.1, 1 and 10 microg kg(-1)) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter effect was antagonized by atropine. 5. In conscious animals, intravenous injection of WIN55212-2 (5 and 50 microg kg(-1)) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve firing. The highest dose of WIN55212-2 (500 microg kg(-1)) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined. 6. The results obtained in pithed rabbits indicate that activation of CB1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212-2 uncovered two effects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal fibres. The highest dose of systemically administered WIN55212-2 produced central sympathoinhibition; the primary site of this action is not known. (+info
Evaluation of CSF leaks: high-resolution CT compared with contrast-enhanced CT and radionuclide cisternography.
BACKGROUND AND PURPOSE: Radiologic evaluation of CSF leaks is a diagnostic challenge that often involves multiple imaging studies with the associated expense and patient discomfort. We evaluated the use of screening noncontrast high-resolution CT in identifying the presence and site of CSF rhinorrhea and otorrhea and compared it with contrast-enhanced CT cisternography and radionuclide cisternography. METHODS: We retrospectively reviewed the imaging studies and medical records of all patients who were evaluated for CSF leak during a 7-year period. Forty-two patients with rhinorrhea and/or otorrhea underwent high-resolution CT of the face or temporal bone and then had CT cisternography and radionuclide cisternography via lumbar puncture. The results of the three studies were compared and correlated with the surgical findings in 21 patients. RESULTS: High-resolution CT showed bone defects in 30 of 42 patients (71%) with CSF leak. High-resolution, radionuclide cisternography and CT cisternography did not show bone defects or CSF leak for 12 patients (29%) who had clinical evidence of CSF leak. Among the 30 patients with bone defects, 20 (66%) had positive results of their radionuclide cisternography and/or CT cisternography. For the 21 patients who underwent surgical exploration and repair, intraoperative findings correlated with the defects revealed by high-resolution CT in all cases. High-resolution CT identified significantly more patients with CSF leak than did radionuclide cisternography and CT cisternography, with a moderate degree of agreement. CONCLUSION: Noncontrast high-resolution CT showed a defect in 70% of the patients with CSF leak. No radionuclide cisternography or CT cisternography study produced positive results without previous visualization of a defect on high-resolution CT. CT cisternography and radionuclide cisternography may be reserved for patients in whom initial high-resolution CT does not identify a bone defect or for patients with multiple fractures or postoperative defects. (+info
Spontaneous cerebrospinal fluid leakage detected by magnetic resonance cisternography--case report.
A 49-year-old male with no history of head trauma suffered cerebrospinal fluid (CSF) discharge from the left nostril for one month. Coronal computed tomography (CT) showed lateral extension of the sphenoid sinus on both sides and CSF collection on the left side. CT cisternography could not identify the site of CSF leakage. Heavily T2-weighted magnetic resonance (MR) imaging (MR cisternography) in the coronal plane clearly delineated a fistulous tract through the sphenoid bone into the sphenoid sinus. Patch graft with muscle fragment completely relieved the CSF rhinorrhea. Postoperative three-dimensional CT showed the two bone defects identified during surgery. Small bony dehiscences in the sphenoid bone and lateral extension of the sphenoid sinus predisposed the present patient to CSF fistula formation. MR cisternography in the coronal and sagittal planes is superior to CT scanning or CT cisternography for detection of the site of active CSF leakage. (+info
Peripheral injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks peripheral CRF- and abdominal surgery-induced delayed gastric emptying in rats.
The effect of the corticotropin-releasing factor (CRF) receptor antagonists astressin and D-Phe CRF(12-41) injected i.v. on CRF-induced delayed gastric emptying (GE) was investigated in conscious rats. Gastric transit was assessed by the recovery of methyl cellulose/phenol red solution 20 min after its intragastric administration. The 55% inhibition of GE induced by CRF (0.6 microgram i.v.) was antagonized by 87 and 100% by i.v. astressin at 3 and 10 microgram, respectively, and by 68 and 64% by i.v. D-Phe CRF(12-41) at 10 and 20 microgram, respectively. CRF (0.6 microgram)-injected intracisternally (i.c.) induced 68% reduction of GE was not modified by i.v. astressin (10 microgram) whereas i.c. astressin (3 or 10 microgram) blocked by 58 and 100%, respectively, i.v. CRF inhibitory action. Abdominal surgery with cecal manipulation reduced GE to 7.1 +/- 3.1 and 27.5 +/- 3.3% at 30 and 180 min postsurgery, respectively, compared with 40.3 +/- 4.3 and 59.5 +/- 2.9% at similar times after anesthesia alone. Astressin (3 microgram i.v.) completely and D-Phe CRF(12-41) (20 microgram i.v.) partially (60%) blocked surgery-induced gastric stasis observed at 30 or 180 min. The CRF antagonists alone (i.v. or i.c.) had no effect on basal GE. These data indicate that CRF acts in the brain and periphery to inhibit GE through receptor-mediated interaction and that peripheral CRF is involved in acute postoperative gastric ileus; astressin is a potent peripheral antagonist of CRF when injected i.v. whereas i.c. doses >/=3 microgram exert dual central and peripheral blockade of CRF action on gastric transit. (+info
HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system.
Recombinant HIV-1 Nef protein, but not Tat, gp120, and gp160, provoked leukocyte recruitment into the CNS in a rat model. The strong reduction of bioactivity by heat treatment of Nef, and the blocking effect of the mAb 2H12, which recognizes the carboxy-terminal amino acid (aa) residues 171-190 (but not of mAb 3E6, an anti-Nef Ab of the same isotype, which maps the aa sequence 168-175, as well as a mixture of mAbs to CD4) provided evidence for the specificity of the observed Nef effects. Using a modified Boyden chamber technique, Nef exhibited chemotactic activity on mononuclear cells in vitro. Coadministration of the anti-Nef mAb 2H12, as well as treatment of Nef by heat inhibited Nef-induced chemotaxis. Besides soluble Nef, chemotaxis was also induced by a Nef-expressing human astrocytoma cell line, but not by control cells. These data suggest a direct chemotactic activity of soluble Nef. The detection of elevated levels of IL-6, TNF-alpha, and IFN-gamma in rat cerebrospinal fluid 6 h after intracisternal Nef injection hint at the additional involvement of indirect mechanisms in Nef-induced leukocyte migration into rat CNS. These data propose a mechanism by which HIV-1 Nef protein may be essential for AIDS neuropathogenesis, as a mediator of the recruitment of leukocytes that may serve as vehicles of the virus and perpetrators for disease through their production of neurotoxins. (+info
High-resolution MR cisternography of the cerebellopontine angle, obtained with a three-dimensional fast asymmetric spin-echo sequence in a 0.35-T open MR imaging unit.
High-resolution MR cisternography performed with 3D fast asymmetric spin-echo imaging (3D fast spin-echo with an ultra-long echo train length and asymmetric Fourier imaging) was optimized in a 0.35-T open MR imaging unit. The 0.35- and 1.5-T images of the two volunteers and three patients with acoustic schwannomas were then compared. The optimal parameters for images obtained by 3D fast asymmetric spin-echo imaging at 0.35 T were as follows: field of view, 15 cm; matrix, 256 x 256 x 40; section thickness, 1 mm; echo train length, 76; and imaging time, 10 minutes 44 seconds. Scans obtained from both normal volunteers showed the facial, cochlear, and superior and inferior vestibular nerves separately in the internal auditory canal on both 0.35- and 1.5-T images. All three acoustic schwannomas were depicted on both 0.35- and 1.5-T images. Screening for disease at the cerebellopontine angle and in the internal auditory canal, without the administration of contrast material on a low-field open MR imaging unit and within a clinically acceptable imaging time, may be possible. Further controlled prospective studies are required, however, before implementation on a wide basis. If proved effective, this may be of particular value for reducing healthcare costs and for imaging claustrophobic and pediatric patients in an open system. (+info
Neurodevelopmental outcome after antenatal diagnosis of posterior fossa abnormalities.
Posterior fossa abnormalities are sonographically diagnosable in the fetus. Anomalies of this region include Dandy-Walker malformation, enlarged cisterna magna, and arachnoid cyst. Despite prenatal diagnosis, the uncertainties related to natural history and neurodevelopmental outcome in survivors make patient counseling difficult. The purposes of this study were to determine the accuracy of prenatal diagnosis of these lesions and elucidate long-term neurodevelopmental outcome in survivors in prenatally diagnosed posterior fossa abnormalities. Fifteen cases of posterior fossa abnormalities were reviewed. Antenatal diagnoses of Dandy-Walker malformation was made in 13 of these cases, arachnoid cyst in one case, and enlarged cisterna magna in one case. Hydrocephalus was present in 66% of patients. The sonographic diagnosis was concordant with the pathologic or neonatal radiologic diagnosis in 13 of 15 cases. Seven fetuses (47%) exhibited additional cranial or extracranial anomalies. A karyotypic abnormality (trisomy 18) was found in one of 15 cases of posterior fossa abnormalities. Neurodevelopmental delay was present in 80% of survivors with follow-up study to 4 years of age. Prenatal diagnosis of posterior fossa abnormalities is highly accurate, yet the differential diagnosis can be challenging. Cognitive and psychomotor developmental delays remain commonplace despite early diagnosis and treatment. The approach with families in cases of prenatal diagnosis of posterior fossa abnormalities should include a search for additional central nervous system and extra-central nervous system anomalies in the fetus and counseling of parents regarding potential adverse outcome for survivors. (+info
Intracisternal nor-binaltorphimine distinguishes central and peripheral kappa-opioid antinociception in rhesus monkeys.
Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting kappa-opioid receptor (kappaOR) antagonism and has kappa(1)-selectivity in nonhuman primates. The aim of this study was to establish the pharmacological basis of central kappaOR antagonism in rhesus monkeys (Macaca mulatta). After intracisternal (i.c.) administration of small doses of nor-BNI, the duration and selectivity of nor-BNI antagonism were evaluated against two kappaOR agonists, (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) and bremazocine. Thermal antinociception was measured in the warm water (50 degrees C) tail-withdrawal assay and sedation was evaluated by observers blind to treatment conditions. Following i.c. pretreatment with 0.32 mg nor-BNI, a 5- to 10-fold rightward shift of the U50,488 baseline dose-effect curve was observed in antinociception. In contrast, this dose of nor-BNI only produced an insignificant 2-fold shift against bremazocine. Pretreatment with a smaller dose (0.032 mg) of nor-BNI produced a 3-fold shift of U50, 488, which lasted for 7 days, but failed to alter the potency of bremazocine. This differential antagonism profile of i.c. nor-BNI also was observed in sedation ratings. In addition, the centrally effective dose of nor-BNI (0.32 mg), when administered s.c. in the back, did not antagonize either U50,488- or bremazocine-induced antinociception and sedation. After i.c. pretreatment with the same dose, nor-BNI also did not antagonize the peripherally mediated effect of U50,488 against capsaicin-induced thermal nociception in the tail. These results indicate that i.c. nor-BNI produces central kappaOR antagonism and support the notion of two functional kappaOR subtypes in the central nervous system. Moreover, it provides a valuable pharmacological basis for further characterizing different sources of kappaOR-mediated effects, namely, from central or peripheral nervous system receptors. (+info