tions for the nitration reaction and its quantitation have been established by comparison of spectrophotometric results with those obtained by amino acid analyses.

Sarafotoxins, a group of 21-residue cardiotoxic peptides from snake venom that induce coronary vasoconstriction, show high-affinity binding to rat atrial and brain membranes and activate the hydrolysis of phosphoinositides. Neither their binding nor their activity is affected by blockers or activators of known receptors and ion channels, suggesting that sarafotoxins act either directly on the phosphoinositide phosphodiesterase system or on a novel receptor. Their amino acid sequence shows a high degree of homology with that of endothelin, a recently described 21-residue vasoconstrictor peptide found in porcine aortic endothelium. This is remarkable, since endothelin is a natural compound of the mammalian vascular system while sarafotoxins are highly toxic components of snake venom.

No abstract

No abstract

Endothelins are a recently discovered group of most powerful vasoconstrictor peptides. Endothelin-1 is produced by endothelial cells, and endothelin-3 is derived from neuronal tissue. Theoretically, endothelin-mediated vasoconstriction may enhance ischemic neuronal damage. This study aimed to measure plasma levels of both endothelins in patients with acute nonhemorrhagic cerebral infarction. Plasma levels of endothelin-1 and endothelin-3 were measured by radioimmunoassay in 16 consecutive patients within the first 72 hours after the onset of nonhemorrhagic cerebral infarct, as diagnosed clinically and by computed tomography. There was a marked (fourfold) elevation in plasma endothelin-1 levels in the patients (median, 11.7 pg/ml; 25th and 75th centiles, 5.4 and 13.2 pg/ml) compared with those in a control group of 13 age-matched subjects (median, 2.56 pg/ml; 25th and 75th centiles, 2.4 and 3.0 pg/ml; p less than 0.0001). The first 24 hours after stroke onset were associated with higher endothelin-1 levels, and there was a trend to elevated levels with more severe neurological deficits. In all patients and controls endothelin-3 levels were below 0.5 pg/ml. Ischemic stroke is associated with acute and marked increases in plasma levels of endothelin-1. This may reflect enhanced production by damaged endothelial cells within the infarcted tissue. Local leakage of endothelin-1 may induce severe and prolonged constriction of collateral vessels and may therefore have a deleterious role in the pathogenesis and final outcome of cerebral infarction.

No abstract

No abstract

Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-A'-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotypy and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.The enantiomers of the synthetic cannabinoid 7-hydroxy-A6-tetrahydrocannabinol 1,1-dimethylheptyl homolog have recently been described (1, 2). The (-)-(3R,4R) enantiomer, code-named HU-210 ( Fig. 1), is a highly potent cannabimimetic compound (-80 times more active than &1-tetrahydrocannabinol, the active component of hashish); the (+)-(3S,4S) enantiomer (code-named HU-211) (Fig. 1) is inactive as a cannabimimetic, even at doses several thousand times higher than the ED50 of HU-210 as assayed in a number of tests (2). In characterizing the drug profile of the nonpsychotropic (+) enantiomer HU-211, we noted a striking similarity between its pharmacological, autonomic, and behavioral effects and those of noncompetitive N-methyl-D-aspartate (NMDA) antagonists over a wide range of activities (including stereotypy, locomotor hyperactivity, and tachycardia). This similarity suggested that HU-211 might be functionally active as an NMDA-receptor antagonist. To explore the action of HU-211 and its interaction with specific receptors in the brain, we conducted both pharmacological experiments and binding studies. MATERIALS AND METHODS 3H-labeled N-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP)(40 Ci/mmol; 1 Ci = 37 GBq; >98% pure) was purchased from the Israel Nuclear Center (Negev, Israel). L-Glutamate and glycine were from Sigma; D-(-)-2-amino-5-phosphonovaleric acid (AP-5) and NMDA were from Cambridge Research Biochemicals (Harston, U.K.). HU-211 and HU-210 were synthesized as described (1). Both enantiomers melt at 140-141°C and have identical IR and NMR spectra. administration and tested 60 min after injection. Locomotor hyperactivity was measured as body displacement over 7-cm squares, movement from one square to the next constituting a score of 1. This movement was independently assessed by three trained observers.Heart rate measured over 75 min was determined by the standard transducer-amplifier-recorder technique, and respiratory frequency was visually observed by three trained independent observers with a very high meter-rater correlation. Tremor and seizure were monitored on a platform mounted on four spring-coils. Any vibration of the platform was transduced into an electrical input to an amplifer and then to an osci...