( -)-A9-t~ans-Tetrahydrocannabinol (A9-THC), when given intravenously (2 mg kg-I) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (Cl-C,) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of AS-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after AS-THC administration. These observations support the hypothesis that AS-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that AS-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that AS-THC did not interact with a-or p-adrenoceptors. The possible action of Ag-THC on central sympathetic structures was investigated by perfusion of As-THC into the lateral cerebral ventricle. AS-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C-A9-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that A9-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.(-)-As-trans-Tetrahydrocannabinol (A9-THC), a psychoactive constituent of marihuana, and several other tetrahydrocannabinols produce cardiovascular alterations in man (Hollister,
Recently we have presented evidence that a soluble factor required for amino acid polymerization in Escherichia coli extracts is involved in the binding of guanosine 5'-triphosphate (GTP).1, 2 The heat lability of the GTP-binding component, as well as its chromatographic behavior on O-(diethylaminoethyl)-Sephadex (DEAE-Sephadex),2 provided evidence that the soluble transfer factor T.3 was involved in the reaction. The GTP-protein complex was demonstrated both by Sephadex chromatography and by retention on a Millipore filter. Seeds and Conway reported additional evidence that T, interacts with GTP by demonstrating that GTP protects T. against heat inactivationsThe function of the GTP-protein complex in the over-all process of polypeptide formation in E. coli remains unclear. Hc'kever, several recent reports have indicated that the GTP protein interacts with aminoacyl-tRNA. Using Sephadex chromatography to assay for GTP binding to a macromolecular fraction,5 Gordon showed that aminoacyl-tRNA was a specific requirement for the stabilization of the GTP-protein complex.6 Ravel et al.7 and Gordon6 have also reported that aminoacyl-tRNA inhibits the retention on a Millipore filter of the GTP-protein complex. In addition, Ravel8 has shown that aminoacyl-tRNA binding to ribosomes in the presence of synthetic messengers was stimulated by the presence of low levels of GTP and a protein fraction required for amino acid polymerization. One possibility that emerges from these data is that a GTP-protein aminoacyl-tRNA complex is involved in the transfer or binding of the aminoacyl-tRNA to the ribosome.8In the present report, we will present evidence that two protein fractions are required for the formation of a GTP-protein complex. Both fractions also stimulate phenylalanyl-tRNA binding to ribosomes and are needed in the presence of factor G for polymerization. It is concluded that the two soluble transfer factors, required for the binding of GTP, are T, and T., initially separated by Lucas-Lenard and Lipmann.3Materials and Methods.-H8-GTP (1 mc/Mumole) and poly U were purchased from Schwartz Biochemicals, and C"Lphenylalanine (300-360 ,Uc/,umole) was purchased from New England Nuclear Corp. Stripped tRNA from E. coli was obtained from General Biochemicals, Inc., and the preparation of aminoacyl-tRNA was done according to a modification of the procedure of Conway.9 E. coli B cells grown on minimal media and harvested at midlog were obtained from Grain Processing Corp.
Studies were carried out to evaluate adaptive responses to water retention in an experimental model of the syndrome of inappropriate antidiuresis (SIAD). Hyponatraemia was induced by continuous s.c. infusions of the antidiuretic vasopressin analogue 1-deamino-[8-D-arginine]-vasopressin in rats ingesting a 5% (w/v) dextrose solution. After 48 h of sustained decreases in the plasma concentration of Na+ to 23-25% of normal levels, all body fluid compartments were significantly expanded: plasma volume estimated by changes in plasma protein concentration was increased by 26%, extracellular fluid volume estimated by 22Na volume of distribution was increased by 24%, and total body water estimated by 3H2O volume of distribution was increased by 16%. Despite marked increases in all body fluid compartment volumes, mean arterial blood pressure was only modestly increased to 110 +/- 2 mmHg in conscious hyponatraemic rats. Consistent with the sustained volume expansion, both basal and stimulated plasma renin activities were significantly suppressed in the hyponatraemic rats. Plasma vasopressin levels were similarly suppressed, and the hyponatraemic rats showed a striking absence of endogenous vasopressin secretion in response to marked intravascular volume depletion (15-45%) produced by s.c. administration of polyethylene glycol. Plasma concentrations of atrial natriuretic peptide were initially stimulated four- to fivefold above basal levels in response to the water-induced volume expansion, but by 48 h fell to ranges not significantly different from basal unstimulated levels, despite continued plasma and extracellular fluid volume expansion at that time. These results illustrate that multiple haemodynamic and hormonal adaptive responses occur with sustained dilutional hyponatraemia in rats, and suggests that these can be of sufficient magnitude to allow continued water retention without necessarily provoking either escape from antidiuresis or continued natriuresis. In contrast with previous studies in experimental animals in which hyponatraemia was maintained by continuous forced administration of hypotonic fluid, rats in this model reached a steady state with characteristics resembling many of those observed clinically in patients with SIAD.
A number of quaternary salts of trans-4-(beta-1-naphthylvinyl)pyridine (NVP) were synthesized and evaluated as inhibitors of the enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Structural variations in the side arm attached to the pyridine nitrogen atom demonstrate that an inductive effect is small but significant for activity. Inhibition of ChAT by alkylated derivatives decreases when electron-withdrawing groups are placed in the side chain. Substitution of a methyl group on the pyridine ring only slightly affects activities toward ChAT and AChE. When the pyridinium moiety is replaced by an imidazolium ring, no ChAT inhibition was observed. The imidazolium compound, however, was a weak inhibitor of AChE. For design of affinity columns for purification of ChAT, the data also supports the use of long chain alkylated amide derivatives of NVP.
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