Terrestrial toxicity evaluation of decabromodiphenyl ethane on organisms from three trophic levels.

Decabromodiphenyl ethane (DBDP-Ethane) was evaluated for its potential to effect sewage sludge respiration, soil nitrification, survival and reproduction in Eisenia fetida, and seedling emergence and growth in Zea mays, Lolium perenne, Glycine max, Allium cepa, Lycopersicon esculentum, and Cucumis sativa. The no observed effect concentrations (NOECs) were identified at the limit concentration level for sewage sludge respiration (>10 mg DBDP-Ethane/kg dry soil), >2500 mg/kg dry soil for soil nitrification, >3720 mg/kg dry soil for earthworm survival, and >6250 mg/kg dry soil for seedling emergence and growth in Z. mays, L. perenne, and G. max . Treatment-related effects were identified for E. fetida reproduction, C. sativa survival, and L. esculentum and A. cepa height and dry weight. The most sensitive endpoints were decreased height and dry weight for A. cepa and decreased reproduction for E. fetida with NOECs of 1563(nominal) (1540(measured)) and 2210(nominal) (1907(mean measured)) mg/kg dry soil. The NOEC for soil nitrification and the lowest NOEC identified for soil (i.e., A. cepa) were used to derive predicted no effect concentrations (PNEC) values of 2500 mg/kg for sewage sludge and 156 mg/kg for soil. The calculated PNECs indicate DBDP-Ethane presents little risk to organisms in the sewage sludge and soil compartments.

[18F]-florbetaben PET/CT Imaging in the Alzheimer's Disease Mouse Model APPswe/PS1dE9.

BACKGROUND: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aß), a pathological hallmark of Alzheimer's disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aß plaques. METHODS: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aß plaque load in cortex, hippocampus and cerebellum were analyzed. RESULTS: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. CONCLUSION: The findings suggest that histopathological characteristics of Aß plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements.

BACKGROUND: Promotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias. METHODS: Here, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL. Further, efficacy of HMA and concomitant application of cytostatic drugs (cytarabine and doxorubicin) were evaluated on established SEM and RS4;11 cell lines. In addition, promising approaches were studied on BCP-ALL cell line- and patient-derived xenograft models. RESULTS: In general, DEC effects were stronger compared to AZA on MLL-positive BCP-ALL cells. DEC significantly reduced proliferation by induction of cell cycle arrest in G0/G1 phase and apoptosis. Most sensitive to HMA were SEM cells which are characterized by a fast cell doubling time. The combination of low-dose HMA and conventional cytostatic agents revealed a heterogeneous response pattern. The strongest antiproliferative effects were observed when ALL cells were simultaneously exposed to HMA and cytostatic drugs. Most potent synergistic effects of HMA were induced with cytarabine. Finally, the therapeutic potential of DEC was evaluated on BCP-ALL xenograft models. DEC significantly delayed leukemic proliferation in xenograft models as demonstrated longitudinally by non-invasive bioluminescence as well as 18F-FDG-PET/CT imaging. Unexpectedly, in vivo concomitant application of DEC and cytarabine did not enhance the antiproliferative effect compared to DEC monotherapy. CONCLUSIONS: Our data reveal that DEC is active in MLL-positive BCP-ALL and warrant clinical evaluation.

Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy.

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.

Preparation and characterization of dialkylphosphoryl-obidoxime conjugates, potent anticholinesterase derivatives that are quickly hydrolyzed by human paraoxonase (PON1192Q).

The potential of the most active pyridinium-4-aldoximes, such as obidoxime and trimedoxime, to reactivate phosphorylated acetylcholinesterase is not fully exploited because of inevitable formation of phosphoryloximes (POXs) with extremely high anticholinesterase activity. Hence, a topochemical equilibrium is expected at the active site, with the freshly reactivated enzyme being rapidly re-inhibited by POX produced during reactivation. In the present study, dimethylphosphoryl-, diethylphosphoryl-, and diisopropyl-obidoxime conjugates were generated and isolated in substance. Their inhibition rate of acetylcholinesterase from human red cell membranes was by a factor of 2250, 480 and 600 higher than that observed with paraoxon-methyl, paraoxon-ethyl, and diisopropyl phosphorofluoridate, respectively. All three POXs were hydrolyzed by human paraoxonase (PON1), with the alloenzyme PON1192Q being about 50-fold more active than PON1192R. The rate of hydrolysis, yielding obidoxime, was 1:6:0.03 for the three POXs, respectively. The rate of non-enzymic degradation, yielding obidoxime mononitrile, was similar with the three POXs and showed a high dependency on the reaction temperature (activation energy 83 kJ/mol), while enzymic hydrolysis required less energy (16 kJ/mol). To determine POX-hydrolase activity, we preferred a reaction temperature of 20 degrees C to reduce the noise of spontaneous degradation. A plot of POX-hydrolase versus salt-stimulated paraoxonase activity showed a highly discriminating power towards the PON1Q192R alloenzymes, which may be based on repulsive forces of the quaternary nitrogen atoms of the protonated arginine subtype and the bisquaternary POXs. It is concluded that the pharmacogenetic PON1Q192R polymorphism may be another contributor to the large variability of susceptible subjects seen in obidoxime-treated patients.

Hyperoxic lung injury in Fischer-344 and Sprague-Dawley rats in vivo.

Supplemental oxygen remains an important therapy for pulmonary insufficiency, despite the potential adverse effects of hyperoxic exposures. Recently, He et al. reported that hyperoxic ventilation more readily damaged isolated perfused lungs from Fischer-344 rats than from Sprague-Dawley rats (Am. J. Physiol. 259:L451), which correlates with the previously reported strain differences in hepatic responses to diquat-induced oxidant stress in vivo (J. Pharmacol. Exp. Ther. 235:172). We therefore examined the differences in hyperoxic lung injury in Fischer-344 and Sprague-Dawley rats in vivo. Adult male rats were exposed to > 95% O2 and were sacrificed after 24, 48, or 60 h. Control animals were maintained in room air. Dramatically greater increases in pleural effusions and bronchoalveolar lavage protein concentrations in response to hyperoxia were observed in the Fischer-344 rats than in the Sprague-Dawley rats (p < .05 at both 48 and 60 h for both measurements). Additionally, the glutathione concentrations in alveolar lining fluid decreased from 800 microM to 115 microM in Fischer-344 rats after 60 h of > 95% O2, but did not change in Sprague-Dawley rats. We conclude that the greater susceptibility of Fischer-344 than of Sprague-Dawley rats to hyperoxic lung injury in vitro reported previously also is observed in vivo and that this strain difference offers unique opportunities to study mechanisms of hyperoxic lung injury.

Effects of prolonged and brief infusions of noradrenaline on arterial pressure and on the plasma concentrations of active renin, angiotensin II, aldosterone and potassium.

Conscious male beagle dogs were given constant intravenous infusions of noradrenaline for 14 days, four receiving 125 ng/kg/min and four 250 ng/kg/min. Before, during and after these infusions dose-response studies were done in which additional noradrenaline was infused at 500, 1000 and 2000 ng/kg/min, each rate for 1 h. Blood samples were taken before and during infusions for measurement of haematocrit and plasma concentrations of noradrenaline, active renin, angiotensin II, aldosterone, sodium and potassium. Fourteen-day infusion of noradrenaline at 125 ng/kg/min did not raise blood pressure significantly though infusion at 250 ng/kg/min did, but for the first week of infusion only. Heart rate decreased significantly at both rates. Arterial pressure fell markedly and significantly on stopping infusion. Mean plasma concentrations of renin, angiotensin II and aldosterone tended to be lower during prolonged infusion of noradrenaline, but only the fall of renin during the second week was significant in one group of dogs. Noradrenaline at higher rates significantly raised blood pressure and increased plasma concentrations of renin and angiotensin II. Plasma aldosterone concentration did not rise significantly, perhaps because plasma potassium concentration decreased; in support of this theory changes of plasma aldosterone correlated with changes of plasma potassium but not with changes of angiotensin II. The rise in arterial pressure during dose-response studies was related to the increase of plasma noradrenaline. Prolonged infusion of noradrenaline did not alter the dose-response relation between plasma noradrenaline concentration and arterial pressure.

Aldosterone antagonists. 1. Synthesis and activities of 6 beta,7 beta:15 beta,16 beta-dimethylene steroidal spirolactones.

Several derivatives of the highly active aldosterone antagonists dihydrospirorenone (2) and spirorenone (3) were synthesized. The purpose of these efforts was to prepare compounds exhibiting reduced endocrinological properties with the same or better aldosterone antagonistic activity than that of spirorenone. The 1 alpha,2 alpha-methylene derivative 20 has a similar aldosterone antagonistic potency compared to that of spirorenone but does not show decreased endocrinological side effects. Other substituents as in compounds 4-11, 15-19, and 21 sharply decreased the aldosterone antagonistic activity of 2 or 3, respectively.

Aldosterone antagonists. 2. New 7 alpha-(acetylthio)-15,16-methylene spirolactones.

Some 15,16-methylene derivatives of the aldosterone antagonist spironolactone were synthesized with the purpose of increasing the antialdosterone potency and reducing the endocrinological effects of this standard compound. By introduction of a 1,2-double bond and a 15 beta,16 beta-methylene ring in the spironolactone molecule both goals were achieved. In animal studies mespirenone exhibited a threefold-greater antialdosterone potency and less than 10% of the antiandrogenic activity of spironolactone.

Effect of infused captopril on blood pressure and the renin-angiotensin-aldosterone system in normal dogs subjected to varying sodium balance.

Infusion of captopril at 20, 200, 2,000 and 6,000 micrograms/kg/hour into sodium-depleted conscious dogs produced a rapid, dose-dependent decrease in blood pressure and plasma angiotensin II and III, maximal suppression being achieved at 200 micrograms/kg/hour (97 +/- 14 to 65 +/- 8 [standard deviation] mm Hg, 38 +/- 10.6 to 3.2 +/- 1.5 pmol/liter and 7.0 +/- 4.8 to 1 +/- 0.5 pmol/liter, respectively). Angiotensin I concentration increased with each infusion rate to a maximal 16-fold increase at 6,000 micrograms/kg/hour (26 to 416 pmol/liter). For all infusion rates the percentage decrease in blood pressure correlated with the percentage decrease in plasma angiotensin II (r = 0.65, p less than 0.001). Infusion of captopril at 6,000 micrograms/kg/hour into sodium-loaded dogs also produced a decrease in both blood pressure (117 +/- 9 to 96.6 +/- 11 mm Hg) and plasma angiotension II (11.0 +/- 3 to 1.6 +/- 1.3 pmol/liter). Plasma aldosterone concentrations decreased whereas both blood angiotensin I and renin concentration increased. In another experiment angiotensin II was infused at 2, 6, 18 and 54 ng/kg/min into sodium-depleted dogs firstly without modification and secondly combined with captopril (6,000 micrograms/kg/hour) given for 1 hour before the angiotensin dose-response study and continued throughout. Angiotensin II infusion raised mean arterial pressure and plasma angiotensin II in each animal. However, the angiotensin II blood pressure dose-response curve was shifted downwards and to the right in the captopril-treated animals. These results suggest that arterial pressure and aldosterone secretion in normal dogs are partly dependent on the renin-angiotensin system but that not all of the acute decrease in blood pressure produced by captopril can be explained by the suppression of the acute vasoconstrictor effect of circulating angiotensin II.

Triazolodiazepines: dissociation of their Paf (platelet activating factor) antagonistic and CNS activity.

The relationship between the activity of thieno- or benzo-triazolodiazepines on platelet-activating factor (Paf)-induced effects and on the CNS (central nervous system) was studied in vitro and in vivo. Brotizolam and triazolam inhibited Paf-induced human platelet aggregation. The IC50 -values were 0.54 and 7.6 microM, respectively. This inhibitory effect was not blocked by the specific central-type benzodiazepine (BDZ) antagonist, Ro 15-1788, or the specific peripheral-type BDZ ligand, Ro 5-4846. These BDZ ligands also showed an inhibitory effect on Paf-induced platelet aggregation (IC50 = 200 and 560 microM, respectively). Ro 15-1788 or Ro 5-4846 in combination with brotizolam or triazolam enhanced the Paf inhibitory effect of these triazolodiazepines. In guinea-pigs, Ro 15-1788, 100 mg kg-1 p.o. and 10 mg kg-1 i.v. completely inhibited the hypnogenic effect of 10 mg kg-1 p.o. and 1 mg kg-1 i.v. of brotizolam, respectively. Similar results were obtained with triazolam but at higher doses. In anaesthetized guinea-pigs, a dose of 100 mg kg-1 p.o. of Ro 15-1788 did not inhibit bronchoconstriction and hypotension caused by Paf (30 ng kg-1 min-1 i.v.). The combination of brotizolam (10 mg kg-1 p.o.) or triazolam (200 mg kg-1 p.o.) with this BDZ antagonist (100 and 400 mg kg-1 p.o., respectively) did not affect the Paf inhibitory activity of these triazolodiazepines. These results show that the Paf antagonistic properties of the triazolodiazepine can be dissociated from their CNS activity. It is conceivable that compounds of this structural type could be the forerunners of a novel series of potent Paf antagonists.

Bronchial and vascular effects of Paf in the rat isolated lung are completely blocked by WEB 2086, a novel specific Paf antagonist.

1 The effect of the platelet-activating factor (Paf) antagonist, WEB 2086, on Paf-induced increase of pulmonary artery perfusion pressure (Pp), bronchial inflation pressure (Pi) and wet-to-dry lung weight ratios (W/D) was investigated in the rat isolated lung. 2 Lungs were perfused with Krebs-Ringer solution (KRS) as controls or with KRS containing WEB 2086 (0.1, 1.0, 10.0 or 100 micrograms ml-1) and then injected with a bolus of 20 micrograms Paf. 3 A dose-related inhibition of the Paf-induced increase of Pp, Pi and W/D was observed, being almost maximal for the 10.0 micrograms ml-1 and complete for the 100 micrograms ml-1 doses of WEB 2086 when compared to controls. 4 It is concluded that WEB 2086 is a highly effective and specific Paf antagonist in the pulmonary vasculature and bronchial tract.

Structure-activity relationship of new steroidal aldosterone antagonists. Comparison of the affinity for mineralocorticoid receptors in vitro and the antialdosterone activity in vivo.

The ability of 18 steroids with structures similar to spironolactone, progesterone or aldosterone to compete with [3H]aldosterone for binding at rat renal cytosol receptors in vitro and the antialdosterone activity in vivo were tested in comparison with spironolactone. The affinity of these compounds for mineralocorticoid receptors was then compared with their pharmacological action in rats. Replacement of the 17-spirolactone ring by a 17 alpha-hydroxypropyl group and a 17 beta-hydroxyl group resulted in a loss of affinity for the [3H]aldosterone binding sites but not in a reduction in antialdosterone activity in vivo. Compared to spironolactone, C6/C7 unsaturated compounds showed a reduced activity both in vitro and in vivo. Substitution of the 7 alpha-thioacetyl group of spironolactone by a 6,7-methylene group in the beta position (prorenone) increased the affinity to the receptor as well as the biological activity by 52 and 41%, respectively. Introduction of a methyl-group at the D-ring of spironolactone resulted in similar significant drops in activity both in vitro and in vivo. The progesterone like steroids were weak competitors for aldosterone in vitro and in vivo. Two of three aldosterone like steroids (18-deoxyaldosterones) still exhibit mineralocorticoid activity and one analogue could be classified as a weak aldosterone antagonist. The studies show in general that the comparison of the affinity for mineralocorticoid receptor sites with the antimineralocorticoid activity in vivo is a valuable procedure in the search for new antimineralocorticoid substances.

Protective effect of WEB 2086, a novel antagonist of platelet activating factor, in endotoxin shock.

WEB 2086, a novel specific platelet activating factor (PAF) antagonist derived from triazolodiazepines, inhibited in a dose-related manner the hypotensive and lethal effect of PAF as well as of E. coli endotoxin in the rat. The hypotension induced by endotoxin (15 mg/kg i.v.) or PAF (30 ng/(kg X min) i.v.) in anaesthetized rats was prevented by oral (1-10 mg/kg) and inhibited or reversed by i.v. (0.1-5.0 mg/kg or 0.1-1.0 mg/kg) doses of WEB 2086. Similar oral and i.v. doses of WEB 2086 protected conscious rats from PAF (15 micrograms/kg i.v.)- and endotoxin (7.5 mg/kg i.v.)-induced death. The results obtained with WEB 2086 confirm that PAF has an important role in the pathophysiology of endotoxin shock. This compound may have a therapeutic effect in human septic shock.

Detection and comparative evaluation of aldosterone antagonists in glucocorticoid-treated, adrenalectomized rats.

An improved method for the evaluation of aldosterone antagonists in adrenalectomized, glucocorticoid-treated rats is described. The method involved assessing the pharmacological effects of spironolactone and potassium canrenoate and comparing them with the action of prorenone and potassium prorenoate, respectively. Adrenalectomized rats were pretreated with fluocortolone caproate (10 mg/kg s.c.), a long-acting glucocorticoid, immediately after surgery. Fluocortolone (1.25 mg/kg s.c.), a short acting preparation, was administered 4 days after this treatment. On the 5th day after adrenalectomy, the actual diuresis experiment was performed. The rats received a continuous i.v. infusion of aldosterone [1 microgram/(kg x h)] for 10, 15 or 20 h. Spirnolactone or prorenone (6.7, 13.4 or 26.8 mg/kg of each steroid) were administered in single oral doses 1 h before or 4 h after the start of the i.v. infusion. Potassium canrenoate and potassium prorenoate (1.9, 3.8, or 6.7 mg/(kg x h) of each compound) were infused intravenously over 10 or 15 h. Urine was collected in 1 h fractions and the anti-aldosterone activity was assessed by the ability of the compounds to reverse the aldosterone effect on the Na/K ratio. The anti-aldosterone activity of the steroids studies was clearly detectable with the method described. Prorenone was as potent as spironolactone and potassium prorenoate was on the average 3.9 times as potent as potassium canrenoate. The method appears suitable for the characterization of the time course and duration of anti-aldosterone activity and for the calculation of relative potencies in comparison to standard compounds.

Triazolodiazepines are potent antagonists of platelet activating factor (PAF) in vitro and in vivo.

The triazolodiazepines brotizolam, triazolam and alprazolam inhibited PAF-induced human platelet aggregation in vitro (IC50 = 0.54, 7.6 and 13.7 microM, respectively) but showed only a weak or no effect against other aggregating agents (ADP, adrenaline, collagen, serotonin, arachidonic acid). In comparison, flunitrazepam and diazepam, two diazepines without the triazole ring, showed IC50-values of 42 and 260 microM, respectively. Flunitrazepam does not possess the specificity shown by the other compounds. Brotizolam and triazolam also inhibited PAF-induced human neutrophil aggregation in vitro, with IC50-values 0.21 and 6.6 microM, respectively. In anesthetized guinea pigs, brotizolam (2.5 to 10 mg/kg p.o. or 0.1 to 0.5 mg/kg i.v.) or triazolam (20 to 100 mg/kg p.o.) inhibited dose-dependently the intrathoracic accumulation and aggregation of 111Indium labelled platelets induced by an i.v. infusion of PAF (30 ng/kg X min). Brotizolam at doses of 1 to 10 mg/kg p.o. and 0.1 to 0.5 mg/kg i.v. inhibited dose-dependently the reduction in tidal volume (bronchoconstriction), the systemic hypotension and the lethal effect due to i.v. PAF in guinea pigs. Triazolam inhibited these effects of PAF at doses of 50 to 200 mg/kg p.o. PAF-induced systemic hypotension in rats can be reversed by cumulative i.v. doses (0.05 to 1.0 mg/kg) of brotizolam. In conclusion, these results show that triazolodiazepines, like brotizolam and triazolam, are potent inhibitors of PAF-induced effects in vitro and in vivo.

Thieno-triazolo-1,4-diazepines as antagonists of platelet-activating factor: present status.

The platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, (PAF) antagonistic activity of thienotriazolodiazepines has recently been described. The lead compound in this series was brotizolam, which also exhibits sedative and hypnotic effects. By combination of brotizolam with the benzodiazepine receptor antagonist RO 15-1788, PAF antagonistic and central nervous system (CNS) activities could be segregated. Systematic structure variation has led to potent and selective PAF antagonists without CNS effects. WEB 2086 and its analogues WEB 2170 and STY 2108 are representative examples of this structural type and have shown a high potency and selectivity in PAF-induced and PAF-dependent in vitro tests and in experimental models. Studies in healthy volunteers have demonstrated potent pharmacological activity and good safety and tolerance of oral, intravenous or inhaled WEB 2086 in man. These agents should therefore prove useful for the further elucidation of the pathophysiological role of PAF and provide an opportunity for therapeutic applications in diseases in which the involvement of PAF has been implicated.

Influence of prostacyclin and indomethacin on castor oil-induced gastrointestinal effects in rats.

The effects of castor oil, alone, as well as in combination with PGI2 and indomethacin on gastrointestinal functions have been examined in rats. Oral administration of the oil to fasted rats induced severe diarrhoea, with increased intestinal motility and fluid volume. Pretreatment with PGI2 (s.c.) inhibited the effect of the oil on intestinal fluid accumulation and decreased intestinal motility below control values, but only delayed the occurrence of mucoid diarrhoea. Indomethacin (i.p.) reduced the accumulation in intestinal fluid after castor oil administration to a much smaller extent (47%) than PGI2 and depressed the increased intestinal motility to control values. In contrast to PGI2, indomethacin inhibited the occurrence of diarrhoea after administration of castor oil. The present results do not definitely confirm the general opinion that the diarrhoeal action of laxative agents is due only to an altered intestinal electrolyte and water transport or an increase of intestinal motility.

Hypothesis:presynaptic receptors controlling renin release.

Presynaptic receptors have recently been identified on nerves supplying vascular smooth muscle. Renin is stored in juxtaglomerular cells in the wall of the afferent glomerular arteriole and the JG cell is probably derived from vascular smooth muscle. Nervous stimuli exert an important influence on release of renin, but the nature of the receptors involved is not agreed. We propose that there are presynaptic receptors associated with the JG apparatus as with vascular muscle and that a mechanism of this sort gives a better account of data on renin release.