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G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 37 records · Page 2Linked to original sources
PubMed1995

Binding of the nonpeptide antagonist, SB 209670, to endothelin receptors on cultured neurons.

We studied the binding characteristics of a novel, nonpeptide endothelin antagonist, SB 209670, to two subtypes of endothelin (ET) receptor in cultured rat cerebellar granule cell neurons. Displacement binding studies of [125I]ET-1 performed in the presence of the ETB receptor-selective agonist, sarafotoxin 6c (S6c), allowed us to measure a Ki of 4.0 +/- 1.5 nM for (+/-)SB 209670 at the ETA receptor (n = 4). Similarly, binding studies in the presence of the ETA receptor-selective antagonist, BQ123, allowed us to measure a Ki of 46 +/- 14 nM for (+/-)SB 209670 at the ETB receptor (n = 4). These studies indicate that the novel endothelin antagonist, SB 209670, has high affinity for both types of neuronal endothelin receptor.

Animals↗
PubMed1995

Aspiration-induced lung injury: role of complement.

OBJECTIVES: To examine the role of complement in the development of acid aspiration-induced lung injury in the rat. It was postulated that inhibition or depletion of complement attenuates aspiration-induced lung injury. DESIGN: Controlled animal trial. SETTING: Animal Laboratory, Jefferson Medical College, Philadelphia, PA. SUBJECTS: Anesthetized rats. INTERVENTIONS: Aspiration was induced by the intratracheal administration of 0.2 mL of 0.1 N hydrochloric acid (n = 7) and lung injury was evaluated by determining water content, myeloperoxidase activity, protein concentration, and leukocyte count in bronchoalveolar lavage fluid. Muscle PO2 was directly measured using a thin-film chamber oxygen sensor and serum tumor necrosis factor-alpha was assayed by enzyme-linked immunosorbent assay. The effect of complement inhibition by recombinant human soluble complement receptor type 1 (n = 8) or complement depletion by cobra venom factor (n = 7) on lung injury was evaluated. MEASUREMENTS AND MAIN RESULTS: Acid aspiration induced pulmonary leukosequestration, edema, and a microvascular permeability defect, along with tissue hypoxia. Pretreatment with soluble complement receptor type 1 (complement inhibition) or cobra venom factor (complement depletion) significantly reduced lung edema (-61 +/- 7%; p < .05), eliminated protein accumulation in bronchoalveolar lavage fluid (p < .01), and improved (p < .05) tissue oxygenation. In contrast, there was no effect of soluble complement receptor type 1 or of cobra venom factor on leukosequestration. CONCLUSIONS: Acid aspiration induces lung injury through a complement-dependent mechanism that leads to microvascular permeability defects. Therefore, the possibility that complement inhibitors may have a salutary effect in humans with aspiration-induced lung injury should be investigated.

Animals↗
PubMed1995

Clinical perspectives of calcitonin gene related peptide pharmacology.

Calcitonin gene related peptide (CGRP), a potent vasoactive and cardiotonic peptide, interacts with specific G-protein-coupled receptors. CGRP is synthesized and released from small, capsaicin-sensitive sensory nerves. This extensive network of sensory nerves, found in virtually all organs, suggest a potential role for CGRP in diverse physiologic and pathophysiologic processes. The potent vasodilation elicited by CGRP in the cerebral, coronary, and peripheral vasculature has led to its therapeutic evaluation in the treatment of cerebral vasospasm following subarachnoid hemorrhage, stable angina, and Raynaud's phenomenon. The potential inotropic action and coronary vasodilation have also led to a potential beneficial effect in congestive heart failure. The enriched localization of CGRP in trigeminal sensory ganglia may indicate a role in the neurogenic inflammation associated with migraine. Thus, CGRP antagonists may represent a novel therapeutic approach to the treatment of migraine. In addition, CGRP and amylin (homologous pancreatic peptide) reduce the tissue--glucose response to insulin. It has been suggested that a CGRP antagonist may therefore improve insulin sensitivity in non-insulin-dependent diabetes, NIDDM. This brief review provides a preliminary exploration of the potential therapeutic opportunities surrounding CGRP and CGRP antagonists. Future advances are dependent on a better understanding of the structure and function of CGRP receptor(s) and the concomitant identification of selective and potent agonists and antagonists useful for addressing therapeutic hypotheses.

Calcitonin Gene-Related Peptide↗
PubMed1995

SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

BACKGROUND AND PURPOSE: Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. METHODS: Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. RESULTS: In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. CONCLUSIONS: These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Animals↗
PubMed1994

Interleukin-1 beta (IL-1 beta) induces transforming growth factor-beta, (TGF-beta 1) production by rat aortic smooth muscle cells.

In cultured rat aortic smooth muscle cells (RASMCs) IL-1 beta induced TGF-beta 1 mRNA expression, which was concentration (10 pM-10 nM)- and time (2-48 h) -dependent, and sensitive to cycloheximide. The maximal increase in TGF beta 1 mRNA was 4.5 times the basal level at 10 nM of IL-1 beta. A parallel increase in TGF-beta 1 protein in the culture medium of IL-1 beta-stimulated RASMCs was also observed. A detectable level of TGF-beta 1 was found 8 h after stimulation and a plateau was reached at 72 h with a maximal increase of 5-fold and was inhibited by IL-1 receptor antagonist (IL-1ra). Our data demonstrate for the first time that IL-1 beta is a potent inducer of TGF-beta 1 synthesis and release in vascular smooth muscle cells.

Animals↗
PubMed1994

Agonist-stimulated release of von Willebrand factor and procoagulant factor VIII in rats with and without risk factors for stroke.

Lipopolysaccharide (LPS)-induced (i.v. or i.c.v., 1.8 mg/kg) release of von Willebrand factor (vWF) was examined in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. SHR rats released significantly (P < 0.05) more vWF than WKY rats in response to LPS. LPS also inhibited factor VIII procoagulant activity (FVIII:c) which may indicate an increase in thrombin activity. Cultured cerebrovascular endothelial cells (EC) derived from both SHR and WKY rats, as well as human umbilical vein EC (HUVEC) cultures constitutively released vWF. Treatment with agonists including LPS, thrombin and tumor necrosis factor-alpha (TNF alpha) did not affect the in vitro secretion of vWF by cerebrovascular EC cultures but significantly upregulated vWF release by HUVEC cultures. Preincubation of cerebrovascular EC cultures with interleukin-1 (IL-1) +/- TNF alpha or co-culturing in the presence of LPS-activated syngeneic monocytes had no effect on vWF secretion. The findings demonstrate that conditions of hypertension may affect endothelial cells and make them more responsive to agonist stimulation and thereby increase secretion of vWF, an important factor in hemostasis as well as thrombosis. The capacity of LPS to significantly affect the in vivo secretion of vWF in SHR and WKY rats but not cultured cerebrovascular EC indicates that observed elevations in plasma vWF were not derived from cerebrovascular EC. It is suggested that hypertension may function as a risk factor for thrombotic stroke by influencing factors involved in coagulation processes, such as vWF and factor VIII:c.

Animals↗
PubMed1994

Neuroprotective effects of carvedilol, a new antihypertensive, as a Na+ channel modulator and glutamate transport inhibitor.

The potent antioxidant activity of carvedilol could explain part of its protective action in brain ischemia, and interaction as a low-affinity non-competitive (uncompetitive) antagonist of the N-methyl-D-aspartate (NMDA) receptor would provide rapid channel blockade at this subtype of glutamate receptor. We have now found carvedilol to be neuroprotective (PC50 = 306 nM) against 40 microM veratridine which kills cerebellar granule cell neurons in 60 min regardless of energy state. Carvedilol was also a potent inhibitor (IC50 = 1.7 microM) of veratridine-stimulated 3[H]aspartate release from preloaded neurons, caused by reversal of the Na(+)-dependent glutamate transporter. Veratridine caused a sustained 4.3-fold increase in intracellular Ca2+ ([Ca2+]i) up to 368 nM (n = 22). Carvedilol reversed the [Ca2+]i levels by a maximum of 73% with an IC50 of 0.9 microM. Such reversal of [Ca2+]i was facilitated by Na+/Ca2+ exchange since the stoichiometry of exchange could be disrupted by prior treatment with 1 microM ouabain to inhibit the Na+/K+ pump. These data suggest that, in addition to its antihypertensive effects, antioxidant activity and ability to act as a non-competitive inhibitor at the NMDA receptor, carvedilol has additional neuroprotective activity as a Na+ channel modulator and glutamate release inhibitor.

Animals↗
PubMed1994

Pharmacological profile of a novel neuronal calcium channel blocker includes reduced cerebral damage and neurological deficits in rat focal ischemia.

Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage following ischemia. Therefore, blocking voltage-operated calcium channels on nerve cells should provide significant neuroprotection in ischemia. We now report on a novel neuronal calcium channel blocker, NNC 09-0026, in terms of its selective effects on neuronal calcium current and its efficacy in reducing infarct size and neurological deficits in a rat model of focal stroke. In the present studies, the effects of NNC 09-0026 on neuronal calcium influx, calcium channel binding, and cardiovascular parameters were determined. Also, phencyclidine, NNC 09-0026, or vehicle were administered i.v. to rats subjected to permanent middle cerebral and common carotid artery occlusions. Infarct volumes and contralateral forepaw and hindlimb neurological deficits were assessed at 24 and 48 h after onset of stroke. NNC 09-0026 exhibited a pharmacological profile suggesting selectivity at neuronal calcium channels. It inhibited potassium-stimulated calcium uptake into rat synaptosomes with an IC50 of 13 microM. Voltage-operated calcium currents measured from cultured rat dorsal root ganglion cells using the patch clamp technique were blocked by 43% at 10 microM (p < 0.05). The compound showed only weak effects on smooth muscle from the guinea pig taenia coli and was relatively inactive at displacing nitrendipine and omega-conotoxin in receptor-binding studies. Single, bolus injections of NNC 09-0026 as high as 10 mg/kg i.v. produced only 12% reduction in heart rate and a 28% decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Characterization of CGRP receptors in various regions of gerbil brain.

The distribution of specific calcitonin gene-related peptide (CGRP) binding sites was investigated in gerbil brain regions such as cortex, cerebellum, hypothalamus, and hippocampus. The binding of [125I]CGRP to membranes prepared from these regions of the gerbil brain was rapid, saturable and specific with dissociation constants (Kd) between 10-40 pM and maximum binding (Bmax) between 10-30 fmol/mg protein. Human and rat CGRP and hCGRP8-37 competed for [125I]hCGRP binding in a concentration-dependent manner with a Ki of 10-100 pM. Salmon calcitonin was very weak in competing for [125I]hCGRP binding (ki > 10 microM). CGRP did not stimulate adenylate cyclase in these brain regions. Cross-linking of [125I] hCGRP to the brain membrane fractions with disuccinimidyl suberate revealed specific incorporation of [125I] hCGRP to a protein band of approximate molecular weight 52 kDa.

Adenylyl Cyclases↗
PubMed1994

Peptidic endothelin-1 receptor antagonist, BQ-123, and neuroprotection.

Endothelin-1 (ET-1) is a potent cerebrovascular constrictor that has been implicated in brain ischemia. Utilizing the ETA receptor antagonist, BQ-123, the role of ET-1 in ischemic neuronal death following global ischemia was studied. BQ-123, administered ICV, either before and after ischemia or only after ischemia, increased hippocampal CA1 neuron survival in gerbils subjected to transient global ischemia. This study suggests that ETA receptor antagonists might be useful in neuronal salvage following stroke.

Animals↗
PubMed1994

Quantitation of perivascular monocytes and macrophages around cerebral blood vessels of hypertensive and aged rats.

The numbers of monocytes and macrophages in the walls of cerebral blood vessels were counted on perfusion-fixed frozen brain sections (16 microns) of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), normotensive Wistar-Kyoto (WKY) rats, and young (16-week-old) and old (2-year-old) normotensive Sprague-Dawley rats (SD-16w and SD-2y, respectively) using monoclonal antibodies against rat macrophages (ED2). The staining was visualized with fluorescein-labeled second antibodies. The ED2-specific staining in brain sections was restricted to macrophages in a perivascular location. The number of perivascular cells per square millimeter of high-power field was significantly greater in SHR-SP (8.6 +/- 2.1; n = 4) and SHR (6.7 +/- 0.9; n = 6) than in normotensive WKY (4.0 +/- 0.5; n = 6; p < 0.01). The number of perivascular macrophages was also greater in SD-2y (7.5 +/- 2.7; n = 9) than in SD-16w (2.9 +/- 1.8; n = 8; p < 0.01). No ED2 staining was found in the resident microglia or in the endothelial cells, which were identified by double staining with rhodamine-labeled anti-factor VIII-related antigen antibodies. The results suggest that the stroke risk factors hypertension and advanced age are associated with increased subendothelial accumulation of monocytes and macrophages. This accumulation could increase the tendency for the endothelium to convert from an anticoagulant to a procoagulant surface in response to mediators released from these subendothelial cells.

Aging↗
PubMed1994

Platelet-activating factor: diminished acetylcholine release from rat brain slices is mediated by a Gi protein.

The effect of platelet-activating factor (PAF) on neurotransmitter release from rat brain slices prelabeled with [3H]acetylcholine ([3H]ACh), [3H]norepinephrine ([3H]NE), or [3H]serotonin ([3H]5-HT) was studied. PAF inhibited K+ depolarization-induced [3H]ACh release in slices of brain cortex and hippocampus by up to 59% at 10 nM but did not inhibit [3H]ACh release in striatal slices. PAF did not affect 5-HT or NE release from cortical brain slices. The inhibition of K(+)-evoked [3H]ACh release induced by PAF was prevented by pretreating tissues with several structurally different PAF receptor antagonists. The effect of PAF was reversible and was not affected by pretreating brain slices with tetrodotoxin. PAF-induced inhibition of [3H]ACh release was blocked 90 +/- 3 and 86 +/- 2% by pertussis toxin and by anti-G alpha i1/2 antiserum incorporated into cortical synaptosomes, respectively. The results suggest that PAF inhibits depolarization-induced ACh release in brain slices via a G alpha i1/2 protein-mediated action and that PAF may serve as a neuromodulator of brain cholinergic system.

Acetylcholine↗
PubMed1994

Interleukin-2-induced lung injury. The role of complement.

Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.

Animals↗
PubMed1994

Neuroprotective effects of tetrodotoxin as a Na+ channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia.

BACKGROUND AND PURPOSE: Studies examining the role of tetrodotoxin-sensitive ion channels in hypoxic-ischemic neuronal damage have concluded that sodium influx is an important initiating event. We examined the neuroprotectant effect of tetrodotoxin on both cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: We studied neuroprotective mechanisms using cultured rat cerebellar granule cells exposed to veratridine, which induced cytotoxicity, neurotransmitter release, and calcium influx. Survival of gerbil CA1 neurons was examined by direct neuron counts 7 days after 6 minutes of global ischemia with reperfusion. RESULTS: Tetrodotoxin protected cultured neurons in a dose-dependent manner from veratridine-induced toxicity (protective concentration [PC50] = 22 nmol/L). Veratridine induced [3H]aspartate efflux that was sodium dependent, only 25% calcium dependent, and was inhibited by tetrodotoxin (inhibitory concentration [IC50] = 60 nmol/L). Veratridine initiated increases in intracellular calcium that were also reversed by tetrodotoxin (IC50 = 63 nmol/L); reversal was dependent on the sodium-calcium exchanger and the sodium-potassium pump. Neuroprotection of 90% (n = 10; P = .001 versus vehicle) of gerbil CA1 hippocampal neurons was achieved by pretreatment with 2 ng of tetrodotoxin delivered three times intracerebroventricularly, without causing hypothermia. CONCLUSIONS: Sodium channel blockers like tetrodotoxin may have utility in treatment of ischemic neuronal injury by preventing excessive neuronal depolarizations, limiting excitotoxic glutamate release through reversal of the sodium-dependent glutamate transporter, preventing intracellular calcium overload, preserving cellular energy stores, and allowing recovery of ionic homeostasis through operation of the sodium-calcium exchanger.

Animals↗
PubMed1994

Nonpeptide endothelin receptor antagonists. II. Pharmacological characterization of SB 209670.

The pharmacological characterization of SB 209670, a highly potent nonpeptide endothelin ETA/ETB receptor antagonist was performed. SB 209670 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in the isolated rat aorta (ETA receptor-mediated vascular contraction). The Kb for inhibition of ETA receptor-mediated contraction by SB 209670 was 0.4 +/- 0.04 nM. Inhibition by SB 209670 was stereoselective as the (+)-antipode of SB 209670 was approximately 575-fold more potent than the (-)-antipode. Relative to other ET receptor antagonists, the potency of SB 209670 for inhibiting ETA receptor-mediated vascular contraction was 45-, 180- and 775-fold more potent than the ETA selective antagonist BQ-123, or the mixed ETA/ETB receptor antagonists bosentan or PD142893, respectively. The pharmacological antagonism produced by SB 209670 was specific for ET-1. SB 209670 inhibited ETB receptors in the isolated rabbit pulmonary artery as demonstrated by concentration-dependent, parallel rightward shifts in either the ET-1 or sarafotoxin S6c (S6c) concentration-response curves. The Kb values for inhibition were 200 +/- 9 and 52 +/- 14 nM for ET-1 and S6c, respectively. In contrast, neither the ETB selective antagonist RES-701 (10 microM) nor BQ-123 (10 microM) inhibited S6c-mediated vasoconstriction. However, PD 142893 (10 microM) and bosentan (10 microM) produced a small rightward shift in the S6c concentration-response curve, each with Kb values of 1.5 to 3.7 microM. In isolated human circumflex coronary arteries, (+/-)-SB 209670 inhibited ET-1 mediated contraction with a Kb value of 7 +/- 3 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗