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Biomedical subjects

G Z Feuerstein

Publications and source records attributed to G Z Feuerstein.

At least 73 records · Page 4Linked to original sources
PubMed1997

Congestive heart failure and genomic medicine: a look into the 21st century.

Congestive heart failure (CHF) has emerged as one of the leading cardiovascular disorders in developed countries, as indicated by the prevalence of the disease; the incidence of hospitalization, morbidity, and mortality; and its global economic burden. Furthermore, it is expected that heart failure and other cardiovascular disorders will become the major disease burdens in developing countries by the year 2020. It is well established that pharmacological therapy of CHF, although still not optimum, improves patient quality of life and reduces morbidity and mortality. However, CHF remains a relentlessly progressive disease. In this brief review an attempt is made to explore the contemporary, state-of-the-art pharmacological approach to the treatment of heart failure, the unmet medical need that still remains, and the potential impact of genomic medicine on the treatment of heart failure in the 21st century.

Genetic Therapy↗
PubMed1997

Pharmacology of carvedilol: rationale for use in hypertension, coronary artery disease, and congestive heart failure.

Carvedilol is a novel, multiple-action cardiovascular drug that is currently approved in many countries for the treatment of hypertension. The reduction in blood pressure produced by carvedilol results primarily from beta-adrenoceptor blockade and vasodilation, the latter resulting from alpha 1-adrenoceptor blockade. These actions, as well as several of the other activities of carvedilol, are associated with cardioprotection in animal models that occurs to a degree that is greater than that observed with other drugs. The multiple actions of carvedilol may also provide the underlying rationale for the use of the drug in the treatment of coronary artery disease and congestive heart failure. By virtue of being both a beta-blocker and a vasodilator, carvedilol significantly decreases myocardial work by reducing all three components of myocardial oxygen demand, namely, heart rate, contractility, and wall tension. The vasodilatory effects of carvedilol reduce afterload, and the resulting decrease in impedance to left ventricular ejection offsets the negative inotropic effect that would normally result from beta-blockade. As a consequence, stroke volume and cardiac output are maintained or even increased in animals and in patients with congestive heart failure who are treated with carvedilol. Carvedilol and several of its metabolites are potent antioxidants, and this activity may account, in part, for the cardioprotective effects of the drug observed in animal models of acute myocardial ischemia and, in theory, could also serve to protect the myocardium of patients with hypertension, coronary artery disease, and congestive heart failure, in which oxidative stress is now recognized to occur. The antioxidant effects of carvedilol may both inhibit the direct cytotoxic actions of reactive oxygen radicals and prevent oxygen-radical induced activation of transcription factors and genes associated with inflammatory and remodeling processes. Accordingly, carvedilol inhibits the gene expression of the intracellular adhesion molecule-1 (ICAM-1), an adhesion molecule for polymorphonuclear leukocytes, which typically infiltrate the myocardium under conditions of ischemia and may exacerbate ischemic injury. The antioxidant activity of carvedilol has been shown to inhibit the oxidation of low density lipoprotein (LDL) in vitro, thereby preventing the formation of this cytotoxic and atherogenic form of LDL. It follows, therefore, that in animal models of hyperlipidemia, carvedilol attenuates aortic lipid accumulation and decreases the aortic content of monocytes and foam cells, and at the same time it has been shown to preserve endothelial integrity and function. These actions of carvedilol are not shared by other beta-blockers or by other drugs currently used in the management of hypertension, coronary artery disease, or congestive heart failure. The multiple actions of carvedilol may provide the underlying pharmacologic rationale for the use of this drug in the treatment of patients with coronary artery disease or congestive heart failure, and these actions may account, at least in part, for the reduction in mortality produced by carvedilol in clinical trials involving patients with congestive heart failure. Likewise, these actions of carvedilol may also provide protection, beyond that afforded from reduction in blood pressure, against secondary organ damage in hypertensive patients treated with the drug.

Adrenergic beta-Antagonists↗
PubMed1997

The effects of SB 206284A, a novel neuronal calcium-channel antagonist, in models of cerebral ischemia.

The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.

Animals↗
PubMed1997

2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas expression.

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol-17beta and the oral contraceptive agent 17-ethylestradiol. 2-ME was recently reported to inhibit endothelial cell proliferation. The current study was undertaken to explore the mechanism of 2-ME effects on endothelial cells, especially whether 2-ME induces apoptosis, a prime mechanism in tissue remodeling and angiogenesis. Cultured bovine pulmonary artery endothelial cells (BPAEC) exposed to 2-ME showed morphological (including ultrastructural) features characteristic of apoptosis: cell shrinkage, cytoplasmic and nuclear condensation, and cell blebbing. 2-ME-induced apoptosis in BPAEC was a time- and concentration-dependent process (EC50 = 0.45 +/- 0.09 microM, n = 8). Nucleosomal DNA fragmentation in BPAEC treated with 2-ME was identified by agarose gel electrophoresis (DNA ladder) as well as in situ nick end labeling. Under the same experimental conditions, estradiol-17beta and two of its other metabolites, estriol and 2-methoxyestriol (< or =10 microM), did not have an apoptotic effect on BPAEC. 2-ME activated stress-activated protein kinase (SAPK)/c-Jun amino-terminal protein kinase in BPAEC in a concentration-dependent manner. The activity of SAPK was increased by 170 +/- 27% and 314 +/- 22% over the basal level in the presence of 0.4 and 2 microM 2-ME (n = 3-6), respectively. The activation of SAPK was detected at 10 min, peaked at 20 min, and returned to basal levels at 60 min after exposure to 2-ME. Inhibition of SAPK/c-Jun amino-terminal protein kinase activation by basic fibroblast growth factor, insulin-like growth factor, or forskolin reduced 2-ME-induced apoptosis. Immunohistochemical analysis of BPAEC indicated that 2-ME up-regulated expression of both Fas and Bcl-2. In addition, 2-ME inhibited BPAEC migration (IC50 = 0.71 +/- 0.11 microM, n = 4) and basic fibroblast growth factor-induced angiogenesis in the chick chorioallantoic membrane model. Taken together, these results suggest that promotion of endothelial cell apoptosis, thereby inhibiting endothelial cell proliferation and migration, may be a major mechanism by which 2-ME inhibits angiogenesis.

2-Methoxyestradiol↗
PubMed1997

Carvedilol inhibits aortic lipid deposition in the hypercholesterolemic rat.

The effects of carvedilol, a vasodilating beta-blocker with antioxidant activity, and nifedipine, a calcium channel blocker, were investigated on aortic lipid deposition and the accumulation of monocytes and foam cells at the sites of atherosclerotic lesions in rats subjected to a hypercholesterolemic diet. Fifty rats were randomly assigned to the following experimental groups: (1) regular rat chow (n = 5); (2) regular rat chow supplemented with a high-cholesterol diet (1% cholesterol and 1% cholic acid; n = 15); (3) a high-cholesterol diet plus nifedipine (n = 15), and (4) a high-cholesterol diet plus carvedilol (n = 15). Animals were maintained on these diets for 12 weeks. None of the treatment groups had blood pressures that were outside the normotensive range, and no significant differences in plasma lipid levels were observed among the high-cholesterol diet and drug-treated groups. There was a significantly lower lipid content (p < 0.001) in the thoracic aortas of the nifedipine-treated (211 +/- 23 nmol/mm2) and carvedilol-treated (182 +/- 23 nmol/mm2) groups compared to cholesterol-fed controls (242 +/- 27 nmol/mm2). Furthermore, carvedilol-treated animals showed significantly less (p < 0.001) lipid accumulation than did the nifedipine-treated animals. The number of monocytes and foam cells were decreased in both drug-treated groups compared to animals receiving high-cholesterol diets without drug treatment. The results demonstrate that treatment with carvedilol or nifedipine can significantly inhibit lipid deposition in the aorta and reduce monocyte and foam cell accumulation, and that carvedilol is significantly more effective than nifedipine in inhibiting lipid deposition.

Adrenergic beta-Antagonists↗
PubMed1997

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade.

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.

Acrylates↗
PubMed1997

Hypercholesterolemia impairs a detoxification mechanism against peroxynitrite and renders the vascular tissue more susceptible to oxidative injury.

Previous studies have shown that glutathione (GSH) plays a central role in the protection against peroxynitrite (ONOO-) toxicity. The present study evaluated the changes of the GSH cytoprotective system against ONOO- in hypercholesterolemia and determined the effects of carvedilol, a beta-blocker with free radical-scavenging activity, on these hypercholesterol-induced changes. New Zealand White rabbits were fed either a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with either carvedilol or propranolol. Eight weeks later, the rabbits were killed, and the thoracic aortas were isolated. Total GSH content of aortic tissue, vasorelaxation response of aortic rings to exogenous ONOO-, No regeneration from ONOO- by aortic homogenate, and ONOO(-)-induced aortic tissue injury were examined. Hypercholesterolemia decreased tissue GSH content (0.52 +/- 0.08 versus 0.86 +/- 0.04 mumol/g in control, P < .01), attenuated the vasorelaxation response to ONOO- (40 +/- 4.1% versus 76 +/- 3.2%, P < .01), reduced NO regeneration from ONOO- (387 +/- 40 versus 662 +/- 51 pmol, P < .01), and potentiated ONOO(-)-induced vascular tissue injury (37 +/- 4.4% versus 14 +/- 2.6% of increase in lactate dehydrogenase release after 3-morpholinosydnonimine exposure, P < .01). Treatment of the hypercholesterolemic rabbits with carvedilol, but not propranolol, significantly preserved tissue GSH content (0.79 +/- 0.05 mumol/g, P < .01 versus nontreated hypercholesterolemic rabbits), restored the vasorelaxation to ONOO- (61 +/- 2%, P < .01), increased NO regeneration from ONOO- (583 +/- 39 pmol, P < .01), and attenuated ONOO(-)-induced tissue injury (19 +/- 1.8%, P < .01). These results suggest that hypercholesterolemia impairs the GSH-mediated detoxification mechanism against ONOO- and renders the vascular tissue more susceptible to oxidative injury. Carvedilol, a novel vasodilating beta-blocker with antioxidant activity, significantly preserved this self-defense system and protected tissue from oxidant injury.

Animals↗
PubMed1997

Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats.

BACKGROUND AND PURPOSE: The expression of interleukin-1 beta (IL-1 beta) is upregulated after focal brain ischemia, and previous work has demonstrated its involvement in ischemic injury. The IL-1 receptor antagonist (IL-1ra), a natural competitive antagonist of IL-1 receptors (IL-1Rs), has been demonstrated to play a role in attenuating brain ischemic injury. To hypothesize the involvement of the IL-1 system in ischemic injury, we examined other IL-1 components, including IL-1ra, IL-1RI, and IL-1RII for their mRNA expression after focal stroke. METHODS: Quantitative reverse transcription and polymerase chain reaction (RT-PCR) technique was used to examine the mRNA expression profile of IL-1ra and two IL-1R isoforms in a temporal fashion (n = 4 for each time point) after permanent occlusion of the middle cerebral artery (MCAO) in spontaneously hypertensive rats. IL-1ra and IL-1R mRNA expression was confirmed by Northern blot analysis using poly(A) RNA isolated after 2 and 12 hours of MCAO. RESULTS: Very low levels of IL-1ra mRNA were detected in sham-operated or nonischemic cortex. IL-1ra mRNA in ischemic cortex was greatly increased at 12 hours (16.5-fold increase over sham samples, P < .001) and remained elevated for up to 5 days (17.2-fold increase, P < .01) after MCAO. IL-1RI mRNA was relatively highly expressed in normal cortex and was further elevated late after ischemic injury (3.3-fold increase at day 5, P < .001). In contrast, the low basal expression of IL-1RII mRNA was remarkably elevated at 6 hours (5.3-fold increase, P < .05), reaching peak levels 12 hours (10.3-fold increase, P < .001) after MCAO. CONCLUSIONS: Differential expression of IL-1 beta, IL-1ra, IL-1RI, and IL-1RII mRNAs after focal stroke may suggest a distinct role(s) for each component of the IL-1 system in ischemic injury. The data also stress the importance of evaluating all the components of a given cytokine system (eg, agonist, receptors, and natural antagonist) after focal stroke.

Analysis of Variance↗
PubMed1997

Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that rapidly upregulates in the brain after injury. The present study was designed to explore the pathophysiological significance of brain TNF-alpha in the ischemic brain by systematically evaluating the effects of lateral cerebroventricular administration of exogenous TNF-alpha and agents that block the effects of TNF-alpha on focal stroke and by examining the potential direct toxic effects of TNF-alpha on cultured neurons to better understand how TNF-alpha might mediate stroke injury. METHODS: TNF-alpha (2.5 or 25 pmol) was administered intracerebroventricularly to spontaneously hypertensive rats 24 hours before permanent or transient (80 minutes and 160 minutes) middle cerebral artery occlusion (MCAO). Animals were examined 24 hours later for neurological deficits and ischemic hemisphere necrosis and swelling. In some of these studies, neutralizing anti-TNF-alpha monoclonal antibody (mAb) (60 pmol) was injected intracerebroventricularly 30 minutes before exogenous TNF-alpha (25 pmol). In addition, the effects of blocking endogenous TNF-alpha on permanent focal ischemic injury were determined with the use of either mAb (60 pmol) or soluble TNF receptor I (sTNF-RI) (0.3 or 0.7 nmol) administered intracerebroventricularly 30 minutes before and 3 and 6 hours after MCAO. Finally, the direct neurotoxic effects of TNF-alpha were studied in cultured rat cerebellar granule cells exposed to TNF-alpha (10 to 2000 U/mL for 6 to 24 hours), and neurotransmitter release, glutamate toxicity, and oxygen radical toxicity were studied. RESULTS: TNF-alpha increased the percent hemispheric infarct induced by permanent MCAO in a dose-related manner from 13.1 +/- 1.3% (vehicle) to 18.9 +/- 1.7% at 2.5 pmol (P < .05) and 27.1 +/- 1.3% at 25 pmol (P < .0001). The high dose of TNF-alpha increased ischemia-induced forelimb deficits from 1.6 +/- 0.2 to 2.3 +/- 0.2 (P < 0.1). TNF-alpha (2.5 pmol) also increased the infarction induced by 80 or 160 minutes of transient MCAO from 1.9 +/- 0.9% to 4.3 +/- 0.4% (P < .01) and from 14.2 +/- 1.3% to 21.6 +/- 2.2% (P < .05), respectively. The exacerbation of infarct size, swelling, and neurological deficit after exogenous TNF-alpha was reversed by preinjection of 60 pmol mAb. Blocking endogenous TNF-alpha also significantly reduced focal ischemic brain injury. Treatment with 60 pmol mAb before and after permanent MCAO significantly reduced infarct size compared with control (nonimmune) antibody treatment by 20.2% (P < .05). Reduced brain infarction also was produced by brain administration of 0.3 nmol (decreased 18.2%) or 0.7 nmol (decreased 26.1%, P < .05) sTNF-RI before and after focal stroke. The intracerebroventricular administration of TNF-alpha or sTNF-RI did not alter brain or body temperature, blood gases or pH, blood pressure, blood glucose, or general blood chemistry. In cultured cerebellar granule cells, the application of TNF-alpha did not directly affect neurotransmitter release or glutamate or oxygen free radical toxicity. CONCLUSIONS: These studies demonstrate that exogenous TNF-alpha exacerbates focal ischemic injury and that blocking endogenous TNF-alpha is neuroprotective. The specificity of the action(s) of TNF-alpha was demonstrated by antagonism of its effects with specific anti-TNF-alpha tools (ie, mAb and sTNF-RI). TNF-alpha toxicity does not appear to be due to a direct effect on neurons or modulation of neuronal sensitivity to glutamate or oxygen radicals and apparently is mediated through nonneuronal cells. These data suggest that inhibiting TNF-alpha may represent a novel pharmacological strategy to treat ischemic stroke.

Animals↗
PubMed1997

Calcium channel blockers in cerebral ischaemia.

Ischaemic stroke usually results from the obstruction of a major cerebral vessel which leads to a decrease in cerebral blood flow, and a subsequent reduction in ATP. This energy loss leads to impaired cellular function due to reduced ATP-dependent processes and a disruption in ionic gradients across membranes. Under these conditions, there is a significant efflux of K+ from cells producing cellular depolarisation and the movement of extracellular calcium into cells through calcium channels. It is this increase in intracellular calcium that leads to the 'calcium toxicity' that has been associated with cerebral ischaemia. Increased intracellular calcium triggers the break-down of phospholipids, proteins and nucleic acids. This is activated by calcium-dependent phospholipases, proteases and endonucleases, and contributes to structural and functional damage of the cell membrane, which compromises cell function and facilitates cell death. Calcium channel blockers are used routinely to treat cardiovascular disease and hypertension. Although some experimental studies over the last decade suggest efficacy/benefit in the treatment of experimental ischaemic stroke, clinical data do not bear this out. This article discusses the role of voltage-operated calcium channel blockers in stroke, and reviews much of the available experimental and clinical data.

Journal Article↗
PubMed1997

Use of differential display reverse transcription--polymerase chain reaction for discovery of induced adrenomedullin gene expression in focal stroke.

Differential display and other techniques such as subtractive library screening and representational difference analysis have been developed and widely used for novel gene discovery in pathological and specific physiological conditions. In the present work, we illustrate the utilization of the differential display method for the investigation of the differentially expressed genes in a rat model of focal brain ischemia. Adrenomedullin, a recently discovered vasodilator peptide, was identified to be upregulated after focal brain ischemia and further demonstrated to play a pathophysiological role in exacerbating ischemic damage. The data suggest a high potential for the application of mRNA differential display, as well as other techniques, for the discovery of novel therapeutic targets.

Adrenomedullin↗
PubMed1996

Carvedilol-liposome interaction: evidence for strong association with the hydrophobic region of the lipid bilayers.

Carvedilol (Kredex, Coreg) is a multiple action antihypertensive drug that has been shown to protect cell membranes from lipid peroxidative damages. In this study the physical and structural effects of carvedilol on lipid bilayers are investigated by fluorescence techniques, differential scanning calorimetry and other physical methods. Carvedilol binds to liposomal membranes (9:1 DMPC:DMPG) strongly with an apparent binding constant on the order of 10(4) M-1 in PBS (pH 7.4). The characteristic changes in its intrinsic fluorescence properties when bound to liposomes suggest that this compound is situated in a non-polar environment. The Stern-Volmer and bimolecular quenching constants, determined using nitrate as the fluorescence quencher, for the free and bound carvedilol indicate that the carbazole moiety is at a depth of > 11 A in the lipid bilayer. Fluorescence anisotropy measurements show that, unlike the membrane probes DPH and TMA-DPH, carvedilol is relatively mobile, and does not have a rigidly-defined molecular orientation in the bilayers. Differential scanning calorimetry results indicate that carvedilol is an effective membrane "fluidizer' as it dose-dependently lowers the gel to liquid crystalline transition temperature and broadens the endothermic transition. Comparative studies of interactions of carbazole, 4-OH carbazole and carvedilol with the model liposomal membranes reveal a possible role of membrane-partitioning in their antioxidant efficacy. These findings are discussed in perspective with the membrane biophysical properties of different classes of therapeutic significant lipid antioxidants in mind.

Antihypertensive Agents↗
PubMed1996

Interferon-inducible protein-10 involves vascular smooth muscle cell migration, proliferation, and inflammatory response.

Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family. Using mRNA differential display, we isolated a rat homologue to murine and human IP-10 from lipopolysaccharide-stimulated carotid arteries. Our studies demonstrated that IP-10 is a potent mitogenic and chemotactic factor for vascular smooth muscle cells, the critical features of smooth muscle cells for their contribution to the pathogenesis of atherosclerosis and restenosis. IP-10 induced a concentration-dependent stimulation of DNA synthesis, cell proliferation, and cell migration of rat aortic smooth muscle cells. A concentration- and time-dependent IP-10 mRNA induction was observed in lipopolysaccharide- or interferon-gamma-stimulated, but not interleukin-1beta- or tumor necrosis factor-alpha-stimulated smooth muscle cells. A marked synergistic effect on IP-10 mRNA expression was observed when smooth muscle cells were challenged with interferon-gamma together with interleukin-1beta or tumor necrosis factor-alpha. Furthermore, IP-10 mRNA expression was induced in the rat carotid artery after balloon angioplasty. The mitogenic and chemotactic features of IP-10 for smooth muscle cells, along with its discrete induction in cultured vascular smooth muscle cells and in carotid arteries after balloon angioplasty (neointima formation) suggest that IP-10 may play an active and distinct role in vascular remodeling processes.

Angioplasty, Balloon↗
PubMed1996

Endothelin receptors: receptor classification, novel receptor antagonists, and potential therapeutic targets.

The development of endothelin receptor antagonists has progressed rapidly since the initial discovery of endothelin. Highly potent, orally active nonpeptide endothelin receptor antagonists have been identified, and are being used as pharmacological tools to elucidate the role of endothelin in pathological disorders. Subtype selective endothelin receptor antagonists will also be useful in understanding the physiological and pathological roles of the different subtypes of the endothelin receptors. The selectivity profile for the ideal endothelin receptor antagonist is presently unknown, and it may actually be that the optimal profile for a compound may depend on the clinical indication. In the near future, data from clinical trials with endothelin receptor antagonists will become available and will help to establish the role of endothelin in the etiology of human disease, as well as to provide valuable information concerning the optimum endothelin receptor subtype selectivity for antagonists needed for therapeutic agents.

Amino Acid Sequence↗
PubMed1996

The role of inflammation and cytokines in brain injury.

The original notion that the brain represented an "immune-privileged" organ lacking the capability to produce an inflammatory response to an injury, would appear no longer tenable. Indeed, accumulating evidence during the last decade has shown that the CNS can mount a well-defined inflammatory response to a variety of insults including trauma, ischemia, transplantation, viral infections, toxins as well as neurodegenerative processes. Many aspects of this centrally-derived inflammatory response parallel, to some extent, the nature of such a reaction in the periphery. Through the recent application of molecular biological techniques, new concepts are rapidly emerging as to the molecular mechanisms associated with the development of brain injury. In particular, the importance of cytokines, especially TNF alpha and IL-1 beta, as well as adhesion molecules, has been emphasized in the propagation and maintenance of a CNS inflammatory response. This review will summarize recent observations as to the involvement of these inflammatory mediators in CNS injury and lay claim to the possibility that inhibitors of peripheral inflammation may also be of benefit in treating CNS injuries such as stroke, head trauma, Alzheimer's disease and multiple sclerosis.

Animals↗