European Journal of Pharmacology (v.434, #1-2)

Green tea polyphenols inhibit human vascular smooth muscle cell proliferation stimulated by native low-density lipoprotein by Rudolf Locher; Luca Emmanuele; Paolo M Suter; Wilhelm Vetter; Matthias Barton (1-7).
This study investigated whether human vascular smooth muscle cell proliferation induced by native low-density lipoprotein (LDL) is affected by green tea catechins. Furthermore, the effects of native LDL on extracellular signal-regulated kinase (ERK) 1/2 activity were determined. Cell proliferation stimulated by native LDL was concentration-dependently inhibited by epigallocatechin, epigallocatechin-3-gallate, green tea polyphenon, and the nonspecific antioxidant N-acetylcysteine (P<0.05). Combined treatment of green tea polyphenon and N-acetylcysteine markedly potentiated the effect of each drug on vascular smooth muscle cell proliferation. ERK1/2 activity was only partly inhibited by green tea catechins alone or in combination with N-acetylcysteine (P<0.05). These data suggest that green tea constituents inhibit proliferation of human vascular smooth muscle cells exposed to high levels of native LDL. Green tea constituents and antioxidants may exert vascular protection by inhibiting human vascular smooth muscle cell growth associated with hypercholesterolemia.
Keywords: Antioxidant; Atherosclerosis; Cell proliferation; Green tea catechin; LDL (low-density lipoprotein); Mitogen-activated kinase; Risk factor; Smooth muscle cell;

Cellular mechanisms of inhibition of superoxide anion generation in rat neutrophils by the synthetic isoquinoline DMDI by Jih-Pyang Wang; Ling-Chu Chang; Shue-Ling Raung; Mei-Feng Hsu; Chi-Ming Chen (9-16).
This study was undertaken to assess the cellular localization of the inhibitory effect of a chemically synthetic isoquinoline compound 1-(3′,4′-dimethoxybenzyl)-6,7-dichloroisoquinoline (DMDI) on the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat neutrophils. The DMDI concentration dependently inhibited the superoxide anion (O2 ⋅−) generation and O2 consumption (IC50 12.2±4.9 and 15.2±8.4 μM, respectively) of neutrophils. DMDI did not scavenge the O2 ⋅− generated during the autoxidation of dihydroxyfumaric acid in a cell-free system. DMDI did not elevate cellular cyclic AMP levels. Inhibition of O2 ⋅− generation by DMDI in neutrophils was not reversed by a cyclic AMP-dependent protein kinase inhibitor, (8R,9S,11S)-(−)-9-hydroxy-9-hexoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one (KT5720). The DMDI concentration dependently inhibited the late plateau phase but not the initial spike of fMLP-induced [Ca2+] i changes in the presence of extracellular Ca2+. However, DMDI had no effect on the fMLP-induced [Ca2+] i changes in the absence of extracellular Ca2+. In addition, DMDI did not affect the fMLP-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activation. DMDI produced a concentration-dependent reduction in the formation of phosphatidic acid and phosphatidylethanol in the presence of ethanol from fMLP-stimulated neutrophils (IC50 13.3±4.0 and 9.4±4.3 μM, respectively). On the basis of the immunoblot analysis of the phosphorylation of the mitogen-activated protein (MAP) kinase, DMDI attenuated the fMLP-stimulated MAP kinase phosphorylation in a similar concentration range. Collectively, these results indicate that the inhibition of the respiratory burst by DMDI in rat neutrophils is mediated through the blockade of phospholipase D and MAP kinase signaling pathways.
Keywords: DMDI (1-(3′,4′-dimethoxybenzyl)-6,7-dichloroisoquinoline); Neutrophil; Respiratory burst; Signal transduction; Phospholipase D; MAP (Mitogen-activated protein) kinase; Ca2+ concentration;

Pergolide protects SH-SY5Y cells against neurodegeneration induced by H2O2 by Daniela Uberti; Laura Piccioni; Anna Colzi; Daniele Bravi; Pier Luigi Canonico; Maurizio Memo (17-20).
We found that pergolide, a dopamine D1/D2 receptor agonist used in the clinical therapy of Parkinson's disease, protects SH-SY5Y neuroblastoma cells from cell death induced by a brief pulse (15 min) of 1 mM H2O2. Neuroprotection was found when pergolide was added to the culture medium either simultaneously with (EC50=60 nM) or 2 h before (EC50=40 nM) H2O2 treatment. These effects were not blocked by different dopamine receptor antagonists. Our data suggest that pergolide, independently of dopamine receptor stimulation, may interfere with the early phases of the oxidative stress-induced neurotoxic process.
Keywords: Apoptosis; Glutathione; Neuroblastoma; Dopamine receptor; Parkinson's disease;

Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic by Hideaki Noguchi; Kazuhiro Kitazumi; Megumi Mori; Toshiharu Shiba (21-28).
The binding properties of CL284,846 (zaleplon), a novel nonbenzodiazepine sedative/hypnotic, at benzodiazepine receptor subtypes were evaluated. Zaleplon was 14.3 times more potent at inhibiting [3H]flunitrazepam binding to membrane preparations of the cerebellum than to membrane preparations of the spinal cord. The γ-aminobutyric acid (GABA) ratio of zaleplon was 2.07. Zaleplon produced significant increases in muscimol binding similar to those of diazepam, and it was antagonized by flumazenil. Furthermore, zaleplon showed little affinity for other receptors. Spectral analysis of the electroencephalogram (EEG) of rabbits showed that zaleplon and 3-methyl-6-[3-(trifluoromethyl) phenyl]-1,2,4,-triazolo [4,3-β] pyridazine (CL218,872), an ω1 receptor-selective compound (1 mg/kg, i.v., respectively), produced large increases in energy of the delta frequency band without affecting the energy of the alpha and beta frequency bands. In contrast, intravenous administration of triazolam and zopiclone increased the energy of the beta frequency band at doses of 0.1 and 2 mg/kg, respectively. In addition, the zaleplon-induced increase in the energy of the delta frequency band was antagonized by pretreatment with flumazenil (1 mg/kg, i.v.), which did not affect the spontaneous EEG alone. The present results clearly demonstrate that zaleplon is a selective full agonist of the ω1 receptor subtype, and thus, zaleplon may induce responses closely resembling the physiological pattern of slow wave sleep.
Keywords: Zaleplon; Nonbenzodiazepine; Hypnotic; ω1 receptor; Binding assay; EEG (electroencephalogram);

Possible involvement of tachykinin NK1 and NMDA receptors in histamine-induced hyperalgesia in mice by Shinobu Sakurada; Tohru Orito; Chikai Sakurada; Takumi Sato; Takafumi Hayashi; Jalal Izadi Mobarakeh; Kazuhiko Yanai; Kenji Onodera; Takehiko Watanabe; Tsukasa Sakurada (29-34).
Intrathecal (i.t.) injection of histamine elicited a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of histamine (800 pmol) and returned to control level with 30 min. Hyperalgesia produced by histamine was inhibited dose-dependently by i.t. co-administration of the histamine H1 receptor antagonist, d-chlorpheniramine, but not the histamine H2 receptor antagonist, ranitidine. The tachykinin NK1 receptor antagonists, (+)-[(2S,3S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine] (CP-99,994), and [Tyr6, d-Phe7, d-His9]substance P-(6–11) (sendide), inhibited histamine-induced hyperalgesic response in a dose-dependent manner. A significant antagonistic effect of [d-Phe7, d-His9]substance P-(6–11), a selective antagonist for substance P receptors, was observed against histamine-induced hyperalgesic response. The tachykinin NK2 receptor antagonist, Asp-Tyr-d-Trp-Val-d-Trp-d-Trp-Lys-NH2 (MEN-10,376), had no effect on hyperalgesia elicited by histamine. The competitive N-methyl-d-aspartate (NMDA) receptor antagonists, and d-(−)-2-amino-5-phosphonovaleric acid (d-APV), (±)-3-(2-carboxypiperazin-yl)propyl-1-phosphoric acid (CPP), the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), and l-N G-nitro arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor, markedly inhibited histamine-induced hyperalgesic response. The present results suggest that hyperalgesic response induced by i.t. injection of histamine may be mediated by tachykinin NK1 receptors, but not NK2 receptors in the spinal cord. In addition, spinal NMDA receptor–NO system may also contribute to elicitation of hyperalgesia following i.t. injection of histamine.
Keywords: Histamine H1 receptor; Tachykinin NK1 receptor; NMDA receptor; Nitric oxide (NO); Hyperalgesia;

Glibenclamide attenuates ischemia-induced acidosis and loss of cardiac function in rats by Roger J Legtenberg; Ralph J.F Houston; Arend Heerschap; Berend Oeseburg; Paul Smits (35-42).
Previous research has shown that the sulfonylurea derivative glibenclamide may improve post-ischemic cardiac functional recovery. Although KATP channel blockade is a possible explanation for this observation, alternative mechanisms exist. Therefore, we simultaneously recorded cardiac function and the intracellular concentration of ATP, phosphocreatine, Pi and pH before and after ischemia in the presence of glibenclamide or vehicle. 31Phophorus magnetic resonance (MS) spectroscopy on erythrocyte-perfused, isolated working rat hearts was performed. Glibenclamide 4 μmol l−1 or vehicle alone was tested (both n=5). The following protocol was used: 8 min performance assessment, 10 min drug treatment, 12 min global ischemia, 20 min reperfusion with drug treatment and 8 min functional recovery assessment. Compared with vehicle, glibenclamide significantly decreased coronary blood flow (59.5±7.0% vs. 94.3±1.3%, P=0.008), ischemia-induced cardiac functional loss (7.4±1.3% vs. 18.8±3.3%; P=0.019) as well as the ichemia-induced intracellular acidosis (6.75±0.01 vs. 6.43±0.03 for vehicle, P=0.03).In conclusion, glibenclamide is able to reduce the myocardial functional loss after ischemia while preserving pH but not ATP levels during ischemia. This suggests that the beneficial response to glibenclamide is probably not the result of myocardial KATP channel blockade, but may be explained by inhibition of glycolysis.
Keywords: 31Phosphorus magnetic resonance spectroscopy; Heart; Ischemia; Metabolism; Diabetes; Glibenclamide; KATP channel;

Antisympathetic and hemodynamic property of a dual L/N-type Ca2+ channel blocker cilnidipine in rats by Akira Takahara; Hajime Koganei; Tomoko Takeda; Seinosuke Iwata (43-47).
The in vivo antisympathetic property of a dual L/N-type Ca2+ channel blocker cilnidipine compared with that of typical N-type Ca2+ channel blockers has never been clarified. We investigated the effects of the drug on a sympathetic nerve-mediated vascular response and vasodilating action in rats in comparison with those of an N-type Ca2+ channel blocker ω-conotoxin MVIIA. In pithed rats, ω-conotoxin MVIIA preferentially suppressed the sympathetic nerve stimulation-induced pressor response, whereas cilnidipine suppressed the pressor response induced by sympathetic nerve stimulation and angiotensin II. In anesthetized rats, cilnidipine or ω-conotoxin MVIIA decreased mean blood pressure, while heart rate was decreased by ω-conotoxin MVIIA, but slightly increased by cilnidipine. These results suggest that cilnidipine can affect sympathetic N-type Ca2+ channels in addition to vascular L-type Ca2+ channels in antihypertensive doses in the rat in vivo. The antisympathetic activity of cilnidipine is not excessive for an antihypertensive drug in comparison with that of ω-conotoxin MVIIA.
Keywords: Cilnidipine; ω-Conotoxin MVIIA; Sympathetic nerve; Ca2+ channel;

Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells by Lars Edvinsson; Rikard Alm; Duncan Shaw; Ruth Z Rutledge; Kenneth S Koblan; Jenny Longmore; Stefanie A Kane (49-53).
Several lines of evidence suggest that a calcitonin-gene related peptide (CGRP) receptor antagonist may serve as a novel abortive migraine treatment. Here we present data on a human cell line and isolated human vessels for such an antagonist, BIBN4096BS. On SK-N-MC membranes, radiolabelled CGRP was displaced by both CGRP-(8-37) and BIBN4096BS, yielding pK i values of 8.5 and 11.4, respectively. Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and BIBN4096BS with pA 2 values of 7.8 and 11.2, respectively. Isolated human cerebral, coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA 2 value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest.
Keywords: CGRP receptor; Cerebral vessel; cAMP production; Dilatation;

Role of mitogen-activated protein kinase pathway in acetylcholine-mediated in vitro relaxation of rat pulmonary artery by Wai Yee Choy; Yung Fat Wong; Yiu Wa Kwan; Alice Lai Shan Au; Wing Hung Lau; Kenneth Raymond; Joan Zhong Zuo (55-64).
This study was designed to characterise the muscarinic receptor subtype responsible for acetylcholine-mediated in vitro pulmonary artery relaxation in rats and the importance of the presence of neostigmine (an anti-cholinesterase) during receptor characterisation. Cumulative administration of acetylcholine elicited concentration-dependent relaxation of phenylephrine (1 μM) precontracted preparations. Inclusion of neostigmine (10 μM) caused a parallel leftward shift with an increase of the pD 2 value (7.09 vs. 6.43) of the concentration–response curve of acetylcholine. The magnitude of maximum relaxation, however, was not affected. Using a range of conventional muscarinic receptor antagonists (atropine, pirenzepine, methoctramine, p-FHHSiD and tropicamide) and the highly selective Green Mamba muscarinic toxins (MT-3 and MT-7), it was found that muscarinic M3 receptors are probably responsible for endothelium-dependent relaxation of the pulmonary artery upon acetylcholine challenge. Preincubation with N G-nitro-l-arginine methyl ester (l-NAME, 20 μM, a nitric oxide synthase inhibitor), but not N G-nitro-d-arginine methyl ester (d-NAME, 20 μM), abolished acetylcholine-elicited relaxation. Moreover, 6-anilino-5,8-quinolinedione (LY 83583, 1 μM) and methylene blue (1 μM) (both are guanylate cyclase inhibitors) markedly attenuated acetylcholine-elicited relaxation. However, the presence of indomethacin (3 μM, a cyclo-oxygenase inhibitor), (−)-perillic acid (30 μM, a p21ras blocker), 2-[2′-amino-3′-methoxy-phenyl]-oxana-phthalen-4-one (PD 98059) (10 μM, a p42/p44 mitogen-activated protein kinase inhibitor), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) (1 μM, a p38 mitogen-activated protein kinase blocker), wortmannin (500 nM, a phosphatidylinositol-3 kinase inhibitor) and genistein (10 μM, a tyrosine kinase blocker) failed to alter acetylcholine-provoked pulmonary arterial relaxation. These results suggest that acetylcholine caused pulmonary arterial relaxation through the activation of muscarinic M3 receptors in the endothelium. Moreover, the p21ras/mitogen-activated protein kinase pathway seems to play no role in mediating acetylcholine-elicited relaxation.
Keywords: Acetylcholine; Pulmonary artery; Muscarinic M3 receptor; Nitric oxide (NO); MAP (mitogen-activated protein) kinase;

Interaction of cyclooxygenase-2 inhibitors and salicylate in gastric mucosal damage by Brigitta M Peskar; Karlheinz Ehrlich; Bernhard A Peskar (65-70).
The interactions of sodium salicylate and the selective cyclooxygenase-2 inhibitors N-{2-(cyclohexyloxy)-4-nitrophenyl}-methanesulfonamide (NS-398) and 5.5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5II)-furanone (DFU), dexamethasone and the nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methylester (l-NAME) were examined in ischaemia–reperfusion damage and adaptive protection in the rat stomach. Ischaemia–reperfusion damage was substantially aggravated by pretreatment with NS-398 (4 mg/kg), DFU (2 mg/kg), dexamethasone (1 mg/kg) or l-NAME (3 and 10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the aggravating effect of NS-398, DFU and dexamethasone, while the effect of l-NAME was counteracted by l-arginine (twice 400 mg/kg) but not salicylate (0.05 or 10 mg/kg). Instillation of 20% ethanol prevented mucosal damage induced by 70% ethanol. This adaptive gastroprotection was abolished by pretreatment with NS-398 (1 mg/kg), DFU (0.2 mg/kg) or l-NAME (10 mg/kg). Salicylate (0.01–0.05 mg/kg) reversed the inhibition of protection by NS-398 and DFU, while the effect of l-NAME (10 mg/kg) was antagonized by l-arginine (100 mg/kg) but not salicylate (0.05 mg/kg). The precise mechanism of the functional antagonism between extremely low doses of salicylate and selective cyclooxygenase-2 inhibitors remains to be investigated.
Keywords: Sodium salicylate; Cyclooxygenase-2; Gastric mucosal damage; Ischaemia–reperfusion; Adaptive gastroprotection; Nitric oxide (NO);

Modulation of airway responsiveness by anionic and cationic polyelectrolyte substances by Tomoyuki Yahata; Yoshihiro Nishimura; Hitoshi Maeda; Mitsuhiro Yokoyama (71-79).
To elucidate the effects of anionic and cationic polyelectrolyte substance on bronchoconstriction, we examined the serial changes in respiratory resistance (Rrs) in ovalbumin-sensitized guinea pigs after antigen exposure with or without preinhalation of low-molecular-weight heparin, poly-l-glutamic acid, poly-l-lysine and dextran, and with or without oral intake of dalteparin. Both immediate and late responses after antigen exposure were significantly decreased after pretreatment with inhaled low-molecular-weight heparin and poly-l-glutamic acid compared with saline alone. The late response was significantly decreased after pretreatment with oral dalteparin. Both low-molecular-weight heparin and poly-l-glutamic acid significantly decreased the airway response to methacholine in sensitized guinea pigs. In sensitized guinea pigs, the airway response to methacholine was significantly increased after pretreatment with inhaled poly-l-lysine. Pretreatment with inhaled low-molecular-weight heparin before poly-l-lysine exposure significantly suppressed the airway hyperresponsiveness after inhaled poly-l-lysine. These findings indicated that the “cationic–anionic interaction” plays an important role in airway responsiveness.
Keywords: Bronchial asthma; Low-molecular-weight heparin; Poly-l-glutamic acid; Poly-l-lysine; Cationic–anionic interaction;

Pathogenesis of nicotine treatment and its withdrawal on stress-induced gastric ulceration in rats by Donna Wong; Marcel W.L Koo; Vivian Y Shin; Edgar S.L Liu; Chi-Hin Cho (81-86).
Previous studies showed that cigarette smoking was closely associated with gastric ulceration. People usually smoke under stress conditions, and together, these could induce more gastric damage. In the present study, we aimed to study the effects of nicotine administration and its withdrawal on stress-induced gastric ulceration in rats. Male Sprague–Dawley rats were given nicotine (25 or 50 μg/ml) for 10 days and then withdrawn for 2, 4 or 6 days. They were subjected to cold-restraint stress for 2 h after nicotine treatment or after nicotine withdrawal, and then killed. The results indicated that both nicotine treatment and its withdrawal potentiated stress-induced gastric damage. The mucosal glutathione (GSH) and mucus levels were reduced by stress and decreased further by nicotine. The prostaglandin E2 concentration remained unchanged. To conclude, the adverse effect of nicotine on stress ulceration was prostaglandin E2-independent but mediated by the depression of glutathione and mucus levels in the gastric mucosa.
Keywords: Blood flow; Glutathione; Mucus; Nicotine; Prostaglandin E2; Gastric ulcer;

Interactions between cannabinoid CB1 and GABA receptors and ligands were investigated in the myenteric plexus-longitudinal muscle of the guinea pig ileum. Electrically evoked contractions of the myenteric plexus-longitudinal muscle were inhibited by the cannabinoid receptor agonist CP55,940 ((−)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), the GABAB receptor agonist, baclofen (4-amino-3-(chlorophenyl) butanoic acid), or exogenous GABA. Electrically evoked contractions of the myenteric plexus-longitudinal muscle were also inhibited by the addition of the GABA releasing agent ethylenediamine. CP55,940 (1 nM) or the endogenous cannabinoid anandamide (arachidonyl ethanolamide, 1 μM) reduced the inhibition produced by ethylenediamine, while in contrast, anandamide (10 μM) significantly increased the inhibition produced by ethylenediamine. The results suggest that while there is no interaction between cannabinoid CB1 and GABAB receptors in the myenteric plexus-longitudinal muscle of the guinea pig, cannabinoid CB1 receptor stimulation reduces the ethylenediamine-evoked GABA release. In addition, anandamide at higher concentrations also potentiates the inhibitory effect of ethylenediamine at least partly by stimulating vanilloid receptors.
Keywords: Ileum; (Guinea pig); Cannabinoid CB1 receptor; GABA (γ-aminobutyric acid) release; Ethylenediamine; Anandamide;

Endothelin in the mechanism of endothelial injury and neutrophil adhesion in the post-ischemic guinea-pig heart by Michał Kurzelewski; Elżbieta Czarnowska; Andrzej Beręsewicz (95-107).
This study addressed the hypothesis that endothelin promotes neutrophil accumulation in ischemic/reperfused myocardium, not only via its direct effect on neutrophils, but also because it mediates post-ischemic endothelial injury. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/35 min reperfusion, and infusion of neutrophils between 15 and 25 min of reperfusion. The infusion of the endothelin ETA/ETB receptor antagonist, tezosentan, the endothelin ETA receptor antagonist, BQ 123 [cyclo(-d-Trp-d-Asp-Pro-d-Val-Leu-], and superoxide dismutase was terminated at reperfusion, 5 min before the start of the neutrophil infusion, to avoid the contact of the drugs with neutrophils. Coronary flow responses to acetylcholine and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Neutrophil adhesion and endothelium glycocalyx ultrastructure were assessed in histological preparations. Ischemia/reperfusion resulted in a 54%-impaired acetylcholine response, endothelium glycocalyx disruption, and enhanced neutrophil adhesion (21.6% of microvessels contained neutrophils vs. 2.6% in sham group), the latter prevented by a selectin blocker, sulfatide, 20 μg/ml. These alterations were completely prevented by 0.5 and 5 nM, but not 0.05 nM, tezosentan, and were greatly attenuated by BQ 123, 1 and 10 nM. The glycocalyx-protective effect of these interventions preceded their effect on neutrophil adhesion. Superoxide dismutase, 150 IU/ml, reported before by us to protect post-ischemic endothelium glycocalyx, here prevented the post-ischemic endothelial dysfunction and neutrophil adhesion. The data imply that neutrophil adhesion in ischemic/reperfused guinea-pig heart is a selectin-dependent process, secondary to mostly endothelin ETA receptor- and free radical-mediated functional and/or structural changes in the coronary endothelium. Thus, endothelin ETA/ETB as well as ETA receptor antagonists may be useful in attenuation of the inflammatory response in ischemic/reperfused heart. The antagonists may be effective because of their direct effect on neutrophils, as demonstrated by others, and because they provide endothelial protection, as demonstrated here.
Keywords: Endothelial dysfunction; Neutrophil adhesion; Endothelium glycocalyx; Reperfusion injury; Heart; Oxygen free radical;