Prostaglandins: enzymatic analysis.

By, means of al specific nicotinamide-adeninie dinucleotide-dependent prostaglanidin dehydrogenase from swine lung, an enizymatic method has been developed for the assay of prostaglandins. The method permits analysis with a lower limit of 10(-12) mole of prostaglandin.

A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy.

OBJECTIVES: To evaluate the efficacy and safety of a therapeutic bacteriophage preparation (Biophage-PA) targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis. DESIGN: Randomised, double-blind, placebo-controlled Phase I/II clinical trial approved by UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Central Office for Research Ethics Committees (COREC) ethical review process. SETTING: A single specialist university hospital. PARTICIPANTS: 24 patients with chronic otitis with a duration of several years (2-58). Each patient had, at the time of entry to the trial, an ear infection because of an antibiotic-resistant P. aeruginosa strain sensitive to one or more of the six phages present in Biophage-PA. Participants were randomised in two groups of 12 treated with either a single dose of Biophage-PA or placebo and followed up at 7, 21 and 42 days after treatment by the same otologist. Ears were thoroughly cleaned on each occasion and clinical and microbiological indicators measured. MAIN OUTCOME MEASURES: Physician assessed erythema/inflammation, ulceration/granulation/polyps, discharge quantity, discharge type and odour using a Visual Analogue Scale (VAS). Patients reported discomfort, itchiness, wetness and smell also using a VAS. Bacterial levels of P. aeruginosa and phage counts from swabs were measured initially and at follow-up. At each visit patients were asked about side effects using a structured form. Digital otoscopic images were obtained on days 0 and 42 for illustrative purposes only. RESULTS: Relative to day 0, pooled patient- and physician-reported clinical indicators improved for the phage treated group relative to the placebo group. Variation from baseline levels was statistically significant for combined data from all clinic days only for the phage treated group. Variation from baseline levels was statistically significant for the majority of the patient assessed clinical indicators only for the phage treated group. P. aeruginosa counts were significantly lower only in the phage treated group. No treatment related adverse event was reported. CONCLUSION: The first controlled clinical trial of a therapeutic bacteriophage preparation showed efficacy and safety in chronic otitis because of chemo-resistant P. aeruginosa.

Formation of phosphatidylethanol in frozen kidneys from ethanol-treated rats.

We recently identified phosphatidylethanol (Pet) in tissues from ethanol-treated rats. Since phosphatidyl esters are formed artefactually during freezing in plants we wanted to examine if PE was elevated during freezing in animal tissues. Rats were treated with 3 g/kg of ethanol, killed after 3 h and PE was isolated from kidneys at once or after storage at 0, -5, -10, -15, -20 and -80 degrees C for 7 days. Kidneys analyzed at once or after storage at -80 degrees C had Pet equivalent to 0.02 mumol Pet/g. Storage at -10 degrees C and -15 degrees C resulted in increases of Pet to 1.5 mumol Pet/g and 1.2 mumol Pet/g, respectively. Thus, Pet is artefactually elevated during storage of tissues from ethanol-treated rats at lower freezing temperatures, reflecting considerable changes in composition of acidic phospholipids.

Oxidative modification of low-density lipoprotein by human polymorphonuclear leucocytes to a form recognised by the lipoprotein scavenger pathway.

The oxidative modification of low-density lipoprotein (LDL) results in the formation of cytotoxic and chemotactic lipids which are thought to be of importance in the development of atherosclerotic lesions. In the present study we show that polymorphonuclear leucocytes (PMNs) can modify LDL to a form which is rapidly incorporated by macrophages via a scavenger receptor pathway. Incubation of 125I-labelled LDL with PMNs in Ham's F-10 medium resulted in oxidation as shown by the appearance of thiobarbituric acid-reactive substances, increased electrophoretic mobility of the LDL and increased degradation of the LDL by mouse peritoneal macrophages. The presence of the anti-oxidant butylated hydroxytoluene or the metal ion chelator, EDTA inhibited the PMN-mediated modification. The degradation of 125I-labelled PMN modified LDL by macrophages was competitively inhibited by unlabelled copper-oxidised LDL but not by native LDL, indicating that the degradation was mediated by the scavenger receptor. The oxidative modification of LDL by PMNs could be of pathophysiological importance in inflammation and in the accelerated atherosclerosis seen following cardiac reperfusion injury.

The effects of LPS and probucol on interleukin 1 (IL-1) and platelet-derived growth factor (PDGF) gene expression in the human monocytic cell line U-937.

We have investigated the effects of lipopolysaccharide (LPS) and probucol (a lipid soluble antioxidant) on the gene expression of interleukin 1 alpha and beta (IL-1 alpha and IL-1 beta), and platelet-derived growth factor A chain and B chain (PDGF-A and PDGF-B) in the human monocytic cell line U-937. Steady-state mRNA levels were measured quantitatively by the reverse transcription-polymerase chain reaction (RT-PCR) using a non-radioactive label. Cells were incubated with LPS, in the presence or absence of probucol for 20 h. The cells were harvested and RNA was then prepared, reverse-transcribed in the presence of an internal standard and subsequently amplified and labelled with digoxigenin-11-dUTP by the PCR reaction. The PCR products were subjected to agarose gel electrophoresis, blotted onto nylon membranes and visualised by immunological detection of digoxigenin followed by a chemiluminescent reaction. We found that: (1) LPS treatment of U-937 cells caused an up-regulation of gene expression of IL-1 beta and PDGF-A chain by approximately 250% and 100% respectively, although it did not stimulate the expression of IL-1 alpha nor PDGF-B chain mRNA. (2) Probucol treatment in vitro had no effect on the basal or LPS-stimulated mRNA levels of IL-1 alpha, IL-1 beta, PDGF-A and PDGF-B despite its reported activity in vivo. (3) PDGF-A and PDGF-B were expressed at a similar level in unstimulated U-937 cells approximately 10-50 copies/ng total RNA, whereas the expression of IL-1 beta mRNA was approximately 2-4 times higher than IL-1 alpha mRNA. (4) Finally, in U-937 monocytic cells the expression of IL-1 alpha and IL-1 beta, and PDGF-A and PDGF-B appear to be independently regulated.

Phosphatidylethanol formation in rat organs after ethanol treatment.

An abnormal acidic phospholipid was found in high concentration in kidney and brain, and also in other organs of rats exposed to ethanol by i.p. injection or by a liquid diet. The compound could be identified as phosphatidylethanol. Phosphatidylethanol is probably formed in cell membranes by a phospholipase D-catalyzed transphosphatidylation reaction.

Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion.

The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.

Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus.

OBJECTIVES: We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus. BACKGROUND: The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP), possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium-dependent vasodilators may provide a measure of endothelial function. METHODS: The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler velocimetry. RESULTS: Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IP(DVP), whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IP(DVP). The time between the first and second peak of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine. The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88). CONCLUSIONS: The IP(DVP) is influenced by pressure wave reflection. The effects of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes.

Antioxidants, diabetes and endothelial dysfunction.

While a damaged endothelium is recognised to be a key accessory to diabetic macroangiopathy, awareness is developing that impairments concerning endothelium- and nitric oxide (NO)-dependent microvascular function, may contribute to several other corollaries of diabetes, such as hypertension, dyslipidaemia and in vivo insulin resistance. There are now several reports describing elevations in specific oxidant stress markers in both insulin resistance syndrome (IRS) and diabetes, together with determinations of reduced total antioxidant defence and depletions in individual antioxidants. Such a pro-oxidant environment in diabetes may disrupt endothelial function through the inactivation of NO, resulting in the attenuation of a fundamental anti-atherogenic and euglycaemic vascular influence. Indeed, experimental and clinical data suggest that the supplementation of insulin resistant or diabetic states with antioxidants such as vitamin E, normalises oxidant stress and improves both endothelium-dependent vasodilation and insulin sensitivity. However, the promising potential efficacy of antioxidant therapy in cardiovascular disease and diabetes, in either a primary or secondary preventative role, awaits definitive clinical demonstration.

Vitamin E restores endothelium dependent vasodilatation in cholesterol fed rabbits: in vivo measurements by photoplethysmography.

OBJECTIVE: Pulse curve plethysmography was used to examine the effect of vitamin E on endothelium dependent and independent vasodilatation in unanaesthetised cholesterol fed rabbits in vivo. The height of the dicrotic notch was used as an index of general arterial vasodilatation. METHODS: Twenty eight rabbits were divided into three study groups; a control group (group 1, n = 8), a group fed 1% cholesterol (group 2, n = 10), and a group fed 1% cholesterol with the addition of 0.2% vitamin E after four weeks (group 3, n = 10). After six weeks on diet the vasodilator responses to acetylcholine and glyceryl trinitrate were measured by photoplethysmography of the rabbit ear. Recordings were made during light sedation at baseline and during infusion of acetylcholine (1.5, 3.0, 6.0, and 12 micrograms.min-1) and glyceryl trinitrate (3.75, 7.5, and 15.0 micrograms.min-1). In a second set of experiments with control fed rabbits (n = 5), acetylcholine infusions were given before and after infusion of L-nitro-arginine (15 mg). RESULTS: The relative height of the dicrotic notch (which predominantly indicates arterial tone in the larger vessels) was reduced by acetylcholine in a dose dependent manner, but in cholesterol fed rabbits (group 2) this response was significantly decreased. Rabbits receiving concomitant dietary vitamin E responded in a similar manner to controls. The difference was most prominent using acetylcholine at a dose of 3.0 micrograms.min-1, where the mean change from baseline was 11(SEM 4)% in group 2, compared to 31(6)% in group 1 (p = 0.01), and to 26(5)% in group 3 (p = 0.02). Similar differences between the groups were observed for the increase in heart rate during acetylcholine infusions. In contrast, the responses to glyceryl trinitrate were similar in all groups. After infusions of L-nitro-arginine, the responses to acetylcholine were blunted. CONCLUSIONS: Supplementation with vitamin E restored the otherwise reduced vascular response to acetylcholine in cholesterol fed rabbits. Analysis of photoplethysmographic pulse curves is a simple non-invasive method of evaluating arterial vasodilator effects. However, the nature of the measured dilator response needs to be characterised further.

Methadone maintenance: plasma levels and therapeutic outcome.

Twenty-one opiate-dependent subjects were inducted into methadone maintenance treatment (MMT) in a closed metabolic ward. A daily dose of 30 mg of d, 1-methadone was given for 10 to 24 days followed by 60 mg/day for another 10 to 24 days. Analysis of plasma levels at 4-day intervals showed accumulation to a peak followed by a decrease to a lower level, indicative development of dispositional tolerance. The outcome of treatment was assessed after 21 to 43 mo (median, 33 mo). The best record of rehabilitation was obtained in subjects discharged with steady-state plasma concentrations above 200 ng/ml. Lower levels of plasma methadone were associated with higher frequency of urines containing illicit drugs and poorer psychosocial rehabilitation. This study indicates that a pharmacokinetically optimized dosage regimen would be useful in increasing the therapeutic effectiveness of MMT.

Disposition of methadone in methadone maintenance.

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C-methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N-monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.

Evaluation of the postprandial effects of a fast-food meal on human plasma F(2)-isoprostane levels.

Measurement of the F(2)-isoprostane, 8-epi-PGF(2alpha) is increasingly used as a sensitive and reliable marker of lipid peroxidation in vivo. Because the majority of 8-epi-PGF(2alpha) in plasma is associated with lipoproteins, it is possible that 8-epi-PGF(2alpha) derived from polyunsaturated fatty acid-rich food may become incorporated within these lipoproteins during synthesis and could contribute to the levels detected in plasma. In this study, we evaluated the postprandial effect of a single fast-food meal (McDonald's Big Mac meal, McDonald's Corp., London, England) on plasma total 8-epi-PGF(2alpha) in nine healthy subjects. Blood was collected before and 2 h postprandially. 8-Epi-PGF(2alpha) was measured by immunoaffinity extraction and gas chromatography-mass spectrometry. Fasting plasma 8-epi-PGF(2alpha) (875 +/- 25 pM) increased postprandially (956 +/- 23 pM, p <.05), although no significant change was observed in the normalized concentrations (2. 78 +/- 0.1 vs. 2.95 +/- 0.3 nmol/mmol arachidonic acid). Plasma lipid hydroperoxides, fatty acids, vitamin E, total antioxidant status, cholesterol, and triglycerides were not altered. Plasma glucose increased postmeal (4.4 +/- 0.1 vs. 4.9 +/- 0.1 mM, p <.05). These results indicate that the overall contribution of this lipid-rich meal to plasma 8-epi-PGF(2alpha) and other lipid peroxidation markers was small.

Formation of F2-isoprostanes during aortic endothelial cell-mediated oxidation of low density lipoprotein.

We investigated the formation of F2-isoprostanes produced by non-enzymatic peroxidation of arachidonic acid during rabbit aortic endothelial cell-mediated oxidation of low density lipoprotein (LDL). Free and total (sum of free and esterified) levels of F2-isoprostanes were measured using a solid-phase extraction procedure and gas chromatography-mass spectrometry. Free levels of F2-isoprostanes in native LDL were 0.06 +/- 0.03 ng/mg protein (n = 4), whereas total levels were 0.28 +/- 0.09 ng/mg protein (n = 4). Both free and total levels of the isoprostanes were found to increase during the oxidation. 8-epi-PGF2 alpha was the major isoprostane formed (free and total concentrations after 24 h, 2.50 +/- 0.24 and 6.42 +/- 1.36 ng/mg protein (n = 4), respectively). The release of F2-isoprostanes during aortic endothelial cell-induced oxidation of LDL could be a contributory factor in the development of atherosclerosis.

Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus.

This study reports plasma levels of a specific nonenzymatic peroxidation product of arachidonic acid, esterified 8-epi-PGF2 alpha, from healthy- and NIDDM individuals as an index of oxidative stress in vivo. Plasma 8-epi-PGF2 alpha was isolated by solid-phase extraction on a C18 followed by an NH2 cartridge and analyzed by GC-MS/NICI as PFB-ester/TMS-ether derivative. We found that the average concentration of esterified 8-epi-PGF2 alpha among NIDDM subjects (0.93 +/- 0.07 nM, n = 39) was higher (P < 0.0001, Mann-Whitney test) than in healthy individuals (0.28 +/- 0.04 nM, n = 15). These data indicate that NIDDM is associated with increased plasma lipid peroxidation.

Effects of the superoxide dismutase-mimic compound TEMPOL on oxidant stress-mediated endothelial dysfunction.

The aim of this study was to investigate the effects of oxidant stress on endothelium-dependent and endothelium-independent arterial relaxation. For this, oxidant stress was generated by preincubation of rat aortic rings (RARs) in either 25 mM glucose (mimicking hyperglycemic stress) or 0.5 mM pyrogallol (a superoxide generator) and the effects of the superoxide dismutase (SOD)-mimetic compound 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy free radical (TEMPOL) on the vasorelaxant and cGMP-producing effects of acetylcholine (ACh) and glyceryl trinitrate (GTN) in control RARs and RARs exposed to oxidant stress were examined. Pyrogallol, and to a lesser extent high glucose concentration, enhanced the contractile response of RARs to phenylephrine and markedly inhibited the vasorelaxant response to ACh. Although they existed, the inhibitory effects of high glucose and pyrogallol on the vasorelaxant response to GTN were less profound, especially with pyrogallol. Moreover, both pyrogallol and high glucose concentration inhibited the basal and the ACh-induced vascular cyclic guanosine monophosphate (cGMP) production. Treatment with TEMPOL (1-5 mM) slightly increased the ACh and GTN-induced cGMP levels in control RARs but had a significant effect in high glucose and pyrogallol-pretreated RARs. Additionally, concomitant treatment of RARs with TEMPOL (5 mM) abolished the difference in the relaxation response between control RARs and RARs exposed to either pyrogallol or high glucose concentration. These results further support the theory that reactive oxygen species (ROS), especially superoxide, play a key role in mediation of endothelial dysfunction accompanying diabetes, probably through their effects on the ability of the endothelium to synthesize, release or respond to endogenous nitric oxide (NO) or NO donated by nitrovasodilators.

Dietary vitamin E increases the resistance to lipoprotein oxidation and attenuates endothelial dysfunction in the cholesterol-fed rabbit.

This study was conducted to determine if vitamin E could reverse or attenuate endothelial dysfunction following an atherogenic diet. Rabbits were initially fed 1% cholesterol for 4 weeks to induce endothelial dysfunction. During the next 4 weeks the rabbits were fed either 1% cholesterol +0.2% vitamin E or 1% cholesterol alone, and were then killed. Endothelium-dependent responses to acetylcholine, calcium ionophore A23187 and sodium nitroprusside (SNP) were studied in the preconstricted perfused rabbit ear. Dietary vitamin E partially reversed the impaired endothelium-dependent responses to acetylcholine associated with cholesterol feeding. The maximum decrease in perfusion pressure in response to acetylcholine was 77.8% +/- 3.6% in control animals, 35.3% +/- 2.6% in cholesterol-fed animals, and 49.1% +/- 4.7% in cholesterol+vitamin E treated animals. The response to A23187 or sodium nitroprusside did not differ between the groups. The susceptibility of rabbit beta-VLDL to oxidation was markedly decreased in the vitamin E treated animals as assessed by the formation of conjugated dienes. The formation of lipid peroxidation products were also significantly inhibited by vitamin E. These data suggest that dietary vitamin E is beneficial in reducing the oxidative injury that may lead to the impairment of nitric oxide (NO)-mediated responses in early hypercholesterolaemia.

Insulin-like growth factor binding protein-1 inhibits arterial smooth muscle cell proliferation in vitro but does not reduce the neointimal response to balloon catheter injury.

The biological effects of the insulin-like growth factors (IGFs) are modulated by circulating binding proteins (BPs), including IGFBP-1. We have investigated the effects of recombinant IGFBP-1 on smooth muscle cell (SMC) proliferation in vitro using cultured rat aortic SMCs and in vivo using the ballooned rat carotid artery model. IGFBP-1 inhibited IGF-1 induced and spontaneous SMC proliferation dose-dependently. In vivo, the effective half-life of IGFBP-1 was approximately 5 h when administered by intraperitoneal injection. High peri-operative plasma levels of IGFBP-1 (mean 1780 ng/ml) were attained by giving and intravenous dose immediately prior to balloon injury in 9 rats. Animals injected with human serum albumin or saline were used as controls. In vivo cell proliferation was assessed by BrdU pulse labeling each animal prior to the termination of the experiment, 6 days after balloon injury. Absolute intimal thickness, intima-media ratio and cell proliferation indices were measured for each animal. Although IGFBP-1 inhibited SMC proliferation in vitro, high plasma concentrations of IGFBP-1 did not reduce neointimal size or cell proliferation. IGFBP-1 administration was, however, associated with a significantly greater loss of body weight (P < 0.05), indicating that the peptide had a profound metabolic effect. Our data suggest that IGF-1 does not have a major role in inducing SMC proliferation in the early phases following angioplasty.

Vitamin E reverses cholesterol-induced endothelial dysfunction in the rabbit coronary circulation.

Hypercholesterolaemia and atherosclerosis are associated with impaired endothelium-dependent vasodilation. In this study we have examined the effects of vitamin E on cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. Rabbits were maintained for 4 or 8 weeks on one of three experimental diets: (a) control chow, (b) 1% cholesterol or (c) 1% cholesterol for the first half of the treatment period followed by 1% cholesterol + 0.2% vitamin E during the last half of the treatment. After sacrifice, vasodilator responses to acetylcholine and sodium nitroprusside in the isolated perfused heart were studied. Responses to sodium nitroprusside were similar between the groups whereas responses to acetylcholine were significantly impaired in cholesterol-fed rabbits after both 4 and 8 weeks when compared to controls. In the cholesterol + vitamin E group, responses to acetylcholine were similar to controls and significantly greater than in the group receiving cholesterol alone. These results show that both 4 and 8 weeks of cholesterol-feeding induces an endothelial dysfunction in the coronary circulation of the rabbit, and that vitamin E protects against this dysfunction. By comparing responses to acetylcholine in the 4 week cholesterol group with the 8 week cholesterol + vitamin E group it was shown that vitamin E may not only prevent further deterioration of the endothelial function in the rabbit heart, but may also reverse the adverse effects of hypercholesterolaemia.

Arterial response to mechanical injury: balloon catheter de-endothelialization.

Coronary angioplasty has been used clinically for over a decade. Its initial promise as an alternative to coronary bypass surgery has only partially been fulfilled because of the high rate of post-operative restenosis. A number of animal models have been devised to study this phenomenon and although none is entirely satisfactory, they have, together with recent advances in molecular biology provided an insight into the cellular mechanisms that may contribute to this complication. This knowledge may ultimately lead to a means of therapeutic intervention. This review summarises our present understanding of the pathology of post-angioplasty re-stenosis as revealed by studies using the balloon catheter de-endothelialization model, and discusses some of the intervention strategies that have been attempted.