Biomedical subjects

M A Adams

Publications and source records attributed to M A Adams.

At least 19 recordsLinked to original sources

PubMed2006

Nitric oxide attenuates resistance to doxorubicin in three-dimensional aggregates of human breast carcinoma cells.

Compared with monolayer culture, tumour cells cultured as multicellular aggregates (spheroids) exhibit much higher levels of resistance to chemotherapeutic agents, a phenomenon known as multicellular resistance (MCR). Associated with multicellular aggregates is a heterogeneous microenvironment characterised by gradients in oxygen, pH, and nutrients. We previously showed that nitric oxide (NO) signalling plays an important role in the regulation of chemosensitivity in cancer cells cultured as monolayer, and that hypoxia increases resistance to anti-cancer agents largely through a mechanism involving the inhibition of NO signalling. The goal of the present study was to determine whether NO mimetics chemosensitize breast cancer cells in spheroid cultures. Survival of MDA-MB-231 breast carcinoma cells was determined by clonogenic assay following spheroid culture, doxorubicin exposure, and NO mimetic administration. When spheroids were incubated for 24 h with the NO mimetics diethylenetriamine/nitric oxide adduct (DETA/NO) and glyceryl trinitrate (GTN), cell survival after doxorubicin (200 microM) exposure was decreased by 33% (p<0.006) and by up to 47% (p<0.02), respectively. Nitric oxide-mediated signalling involves the generation of the second messenger cyclic guanosine monophosphate (cGMP). Administration of a non-hydrolysable cGMP analogue, 8-Bromo-cGMP, significantly decreased MCR (p<0.04). The effect of NO mimetic exposure on tumour cell chemosensitivity was not due to increased penetration of doxorubicin into spheroids, nor was it associated with an increase in cell proliferation. These results suggest that NO mimetics attenuate MCR to doxorubicin through a mechanism involving cGMP-dependent signalling. Therefore, NO-mimetics may potentially be used as chemosensitizers in cancer therapy.

Antibiotics, Antineoplastic↗

PubMed2005

One-dimensional and two-dimensional quantum systems on carbon nanotube bundles.

We report the first measurement of the structure of 4He atoms adsorbed on bundles of single-walled carbon nanotubes. Neutron diffraction techniques and nanotube samples closed at the end were used. At low coverage, 4He forms a 1D, single line lattice along the grooves between two nanotubes on the surface of the nanotube bundles. As coverage is increased, additional lines of 1D lattices form along the grooves. This is followed by an incommensurate, 2D monolayer covering the whole nanotube bundle surface. The lattice constants of these 1D and 2D systems are largely independent of filling once a single 1D line is formed. No occupation of the interstitial channels between nanotubes is observed in the present sample.

Journal Article↗

PubMed2005

Inhomogeneous level splitting in Pr 2-x BixRu2O7.

We report that Bi doping drives Pr 2-x BixRu2O7 from an antiferromagnetic insulator (x = 0) to a metallic paramagnet (x approximately 1) with a broad low T maximum in C/T. Neutron scattering reveals local low energy spin excitations (variant Planck's omega approximately 1 meV) with a spectrum that is unaffected by heating to k(B)T >> variant Planck's omega. We show that a continuous distribution of splittings of the non-Kramers Pr3+ ground-state doublet such as might result from various types of lattice strain can account for all the data.

Journal Article↗

PubMed2005

A potential role for the endothelin ETA receptor in salt-sensitive hypertension of the proANP gene-disrupted mouse.

We have previously shown that the partial disruption of the gene for atrial natriuretic peptide (ANP) results in a salt-sensitive phenotype. The present study examined the possibility that alterations in either the ANP natriuretic pathway or endothelin (ET) system in the kidney of the salt-challenged ANP +/- mouse was responsible for its salt-sensitive phenotype. Plasma ANP levels and renal cGMP activity were increased in response to a salt load in both ANP +/+ and +/- mice. However, the mRNA expression of proANP was found to be increased only in the ANP +/- kidney along with its guanylyl cyclase-linked receptor, NPRA; the upregulation of NPRA mRNA was limited to the renal medulla. This suggests that the renal ANP pathway remains capable of responding to a salt load in the ANP +/- animal, but may be compensating for other dysfunctional pathways. We also report a significant increase in renal ET-1 mRNA and ETA receptor protein expression in medulla and cortex of the salt-treated, ANP +/- mouse, but not its wild-type counterpart. In fact, ETA expression decreased in the renal cortex of the ANP +/+ salt-treated animal. The ETB receptor expression was not affected by diet in either genotype. We hypothesize that the salt-sensitive hypertension in the ANP +/- mouse is exacerbated, and possibly driven by the vasoconstrictive effects resulting from an upregulated ET-1/ETA pathway.

Animals↗

PubMed2005

Common therapeutic strategies in the management of sexual dysfunction and cardiovascular disease.

Sexual dysfunction is a frequent complication of treated and untreated cardiovascular disease. In fact, approximately 30% of hypertensives have been found to suffer from erectile dysfunction (ED) resulting from arterial dysfunction. Recent evidence has suggested that ED may be an early indicator of subclinical cardiovascular disease. In women, the evidence is similar, but more limited, showing that in hypertensive patients there is an increased prevalence of sexual dysfunction involving decreased vaginal lubrication, decreased orgasm, and increased pain. Clouding the issue, however, is that some antihypertensive agents may induce sexual dysfunction in hypertensives with normal sexual function. In contrast to the chronic treatments used in hypertension, therapies for ED involve acute treatments (none currently approved for women) targeting vasodilation of penile arteries, resulting in erection. Common to the treatment of hypertension and ED is that the current therapies were not designed to target underlying disorders of local, neural, vascular, or endocrine origin. In fact, while blood pressure is lowered, and erectile responses are improved with the respective therapies, the causal abnormalities may progress thereby limiting the long-term effectiveness of the medication. Some antihypertensive agents have been shown to have additional effects beyond blood pressure reduction and their impact on sexual function is a key focus of this review. This review examines the current and future strategies for treatments of male and female sexual dysfunction and the potential for therapeutic modalities that go beyond the recovery of the responses by targeting the fundamental mechanisms common to both sexual dysfunction and cardiovascular disease.

Cardiovascular Diseases↗

PubMed2004

Neural arch load-bearing in old and degenerated spines.

We validate a technique for measuring neural arch load-bearing in cadaveric spines, and use it to test the hypothesis that such load-bearing rises to high levels in old and degenerated spines. Fifty-nine cadaveric lumbar motion segments, aged 19-92 yr, were subjected to compressive creep loading to reduce intervertebral disc water content and height to in vivo levels. The distribution of compressive "stress" within the disc was then measured by pulling a miniature pressure transducer, side-mounted in a 1.3mm-diameter needle, along its mid-sagittal diameter. During these measurements, the motion segment was subjected to a compressive load of 2 kN, and positioned in 2 degrees of extension to simulate erect standing. Measurements of compressive "stress" were integrated over disc area, and this force subtracted from the applied 2 kN to give the force resisted by the neural arch. An empirical calibration factor was applied to normalise results from each disc to values obtained under conditions when all of the compressive force could be assumed to pass through the disc. Disc degeneration was graded macroscopically on a scale of 1-4. Validation tests showed that calculated values of disc loading were proportional to actual applied load (r(2)>0.96) and predicted it with errors of 2-8%. Neural arch load-bearing in non-degenerated specimens was generally less than 20%, but averaged 49% for specimens aged over 70 yr. Multiple regression showed that neural arch load bearing (%)=14.4 x disc degeneration score+0.46 x age-35. These results indicate a substantial shift in vertebral load-bearing with increasing age and degeneration.

Adult↗

PubMed2003

Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response.

PURPOSE: In spite of rapidly growing interest, few research tools have been developed to study female sexual dysfunction. Using the D(1)/D(2) agonist, apomorphine (APO), our objective was to develop a new model of the sexual arousal response in female rats based on one previously established for the male condition. METHODS: APO (80 micro g/kg, s.c.) was given during proestrus (P), estrus (E), metestrus (M), early diestrus (DI) and late diestrus (DII), and in ovariectomized (OVX) female Wistar rats. APO-induced behavioral and genital responses were characterized (30 min) using video monitoring. RESULTS: APO-induced reproducible, periodic morphological changes in the external genitalia. The onset, timing and duration of these female APO responses were consistent with genital vasocongestive arousal (GVA) responses in males (ie erections). APO-induced GVAs occurred throughout the estrous cycle, peaking in E (1.4+/-1.21 overall; 0.9+/-0.64 in DII; 1.8+/-1.66 in E) and were markedly diminished by ovariectomy (OVX, 0.4+/-0.51). CONCLUSION: APO induced a reproducible sexual arousal response in female rats involving obvious genital vasocongestive engorgement. Further, the findings demonstrate that the APO-induced genital arousal responses are hormonally regulated.

Animals↗

PubMed2003

Update on central function relevant to sex: remodeling the basis of drug treatments for sex and the brain.

Sexual function draws on a complex network of peripheral and central neural pathways. The standard focus on erectile difficulties and peripheral therapies has been highly successful clinically but there are many unresolved issues in men and newly discussed issues in women that will likely benefit from improved understanding of the central nervous system and sexual function. The spectrum of future therapies, based on evolving central neurophysiological understanding, will include the management of problems related to orgasm, ejaculation, desire, motivation, anxiety, and pleasure. This new range of therapies will employ old and new neurochemicals and pathways singly or in combination. The capability of hormones to modulate many of the sexual pathways will also contribute to the rise of multiagent therapy. The expanded understanding, in combination with enhanced imaging technologies, will renew the role of diagnosis and cause-specific treatment.

Animals↗

PubMed2003

A framework for the present and future development of experimental models of female sexual dysfunction.

Female sexual dysfunction (FSD) is currently categorized according to disorders of (i). desire, (ii). arousal, (iii). orgasm and (iv). sexual pain. The advancement of research defining the physiological, pathophysiological and psychological mechanisms of these disorders, and to develop treatments for FSD, has been hampered by the paucity of experimental paradigms and animal models. It may be that animal models of FSD are best suited to address arousal disorders that include persistent or routine inability to attain or maintain genital lubrication or engorgement. Although still limited in scope, experimental models of FSD have involved a range of in vitro to in vivo methodologies. Specifically, the in vitro and in situ models include vaginal or clitoral smooth muscle preparations, histological evaluation and vaginal blood flow assessments. Previously, in vivo studies of sexual responses focussed on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method. Recently, a new model of female sexual arousal was developed using pharmacological CNS stimulation; responses that were found to be sensitive to cardiovascular status, aging and hormonal conditions. It is important that a wide variety of animal models continue to be developed to reflect the multifactorial basis of the condition.

Animals↗

PubMed2002

Development of a rat model of sexual performance anxiety: effect of behavioural and pharmacological hyperadrenergic stimulation on APO-induced erections.

As part of the multifactorial nature of erectile dysfunction, anxiety associated with sexual performance (SPA) remains a major contributing factor to its progression. In fact, the heightened sympathetic activity associated with sexual performance anxiety may be a key early component of this disruption of normal erectile responses. We are not aware that any animal models have been developed to assess this phenomenon. Using apomorphine (APO, 80 microg/kg s.c.)-induced erections in rats we characterised the effects of behavioural or pharmacological hyperadrenergic stimulation (that is, anxiety) on erections and hemodynamics. We developed an experimental SPA paradigm by exposing male rats to the stress of being observed by a larger, older male rat placed in close proximity to test rats during APO testing. In a separate group, adrenergic stress was simulated using a sympathomimetic, methoxamine (MXA) given prior to APO testing. In a third group, the changes in circulatory parameters (mean arterial pressure, heart rate) were determined following instrumentation with radiotelemetric transducers for each scenario. APO-induced erections were significantly lower in both the behavioural (1.25+/-0.8) and pharmacological (0.33+/-0.5) stressor paradigms compared to controls (2.81+/-0.9). Further, erections in MXA-treated rats were significantly lower than in the observed scenario. Despite the differences in erections hemodynamic assessments showed no differences in MAP or HR changes between the different experimental conditions. Thus, both the behavioural and pharmacological paradigms of SPA decreased erections, but did not affect the circulation. This suggests that the level of hyperadrenergic input required to induce erectile dysfunction can be subtle, and target only erectogenic pathways.

Animals↗

PubMed2002

Bioenergetic remodeling of heart during treatment of spontaneously hypertensive rats with enalapril.

We used spontaneously hypertensive rats to study remodeling of cardiac bioenergetics associated with changes in blood pressure. Blood pressure was manipulated with aggressive antihypertensive treatment combining low dietary salt and the angiotensin-converting enzyme inhibitor enalapril. Successive cycles of 2 wk on, 2 wk off treatment led to rapid, reversible changes in left ventricular (LV) mass (30% change in <10 days). Despite changes in LV mass, specific activities of bioenergetic (cytochrome-c oxidase, citrate synthase, lactate dehydrogenase) and reactive oxygen species (ROS) (total cellular superoxide dismutase) enzymes were actively maintained within relatively narrow ranges regardless of treatment duration, organismal age, or transmural region. Although enalapril led to parallel declines in mitochondrial enzyme content and ventricular mass, total ventricular mtDNA content was unaffected. Altered enzymatic content occurred without significant changes in relevant mRNA and protein levels. Transcript levels of gene products involved in mtDNA maintenance (Tfam), mitochondrial protein degradation (LON protease), fusion (fuzzy onion homolog), and fission (dynamin-like protein, synaptojanin-2alpha) were also unchanged. In contrast, enalapril-mediated ventricular and mitochondrial remodeling was accompanied by a twofold increase in specific activity of catalase, an indicator of oxidative stress, suggesting that rapid cardiac adaptation is accompanied by tight regulation of mitochondrial enzyme activities and increased ROS production.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Recovery of erectile function after brief aggressive antihypertensive therapy.

PURPOSE: We have previously demonstrated that antihypertensive therapy could structurally modulate blood vessels in the penis, although the impact on erectile function was not established. Given the importance of inadequate penile arterial inflow as a cause of erectile dysfunction we determined in spontaneously hypertensive rats the impact of brief aggressive antihypertensive therapy on structurally based penile vascular resistance, erectile function and mean arterial pressure during and after treatment. MATERIALS AND METHODS: Young (15-week-old) and aged (40-week-old) spontaneously hypertensive rats were treated for 2 weeks (enalapril 30 mg./kg. daily plus a low salt diet). Mean arterial pressure was continuously monitored via radio telemetry. Erectile responses were assessed by administering apomorphine (80 microg./kg. subcutaneously) before, during and after treatment. Structurally based vascular resistance was determined in the isolated, perfused penile vasculature 2 weeks after stopping treatment in aged spontaneously hypertensive rats. Certain responses were determined, including resistance at maximum dilatation (lumen size) and at maximum constriction (medial bulk), and EC50 of the alpha-adrenoceptor agonist methoxamine. RESULTS: In the period after the cessation of drug treatment there was a persistent reduction in the level of arterial pressure (16%) and a doubling of erectile responses compared with pre- treatment. Cardiac and vascular structure regressed, as determined by the mean decrease plus or minus standard deviation in vascular resistance at maximum dilatation (21% +/- 4.5%) and mean reduction in left ventricle mass (10.4% +/- 3.7%). Furthermore, treatment induced a significant right shift in alpha1-adrenoceptor concentration response curve in treated versus control rats (mean EC50 1.09 +/- 0.111 versus 0.76 +/- 0.111). CONCLUSIONS: The improvement in erectile function after brief aggressive treatment may be related to improvement in structurally based vascular resistance within the penis and the decrease in responsiveness of alpha1-adrenoceptor mediated erectolytic signaling. These findings are suggestive of a new therapeutic strategy for hypertension and erectile dysfunction.

Animals↗

PubMed2001

Nitric oxide-mediated regulation of chemosensitivity in cancer cells.

BACKGROUND: Hypoxia in tumors is associated with malignant progression, metastatic spread, and increased resistance to radiotherapy and chemotherapy. Molecular O(2) is required for the cellular production of nitric oxide (NO) by the enzyme NO synthase (NOS), and NO may block components of the adaptive response to hypoxia. Hence, we hypothesized that hypoxia increases drug resistance in tumor cells by inhibiting endogenous NO production. METHODS: Human breast carcinoma (MDA-MB-231) and mouse melanoma (B16F10) cells were pre-exposed to 20% O(2), 5% O(2), or 1% O(2), incubated with a pharmacologic inhibitor of endogenous NO production, and then treated with chemotherapeutic agents. Resistance was assessed by colony-formation assays, and western blot analysis was used to measure NOS protein levels. All P values were two-sided. RESULTS: Incubation of MDA-MB-231 tumor cells in 1% O(2) maximally increased their resistance to doxorubicin and 5-fluorouracil by 8.5-fold (P =.002) and 2.3-fold (P =.002), respectively, compared with incubation in 20% O(2). B16F10 mouse melanoma cells preincubated in 1% O(2) (versus 20% O(2)) for 12 hours exhibited a twofold increase in resistance to doxorubicin (P<.001). The rapid acquisition of drug resistance after exposure to 1% O(2) could be mimicked by incubating the MDA-MB-231 cells for 12 hours with the NOS inhibitor N(G)-monomethyl-Larginine (fivefold increase; P<.001). Conversely, replacement of NO activity by use of the NO-mimetic glyceryl trinitrate (GTN) and diethylenetriamine NO adduct produced statistically significant attenuations in the development of resistance of 59% (P<.001) and 40% (P<.001), respectively, in MDA-MB-231 cells. Treatment of B16F10 cells with GTN produced a 58% reduction in resistance (P<.001). MDA-MB-231 cells expressed all three isoforms of the NOS enzyme at levels that were not altered by exposure to hypoxia. CONCLUSIONS: NO mediates chemosensitivity in tumor cells, and hypoxia-induced drug resistance appears to result, in part, from downstream suppression of endogenous NO production. These results raise the possibility that administration of small doses of NO mimetics could be used as an adjuvant in chemotherapy.

Animals↗

PubMed2001

Recent advances in lumbar spinal mechanics and their significance for modelling.

Mathematical models are often used to quantify the overall forces and moments acting on the lumbar spine. However, if the purpose of the research is to explain how spinal tissues can be injured, it is necessary to distribute the overall forces and moments between (and within) different spinal structures, because it is the concentration of force which causes injury, and elicits pain. This paper reviews recent experimental evidence concerning the distribution of forces and moments acting on the lumbar spine. Lordotic postures increase loading of the posterior annulus and apophyseal joints, whereas moderately flexed postures tend to equalise compressive stress across the disc, and unload the apophyseal joints. Sustained compression reduces the volume and pressure of the nucleus pulposus, while increasing compressive stresses in the annulus and neural arch. Sustained compression also reduces disc height, giving some slack to collagen fibres in the intervertebral disc and ligaments, and causing them to resist bending less. Disc degeneration has a similar effect on disc height, and stress distributions. On the other hand, discs and ligaments can be subjected to greater bending moments following a period of sustained or repetitive bending, because sustained bending impairs the normal protective reflex from the back muscles, and repetitive bending fatigues the back muscles, reducing their ability to protect the spine. Incorporating this information into mathematical models will make them better able to identify which activities are most likely to injure the lumbar spine in life.

Biomechanical Phenomena↗

PubMed2001

An EMG technique for measuring spinal loading during asymmetric lifting.

OBJECTIVES: To compare two methods of calibrating the erector spinae electromyographic signal against moment generation in order to predict extensor moments during asymmetric lifting tasks, and to compare the predicted moments with those obtained using a linked-segment model. METHODS: Eight men lifted loads of 6.7 and 15.7 kg at two speeds, in varying amounts of trunk rotation. For each lift, the following were recorded at 60 Hz; the rectified and averaged surface electromyographic signal, bilaterally at T10 and L3, lumbar curvature using the 3-Space Isotrak, movement of body segments using a 4-camera Vicon system, and ground reaction forces using a Kistler force-plate. Electromyographic (EMG) and Isotrak data were used to calculate lumbosacral extensor moments using the electromyographic model, whereas movement analysis data and ground reaction forces were used to estimate net moments using the linked-segment model. For the electromyographic technique, predictions of extensor moment were based on two different sets of EMG-extensor moment calibrations: one performed in pure sagittal flexion and the other in flexion combined with 45 degrees of trunk rotation. RESULTS: Extensor moments predicted by the electromyographic technique increased significantly with load and speed of lifting but were not influenced by the method of calibration. These moments were 7-40%greater than the net moments obtained with the linked-segment model, the difference increasing with load and speed. CONCLUSIONS: The calibration method does not influence extensor moments predicted by the electromyographic technique in asymmetric lifting, suggesting that simple, sagittal-plane calibrations are adequate for this purpose. Differences in predicted moments between the electromyographic technique and linked-segment model may be partly due to different anthropometric assumptions and different amounts of smoothing and filtering in the two models, and partly due to antagonistic muscle forces, the effects of which cannot be measured by linked-segment models. RelevanceAsymmetric lifting is a significant risk factor for occupationally-related low back pain. Improved techniques for measuring spinal loading during such complex lifting tasks may help to identify work practices which place the spine at risk of injury.

Adult↗

PubMed2001

Lumbar loading during lifting: a comparative study of three measurement techniques.

Low back loading during occupational lifting is thought to be an important causative factor in the development of low back pain. In order to regulate spinal loading in the workplace, it is necessary to measure it accurately. Various methods have been developed to do this, but each has its own limitations, and none can be considered a "gold standard". The purpose of the current study was to compare the results of three contrasting techniques in order to gain insight into possible sources of error to which each is susceptible. The three techniques were a linked segment model (LSM), an electromyographic (EMG)-based model, and a neural network (NN) that used both EMG and inertial sensing techniques. All three techniques were applied simultaneously to calculate spinal loading when eight volunteers performed a total of eight lifts in a laboratory setting. Averaged results showed that, in comparison with the LSM, the EMG technique calculated a 25.5+/-33.4% higher peak torque and the NN technique a 17.3+/-10.5% lower peak torque. Differences between the techniques varied with lifting speed and method of lifting, and could be attributed to differences in anthropometric assumptions, antagonistic muscle activity, damping of transient force peaks by body tissues, and, specific to the NN, underestimation of trunk flexion. The results of the current study urge to reconsider the validity of other models by independent comparisons.

Adult↗

PubMed2001

How severe must repetitive loading be to kill chondrocytes in articular cartilage?

OBJECTIVE: Little is known about the effects of severe repetitive loading on articular cartilage chondrocytes, even though epidemiological studies associate this type of loading with osteoarthritis. We hypothesize that repetitive loading can kill cartilage chondrocytes in a dose-related manner. DESIGN: Large cartilage-on-bone specimens were cut from the patella groove of bovine knees obtained directly from a slaughterhouse. Cartilage was loaded using a flat impermeable indenter in such a manner that the loaded region was supported naturally by surrounding cartilage and subchondral bone. Specimens received 3600 cycles of compressive loading at 1 Hz, with the peak load lying in the range 1-70% of the force required to damage cartilage in a single loading cycle (35 MPa). Cell viability was assessed in thick sections of loaded and control cartilage using a paravital staining method: fluorescein diacetate stained live cells green, and propidium iodide stained dead cells red. The assay was validated on cartilage which had been subjected to repeated freeze-thaw cycles to kill the chondrocytes. RESULTS: Paravital staining revealed 100% cell death after one freeze-thaw cycle at -196 degrees C and three cycles at -20 degrees C. Baseline chondrocyte viability was 80% in unloaded cartilage, and viability decreased when applied compressive loading exceeded 6 MPa. Above this threshold, cell viability was inversely proportional to applied stress. When gross damage to the cartilage surface first became evident, above 14 MPa, 40% of cells remained viable. Load-induced chondrocyte death was greatest in the surface zone, and extended beyond the loaded area. Electron micrographs indicated that some cells were dying by apoptosis. CONCLUSIONS: Some chondrocytes are much more vulnerable to repetitive mechanical loading than others, suggesting that vigorous activity may lead to cell death in articular cartilage.

Animals↗

PubMed2001

Does nitric oxide play a role in the aetiology of pre-eclampsia?

Although progress has been made toward our understanding of the pathophysiology of pre-eclampsia, the precise aetiology of this disease still remains an enigma. One of the hallmarks of pre-eclampsia is a failure of the extravillous cytotrophoblast cells to invade and remodel the uterine spiral arterioles during the first trimester of pregnancy. Moreover, studies suggest that the cause of this disorder may be immunological in nature. Evidence is provided here suggesting that impaired trophoblastic invasion of the spiral arterioles may be linked to the altered immunological response associated with pre-eclampsia. Previous studies by Reister et al., 1999 demonstrated a direct relationship between macrophage infiltration of the myometrial segments of spiral arterioles and reduced trophoblastic invasion in pre-eclampsia. Also, it is well established that activated macrophages produce large amounts of nitric oxide (NO). Our present findings reveal that low concentrations of NO-mimetic drugs (glyceryl trinitrate and sodium nitroprusside) inhibit the ability of trophoblast cells to penetrate through reconstituted extracellular matrix (Matrigel). This inhibition is accompanied by a reduced expression of the cell surface urokinase receptor, a molecule important for invasion. These results suggest a possible mechanistic link between the aberrant macrophage infiltration associated with pre-eclampsia, and the maladapted uteroplacental arterioles that characterize the disease.

Adult↗