Biomedical subjects

Michael A Adams

Publications and source records attributed to Michael A Adams.

At least 19 recordsLinked to original sources

PubMed2007

Mechanical efficacy of vertebroplasty: influence of cement type, BMD, fracture severity, and disc degeneration.

INTRODUCTION: Osteoporotic vertebral fractures can be treated by injecting bone cement into the damaged vertebral body. "Vertebroplasty" is becoming popular but the procedure has yet to be optimised. This study compared the ability of two different types of cement to restore the spine's mechanical properties following fracture, and it examined how the mechanical efficacy of vertebroplasty depends on bone mineral density (BMD), fracture severity, and disc degeneration. METHODS: A pair of thoracolumbar "motion-segments" (two adjacent vertebrae with intervening soft tissue) was obtained from each of 15 cadavers, aged 51-91 years. Specimens were loaded to induce vertebral fracture; then one of each pair underwent vertebroplasty with polymethylmethacrylate (PMMA) cement, the other with another composite material (Cortoss). Specimens were creep loaded for 2 h to allow consolidation. At each stage of the experiment, motion segment stiffness in bending and compression was measured, and the distribution of compressive loading on the vertebrae was investigated by pulling a miniature pressure transducer through the intervertebral disc. Pressure measurements, repeated in flexed and extended postures, indicated the intradiscal pressure (IDP) and neural arch compressive load-bearing (F(N)). BMD was measured using DXA. Fracture severity was quantified from height loss. RESULTS: Vertebral fracture reduced motion segment stiffness in bending and compression, by 31% and 43% respectively (p<0.001). IDP fell by 43-62%, depending on posture (p<0.001), whereas F(N) increased from 14% to 37% of the applied load in flexion, and from 39% to 61% in extension (p<0.001). Vertebroplasty partially reversed all these effects, and the restoration of load-sharing was usually sustained after creep-consolidation. No differences were observed between PMMA and Cortoss. Pooled results from 30 specimens showed that low BMD was associated with increased fracture severity (in terms of height loss) and with greater changes in stiffness and load-sharing following fracture. Specimens with low BMD and more severe fractures also showed the greatest mechanical changes following vertebroplasty. CONCLUSIONS: Low vertebral BMD leads to greater changes in stiffness and spinal load-sharing following fracture. Restoration of mechanical function following vertebroplasty is little influenced by cement type but may be greater in people with low BMD who suffer more severe fractures.

Aged↗

PubMed2006

Outer annulus tears have less effect than endplate fracture on stress distributions inside intervertebral discs: relevance to disc degeneration.

BACKGROUND: Annulus tears and endplate fracture are common lesions in human intervertebral discs. Both cause degenerative changes in animal models, but the time course appears to be different. The purpose of the present experiment is to compare the effects of outer annulus tears and endplate fracture on intradiscal stresses. We hypothesise that endplate fracture provides a greater stimulus for disc degeneration. METHODS: Seven cadaveric lumbar "motion segments" aged 49-70 years were compressed at 2 kN while the distribution of compressive stress was measured in each disc by pulling a 1.3 mm-diameter pressure transducer along its mid-sagittal diameter. Measurements were repeated after rim tears were simulated by 10 mm-deep scalpel cuts into the outer anterior annulus. The first cut was horizontal, 15 mm to the right of the disc midline, near the junction with the upper endplate. The second cut was vertical, 15 mm to the left of the disc midline, at mid-disc height. The third cut was horizontal, in the disc midline and at mid-disc height, so that the cut passed through the needle hole of the pressure transducer. Stress profiles were recorded in three postures and at two load levels, after each cut. Stress measurements were repeated a final time following compressive overload sufficient to fracture the endplate. FINDINGS: Outer annulus tears had negligible effect on compressive stress distributions in the annulus fibrosus more than 15 mm from the scalpel cut, and they caused nucleus pressure to fall by only 1% (SD 1.3%, NS). In contrast, endplate fracture reduced nucleus pressure by 37% (P=0.004) and increased maximum stress within the posterior annulus by 93% (P=0.033). INTERPRETATION: Outer annulus tears have less (immediate) effects on intradiscal compressive stresses than endplate fracture, supporting our hypothesis.

Aged↗

PubMed2006

What is intervertebral disc degeneration, and what causes it?

STUDY DESIGN: Review and reinterpretation of existing literature. OBJECTIVE: To suggest how intervertebral disc degeneration might be distinguished from the physiologic processes of growth, aging, healing, and adaptive remodeling. SUMMARY OF BACKGROUND DATA: The research literature concerning disc degeneration is particularly diverse, and there are no accepted definitions to guide biomedical research, or medicolegal practice. DEFINITIONS: The process of disc degeneration is an aberrant, cell-mediated response to progressive structural failure. A degenerate disc is one with structural failure combined with accelerated or advanced signs of aging. Early degenerative changes should refer to accelerated age-related changes in a structurally intact disc. Degenerative disc disease should be applied to a degenerate disc that is also painful. JUSTIFICATION: Structural defects such as endplate fracture, radial fissures, and herniation are easily detected, unambiguous markers of impaired disc function. They are not inevitable with age and are more closely related to pain than any other feature of aging discs. Structural failure is irreversible because adult discs have limited healing potential. It also progresses by physical and biologic mechanisms, and, therefore, is a suitable marker for a degenerative process. Biologic progression occurs because structural failure uncouples the local mechanical environment of disc cells from the overall loading of the disc, so that disc cell responses can be inappropriate or "aberrant." Animal models confirm that cell-mediated changes always follow structural failure caused by trauma. This definition of disc degeneration simplifies the issue of causality: excessive mechanical loading disrupts a disc's structure and precipitates a cascade of cell-mediated responses, leading to further disruption. Underlying causes of disc degeneration include genetic inheritance, age, inadequate metabolite transport, and loading history, all of which can weaken discs to such an extent that structural failure occurs during the activities of daily living. The other closely related definitions help to distinguish between degenerate and injured discs, and between discs that are and are not painful.

Animals↗

PubMed2006

Pesticides and polychlorinated biphenyls as potential risk factors for erectile dysfunction.

While it is biologically plausible that environmental chemicals such as pesticides and polychlorinated biphenyls (PCBs) with suspected hormone disrupting properties may have an impact on risk of erectile dysfunction (ED), few epidemiologic studies have assessed this potential association. In a clinic-based case-control study in Kingston, Ontario, consenting subjects completed a questionnaire and donated 15 mL of blood for analysis of organochlorines and lipids by gas chromatography. Exposures were compared for 101 cases with ED and 234 comparable control subjects. For most PCB congeners and organochlorine pesticides, geometric mean levels are similar for cases and controls. Multivariate logistic regression results do not show an increased or decreased risk of ED associated with levels of most detectable environmental substances after adjustment for age, total lipids, and confounders. Levels of 2 of the ubiquitous chlorinated pesticides, oxychlordane and trans-nonachlor, which are highly correlated, appear to associate with a reduced risk of ED, but the role of chance cannot be ruled out. To our knowledge, this study is the first to investigate the possible relationship between plasma levels of organochlorines and ED risk, and results do not provide evidence of an association.

Aged↗

PubMed2006

Point of view.

Explore the source record for details and available documents.

Edema↗

PubMed2006

Kidney transplantation procedures in rats: assessments, complications, and management.

Kidney transplantation in rats is an experimental model often used for the development of general microsurgical or transplantation techniques, for immunologic studies, and for analyzing transplant-associated long-term arterial blood-pressure changes. The aim of the present study was to analyze different surgical techniques of kidney transplantation in rats, with emphasis on minimizing surgical complications and establishing guidelines for their prevention and management. Complications were categorized into general (e.g., core body temperature drop, ischemic time) and surgically related vascular and urinary tract complications. In conclusion, a significant reduction of the complication rate in renal transplantation in rats can be achieved by placing the animal on a heating pad at an appropriate temperature. To reduce the risk of vascular thrombosis, ice-cold saline with heparin and careful flushing of the donor kidneys are recommended. Vascular complications can be avoided by performing "end-to-end" anastomosis techniques. The use of stents and cannulas in the urinary tract is associated with a high risk of urinary tract obstruction, and therefore is not recommended.

Anastomosis, Surgical↗

PubMed2006

Impact of antihypertensive treatments on erectile responses in aging spontaneously hypertensive rats.

OBJECTIVE: We previously demonstrated that brief, aggressive antihypertensive therapy recovered erectile function in 40-week-old spontaneously hypertensive rats (SHR). The present study examined the impact of antihypertensive and testosterone treatments on erectile function in aging SHR. DESIGN AND METHODS: Centrally initiated erections were determined in response to apomorphine throughout. At 30 and 49 weeks, SHR were treated for 2 weeks with enalapril or hydralazine. A third more aggressive treatment (68 weeks) involved enalapril or losartan plus a low salt diet or a triple therapy (hydralazine, nifedipine, hydrochlorothiazide). In a separate study, cross-over kidney transplantations were performed between untreated and losartan-treated SHR. Arterial pressure was assessed post-transplantation using radio-telemetric transducers. RESULTS: There was an age-related decrease in erections between 30 and 68 weeks (3.1 +/- 0.79 versus 0.2 +/- 0.38) that was not improved by testosterone administration. Early treatment with enalapril or hydralazine did not prevent this decline, although the second treatment resulted in significant improvements (enalapril, 0.8 +/- 0.70; hydralazine, 0.8 +/- 0.41 versus control, 0.3 +/- 0.60). A 2-week aggressive antihypertensive treatment at 68 weeks increased erections approximately two-fold, with the previously treated rats receiving triple therapy having markedly improved erectile responses (0.2 +/- 0.53 versus 1.1 +/- 1.67). In the transplantation study, previously losartan-treated SHR given an untreated kidney had higher arterial pressure but twice the number of erections in comparison with the SHR with lower arterial pressure resulting from transplanting a treated kidney. CONCLUSIONS: Aggressive antihypertensive treatments may be more beneficial in improving erectile function in aged SHR, via an effect that appears to be tissue specific, and not based on changes in blood pressure.

Aging↗

PubMed2006

Further insights into the role of angiotensin II in kidney development.

Over the past decade, compelling studies have highlighted the fundamental role of the renin-angiotensin system (RAS) in renal development and long-term control of renal function and arterial pressure. The present review provides an update of the understanding of how the RAS controls nephrogenesis and nephrovascular development. In addition, the investigations linking the perinatal development of RAS inhibition-induced renal dysmorphology and establishment of adult blood pressure are discussed.

Angiotensin II↗

PubMed2006

Effect of AT2 blockade on cardiac hypertrophy as induced by high dietary salt in the proatrial natriuretic peptide (ANP) gene-disrupted mouse.

The role of the angiotensin II type 2 receptor (AT2) during alterations in cardiac size remains largely unclear. Through employment of an AT2 antagonist, the present study explored a possible involvement of the AT2 receptor during salt-induced cardiac hypertrophy in the proatrial natriuretic peptide gene-disrupted mouse (ANP-/-). ANP-/- mice received either saline solution or the AT2 antagonist, PD123319, and were then placed on a high salt diet (8.0% NaCl) for 3 weeks. Cardiac and pulmonary size, expression of the renin-angiotensin system (RAS), and the behaviour of various hypertrophy marker genes were assessed. PD123319 caused enhanced expression of the systemic RAS, yet the cardiac RAS was largely unaffected. Although AT2 blockade did not alter whole cardiac mass, right ventricle mass, as well as pulmonary mass-to-body mass ratios were significantly decreased. Collagen type I was decreased in the latter tissues, likely contributing to the regression in mass. Several players essential in the maintenance of myocardial extracellular matrix homeostasis including B-type natriuretic peptide, matrix metalloproteinase-2, tumour necrosis factor, and transforming growth factor were also significantly altered by PD123319. These data suggest that AT2 blockade is involved in significant changes in myocardial extracellular matrix components translating into decreases in tissue mass in the salt-sensitive ANP-/- animal.

Angiotensin II Type 2 Receptor Blockers↗

PubMed2006

Intervertebral disc degeneration can predispose to anterior vertebral fractures in the thoracolumbar spine.

UNLABELLED: Mechanical experiments on cadaveric thoracolumbar spine specimens showed that intervertebral disc degeneration was associated with reduced loading of the anterior vertebral body in upright postures. Reduced load bearing corresponded to locally reduced BMD and inferior trabecular architecture as measured by histomorphometry. Flexed postures concentrated loading on the weakened anterior vertebral body, leading to compressive failure at reduced load. INTRODUCTION: Osteoporotic fractures are usually attributed to age-related hormonal changes and inactivity. However, why should the anterior vertebral body be affected so often? We hypothesized that degenerative changes in the adjacent intervertebral discs can alter load bearing by the anterior vertebral body in a manner that makes it vulnerable to fracture. MATERIALS AND METHODS: Forty-one thoracolumbar spine "motion segments" (two vertebrae and the intervertebral disc) were obtained from cadavers 62-94 years of age. Specimens were loaded to simulate upright standing and flexed postures. A pressure transducer was used to measure the distribution of compressive "stress" inside the disc, and stress data were used to calculate how compressive loading was distributed between the anterior and posterior halves of the vertebral body and the neural arch. The compressive strength of each specimen was measured in flexed posture. Regional volumetric BMD and histomorphometric parameters were measured. RESULTS: In the upright posture, compressive load bearing by the neural arch increased with disc degeneration, averaging 63 +/- 22% (SD) of applied load in specimens with severely degenerated discs. In these specimens, the anterior half of the vertebral body resisted only 10 +/- 8%. The anterior third of the vertebral body had a 20% lower trabecular volume fraction, 16% fewer trabeculae, and 28% greater intertrabecular spacing compared with the posterior third (p < 0.001). In the flexed posture, flexion transferred 53-59% of compressive load bearing to the anterior half of the vertebral body, regardless of disc degeneration. Compressive strength measured in this posture was proportional to BMD in the anterior vertebral body (r2 = 0.51, p < 0.001) and inversely proportional to neural arch load bearing in the upright posture (r2 = 0.28, p < 0.001). CONCLUSIONS: Disc degeneration transfers compressive load bearing from the anterior vertebral body to the neural arch in upright postures, reducing BMD and trabecular architecture anteriorly. This predisposes to anterior fracture when the spine is flexed.

Aged↗

PubMed2005

Discogenic origins of spinal instability.

STUDY DESIGN: Cadaveric motion segment experiment. OBJECTIVE: To show how two physical aspects of disc degeneration (dehydration and endplate disruption) contribute to spinal instability. SUMMARY OF BACKGROUND DATA: The origins of spinal instability and its associations with back pain are uncertain. METHODS.: Twenty-one cadaveric thoracolumbar motion segments aged 48 to 90 years were secured in cups of dental plaster and loaded simultaneously in bending and compression to simulate full flexion, extension, and lateral bending movements. Vertebral movements, recorded using a two-dimensional "MacReflex" motion analysis system, were analyzed to calculate neutral zone (NZ), range of motion (ROM), bending stiffness (BS), horizontal translational movements, and the location of the center of rotation (COR). Intradiscal "stresses" were measured by pulling a miniature pressure transducer through the disc along its midsagittal diameter. All experiments were repeated after each of two treatments, which simulated physical aspects of disc degeneration: creep loading to dehydrate the disc and compressive overload to disrupt the endplate. Results were analyzed using ANOVA and linear regression. RESULTS: Motion segment height was reduced by 1.0 (SD 0.3) mm during creep and by a further 1.7 (0.6) mm after endplate disruption. In flexion and lateral bending, the combined treatments increased NZ and ROM by 89% to 298%, and increased the "instability index" (NZ/ROM) by 43% to 61%. Translational movements increased by 58% to 86%, whereas BS decreased by 42% to 48%. In extension, ROM and NZ were little affected, although the COR moved closer to the apophyseal joints. Measures of instability increased most in lateral bending, and following endplate disruption. Stress concentrations in the posterior anulus fibrosus increased markedly after endplate disruption. CONCLUSIONS: Two physical aspects of disc degeneration (dehydration and endplate disruption) cause marked segmental instability. Back pain associated with instability may be attributable to stress concentrations in degenerated discs.

Aged↗

PubMed2005

Nitric oxide signalling and cellular adaptations to changes in oxygenation.

Fluctuations in oxygen (O2) levels characterise the cellular microenvironment in physiological and pathological processes such as placentation and malignant progression. Cells adapt to such changes in oxygenation by modifying gene expression, thereby regulating a spectrum of functions. Recent studies indicate that an important mechanism by which cells adapt to changes in oxygenation involves modifications in endogenous nitric oxide (NO) signalling. The effect of oxygen on the NO pathway involving cyclic guanosine monophosphate (cGMP)-dependent signalling appears to play a critical role in the regulation of cellular phenotypes. This specific NO signalling pathway may also operate in conjunction with gene expression regulated by the transcription molecule hypoxia inducible factor 1 (HIF-1). Thus, NO is emerging as a novel regulator of oxygen-sensitive phenotypes.

Animals↗

PubMed2005

Intradiscal electrothermal therapy can alter compressive stress distributions inside degenerated intervertebral discs.

STUDY DESIGN: Mechanical testing of cadaveric motion segments. OBJECTIVES: To test the hypothesis that intradiscal electrothermal therapy (IDET) can affect the internal mechanical functioning of lumbar discs. SUMMARY OF BACKGROUND DATA: The clinical efficacy of IDET is variable, and its mode of action uncertain. METHODS: Eighteen lumbar motion segments (64-97 years old) were incubated at 37 degrees C. A miniature pressure transducer, side mounted in a 1.3-mm diameter needle, was used to measure the distribution of compressive "stress" along the midsagittal diameter of each disc while it was compressed at 1.5 kN. Measurements were repeated in 3 simulated postures. Standard IDET was performed using biplanar radiography to confirm the placement of the heating element and an independent thermocouple to measure temperature in the inner lateral anulus. Stress profilometry was repeated immediately after IDET. RESULTS: Peak temperatures in the inner lateral anulus during IDET averaged 40.0 degrees C (standard deviation [STD] 2.3). Stress measurements repeated before IDET differed by less than 8%, and a sham IDET procedure produced no consistent changes. After IDET, pressure in the nucleus decreased by 6% to 13% (P < 0.05), and stress concentrations in the anulus were reduced by an average 0.28 MPa (P < 0.004). In 12 of the 18 specimens, anulus stress concentrations were reduced by more than 8%, and in these "responders," mean reduction was 78%. Stress concentrations were increased by more than 8% in 2 specimens. CONCLUSIONS: IDET has a significant but inconsistent effect on compressive stresses within intervertebral discs. These results may partly explain the variable clinical success of IDET.

Aged↗

PubMed2005

Spine biomechanics.

Current trends in spine research are reviewed in order to suggest future opportunities for biomechanics. Recent studies show that psychosocial factors influence back pain behaviour but are not important causes of pain itself. Severe back pain most often arises from intervertebral discs, apophyseal joints and sacroiliac joints, and physical disruption of these structures is strongly but variably linked to pain. Typical forms of structural disruption can be reproduced by severe mechanical loading in-vitro, with genetic and age-related weakening sometimes leading to injury under moderate loading. Biomechanics can be used to quantify spinal loading and movements, to analyse load distributions and injury mechanisms, and to develop therapeutic interventions. The authors suggest that techniques for quantifying spinal loading should be capable of measurement "in the field" so that they can be used in epidemiological surveys and ergonomic interventions. Great accuracy is not required for this task, because injury risk depends on tissue weakness as much as peak loading. Biomechanical tissue testing and finite-element modelling should complement each other, with experiments establishing proof of concept, and models supplying detail and optimising designs. Suggested priority areas for future research include: understanding interactions between intervertebral discs and adjacent vertebrae; developing prosthetic and tissue-engineered discs; and quantifying spinal function during rehabilitation. "Mechanobiology" has perhaps the greatest future potential, because spinal degeneration and healing are both mediated by the activity of cells which are acutely sensitive to their local mechanical environment. Precise characterisation and manipulation of this environment will be a major challenge for spine biomechanics.

Aging↗

PubMed2005

Smoking and other lifestyle factors in relation to erectile dysfunction.

OBJECTIVE: To assess the association between erectile dysfunction (ED) and various lifestyle and medical factors, including smoking and cardiovascular disease (CVD) medications, among men attending urology clinics in Kingston, Canada. SUBJECTS AND METHODS: We conducted a case-control study of men aged 50-80 years in Kingston, Ontario who agreed to participate at visits to urology clinics during 1997-99. We compared 101 men with clinically diagnosed ED and 234 controls with various benign urological conditions. All men completed a questionnaire on lifestyle and medical factors. RESULTS: Men with ED were twice as likely to be former smokers (odds ratio 2.2, 95% confidence interval, 1.2-3.9), and cumulative smoking in pack-years suggests a dose-response pattern with the risk of ED. Having diabetes was associated with double the risk of ED, and increased alcohol intake appeared to increase the risk. CONCLUSION: There was a greater risk of ED among former smokers, and the suggestion of a dose-response relationship with cumulative smoking.

Age Distribution↗

PubMed2004

Persistent lowering of pressure by transplanting kidneys from adult spontaneously hypertensive rats treated with brief antihypertensive therapy.

Kidney function is critical in determining the level of arterial pressure and in the pathogenesis of hypertension. Important evidence comes from studies in which the level of blood pressure is dictated by the donor when kidneys are transplanted between genetically hypertensive and normotensive rats. We have hypothesized that pharmacotherapy modifies specific properties of the kidney, particularly the vasculature, such that after kidney transplantation, there are persistent changes in the level of arterial pressure. Consistent with previous studies, a 2-week aggressive treatment of adult (15 weeks) spontaneously hypertensive rats with an angiotensin-converting enzyme inhibitor (enalapril) combined with a low-salt diet induced a persistent change in the kidney and a decrease in arterial pressure (18%). These persistent changes in arterial pressure could be completely transferred to untreated adult spontaneously hypertensive rats by kidney transplantation (ie, pressure in untreated rats was decreased after transplantation of a kidney donated from a previously treated rat). Further, the importance of kidney-specific changes was demonstrated by finding that the treatment-induced lowering of arterial pressure was completely reversed by transferring an untreated kidney into a previously treated rat. The specific treatment-induced changes to the kidney included a decrease in structurally based renal vascular resistance that was similar to the persistent lowering of arterial pressure. These data provide evidence for a link between the treatment-induced changes in kidney vascular structure and the persistent lowering of arterial pressure. The findings also suggest that a key pharmacotherapeutic target in hypertension should be kidney-specific changes, such as renal vascular structure.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Intervertebral disc degeneration can lead to "stress-shielding" of the anterior vertebral body: a cause of osteoporotic vertebral fracture?

STUDY DESIGN: Mechanical testing of cadaveric lumbar motion segments. OBJECTIVES: To test the hypothesis that degenerative changes in the intervertebral discs can influence loading of the anterior vertebral body in a manner that makes it vulnerable to fracture. SUMMARY OF BACKGROUND DATA: Measurements of systemic bone loss do not fully explain the patterns of osteoporotic vertebral fractures. METHODS: Thirty-three cadaveric lumbar motion segments (aged 19-82 years) were subjected to 2 kN of compressive loading while positioned to simulate habitual erect standing postures and forwards bending. Intradiscal stresses were measured in each posture by pulling a miniature pressure transducer along the midsagittal diameter of the disc. "Stress profiles" were then integrated over area to calculate the force acting on the anterior and posterior halves of the vertebral body. These forces were subtracted from the applied 2 kN to determine the compressive force on the neural arch. RESULTS: In motion segments with nondegenerated discs, <5% of the compressive force was resisted by the neural arch, and forces on the vertebral body were always distributed evenly, irrespective of posture. However, with severely degenerated discs, neural arch load-bearing increased to 40% in the erect posture, and the compressive force on the vertebral body was concentrated anteriorly in forwards bending, and posteriorly in erect posture. CONCLUSIONS: Severe disc degeneration causes the anterior vertebral body to be stress-shielded during the usual erect posture, and yet severely loaded whenever the spine is flexed. This could help to explain why this region is frequently the site of osteoporotic fracture, and why forward bending movements often precipitate the injury.

Adult↗

PubMed2004

Nitric oxide-mediated regulation of hypoxia-induced B16F10 melanoma metastasis.

Tumour hypoxia is associated with resistance to therapy and with increased invasion and metastatic potential. Recent studies in our laboratory have shown that the hypoxic up-regulation of tumour cell invasiveness and chemoresistance is in part due to reduced nitric oxide (NO) signaling. Using B16F10 murine melanoma cells, we demonstrate here that the increased metastatic potential associated with exposure to hypoxia is mediated by a reduction in cGMP-dependent NO-signaling. Pre-incubation of B16F10 cells in hypoxia (1% vs. 20% O(2)) for 12 hr increased lung colonization ability by over 4-fold. This effect of hypoxia on metastasis was inhibited by co-incubation with low concentrations of the NO-mimetic drugs glyceryl trinitrate (GTN) and diethylenetriamine NO adduct (DETA/NO). In a manner similar to hypoxia, pharmacological inhibition of NO synthesis resulted in a significant increase in lung nodule formation, an effect that was prevented by co-incubation with GTN. An important NO-signaling pathway involves the activation of soluble guanylyl cyclase and the consequential generation of cGMP. Culture in the presence of a non-hydrolysable cGMP analogue (8-Br-cGMP) abrogated the hypoxia-induced lung nodule formation, suggesting that the effects of NO on metastasis are mediated via a cGMP-dependent pathway. These findings suggest that a novel mechanism whereby hypoxia regulates metastatic potential involves a downstream inhibition of cGMP-dependent NO signaling.

Animals↗