Randomized clinical field trial on the effects of butaphosphan-cyanocobalamin and propylene glycol on ketosis resolution and milk production.

The purpose of this study was to determine the effects of a butaphosphan-cyanocobalamin combination product (B+C) and 2 durations of propylene glycol treatment (PG; 3 versus 5 d) on ketosis resolution and early lactation milk yield. Cows from 9 freestall herds (8 in Ontario and 1 in Michigan) were tested at weekly intervals between 3 and 16 d in milk. Ketosis was defined as blood ß-hydroxybutyrate (BHB) ≥1.2 mmol/L. Ketotic cows were randomly assigned to treatment with 25 mL of B+C or 25 mL of saline placebo for 3 d and 3 or 5 d of 300 g of PG orally in a 2 × 2 factorial arrangement. Outcomes evaluated for all farms included ketosis cure (blood BHB <1.2 mmol/L at 1 wk after enrollment), maintenance of ketosis cure (blood BHB <1.2 mmol/L 1 and 2 wk after enrollment), and blood BHB concentrations at 1 and 2 wk after enrollment. Daily milk weights were collected in 3 herds. Poisson regression was used to evaluate cure and maintenance of cure, whereas repeated-measures ANOVA was used to evaluate blood BHB concentrations in the 2 wk after enrollment and average daily milk production in the 30 d after treatment. A total of 594 animals were enrolled in the study with 124 treated with B+C and 5 d of PG, 176 treated with B+C and 3 d of PG, 128 treated with saline and 5 d of PG, and 166 treated with saline and 3 d of PG. Animals with blood BHB >2.4 mmol/L at the time of enrollment were 1.7 times more likely [95% confidence interval (CI): 1.4 to 2.2] to cure and had a decrease of 0.25 ± 0.11 mmol/L blood BHB at 1 wk after enrollment if treated with 5 d of PG compared with 3 d, though this response was not seen in animals with BHB of 1.2 to 2.4 mmol/L at enrollment. Cows with blood glucose concentrations <2.2 mmol/L at enrollment produced 3.1 kg/d (95% CI: 1.3 to 5.0) more milk if treated with B+C and 3.4 kg/d (95% CI: 1.7 to 5.1) more milk if treated with 5 d of PG compared with their respective controls. This response was not seen in animals with blood glucose ≥2.2 mmol/L at enrollment and there was no interaction between treatments. These results indicate that extended PG treatment is beneficial in decreasing blood BHB concentrations in more severely affected animals. Additionally, both B+C treatment and extended PG treatment improved milk yield in animals with low blood glucose at the time of ketosis diagnosis.

Effects of a combination butaphosphan and cyanocobalamin product and insulin on ketosis resolution and milk production.

The objective of this study was to determine the effects of butaphosphan-cyanocobalamin (B+C), glargine insulin, and propylene glycol on resolution of ketosis and average daily milk yield after treatment. Cows from 16 herds in Ontario, Canada, and 1 herd in Michigan were tested at weekly intervals between 3 and 16 DIM. Ketosis was defined as blood ß-hydroxybutyrate (BHB) ≥1.2 mmol/L. All ketotic cows were given a baseline treatment of 3 d of 300 g of propylene glycol orally. Animals were then randomly assigned to treatment with 3 doses of either 25 mL of B+C or 25 mL of saline placebo and 1 dose of either 2 mL (200 IU) of glargine insulin or 2 mL of saline placebo in a 2 × 2 factorial arrangement. Outcomes of interest on all farms were ketosis cure (blood BHB <1.2 mmol/L 1 wk postenrollment), maintenance of ketosis cure (blood BHB <1.2 mmol/L 1 and 2 wk postenrollment), and blood BHB concentrations at 1 and 2 wk postenrollment. Milk weights were collected daily in 1 large freestall herd. Repeated measures ANOVA was used to evaluate blood BHB concentrations 2 wk after treatment and milk production for 30 d after treatment. Poisson regression was used to examine the effect of treatment on cure and maintenance of cure. Due to a regulatory delay causing temporary unavailability of B+C in Canada, data were analyzed in 2 sets of models: one for insulin and the corresponding placebo (n = 620) and one for the full trial (n = 380). Animals with blood glucose concentrations ≤2.2 mmol/L at the time of ketosis diagnosis were 2.1 times more likely (95% CI = 1.2 to 3.7) to be cured if treated with B+C. Animals in lactation 3 or higher that had blood glucose concentrations <2.2 mmol/L at enrollment produced 4.2 kg/d (95% CI = 1.4 to 7.1) more milk if treated with insulin versus placebo and 2.8 kg/d (95% CI = 0.9 to 4.7) more milk if treated with B+C versus placebo. Animals in lactation 3 or higher with blood glucose ≥2.2 mmol/L that were treated with insulin produced 2.3 kg/d (95% CI = 0.3 to 4.4) less milk than untreated controls. No interaction was observed between treatments. This evidence suggests that B+C and insulin may be beneficial for ketosis treatment in animals with blood glucose <2.2 mmol/L at ketosis diagnosis. It also suggests that blood glucose concentration may be an important predictor of success of ketosis treatment.

Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

UNLABELLED: Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. INTRODUCTION: Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. METHODS: Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. RESULTS: C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. CONCLUSIONS: Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies utilizing mice as preclinical models for osteoporosis.

Draft Genome Sequence of Xanthomonas axonopodis pv. allii Strain CFBP 6369.

We report here the draft genome sequence of Xanthomonas axonopodis pv. allii strain CFBP 6369, the causal agent of bacterial blight of onion. The draft genome has a size of 5,425,942 bp and a G+C content of 64.4%.

Differential association of insulin resistance with cognitive and somatic symptoms of depression.

AIM: To examine the associations of depressive symptoms with insulin resistance, evaluating somatic and cognitive depressive symptoms separately. METHODS: A total of 328 individuals (mean age 60 years) referred for exercise stress testing, taking part in the Mechanisms and Outcomes of Silent Myocardial Ischemia study, completed the Beck Depression Inventory II. A fasting venous blood sample was collected for assessments of insulin and glucose level; the HOMA-IR (homeostatic model assessment of insulin resistance) was calculated. In principal component analysis, Beck Depression Inventory II items were forced to load onto two components (somatic and cognitive depressive symptoms). Adjusting for age, sex, BMI, medication use, smoking, physical activity, diabetes and cardiovascular disease, general linear model analyses were conducted to examine the associations between the components and log HOMA-IR . RESULTS: Principal component analysis showed that nine items loaded onto a cognitive depressive symptoms component and 10 items loaded onto a somatic depressive symptoms component. When examined separately, both components were significantly associated with log HOMA-IR however, when including both components simultaneously in the model, only somatic depressive symptoms remained significantly associated with log HOMA-IR. Back-transformed, a one-unit change in somatic depressive symptoms was associated with a 1.07 (95% CI 1.002, 1.14) change in HOMA-IR and a one-unit change in cognitive depressive symptoms was associated with a 1.03 (95% CI 0.97, 1.14) change in HOMA-IR. CONCLUSION: Somatic depressive symptoms seem to be more strongly associated with insulin resistance than do cognitive depressive symptoms. Monitoring somatic depressive symptoms may be more appropriate than monitoring cognitive depressive symptoms among depressed individuals with high insulin resistance.

Short communication: the effect of temperature on performance of milk ketone test strips.

Ketosis is estimated to affect 15% of early lactation dairy cows. A ketone test strip (Keto-Test; Elanco Animal Health, Greenfield, IN) allows producers a method to determine the concentration of ß-hydroxybutyrate (BHBA) in milk to track individual animal and herd incidence of ketosis. The objective of this study was to determine the effect of altering the temperature of milk and the test strips at the time of the test on the reliability of the Keto-Test. A total of 118 Holstein cows, ranging from 5 to 17 DIM, were selected from a commercial Holstein dairy herd in Michigan. A milk sample was collected from the right rear quarter of each cow during the a.m. milking. Each sample was tested under 4 temperature conditions: (1) Keto-Test strips and milk at room temperature (RT; 24.0 ± 0.1°C; control; manufacturer's instructions), (2) cold strips (10.8 ± 0.9°C) and milk at RT, (3) cold strips and fresh milk, and (4) strips at RT and fresh milk. Milk was recorded as negative (0-99 µmol/L), weak positive (100-199 µmol/L), positive (200-499 µmol/L), or highly positive (≥ 500 µmol/L). Blood samples were collected immediately following milk collection and analyzed for BHBA concentration using a ketone test meter. Cows with blood BHBA concentration of ≥ 1,400 µmol/L were considered positive for subclinical ketosis. Accuracy of the Keto-Test strips under the 4 conditions was determined by the κ coefficient of agreement, using the result of condition 1 as the accepted true value. Additionally, sensitivity and specificity were calculated using the blood BHBA concentrations and results of each of the 4 conditions. Using the Keto-Test 60.2% of cows tested negative for milk BHBA, 24.6% tested weak positive, 14.4% tested positive, and 0.8% tested highly positive. The weighted κ coefficient of agreement between the control condition (1) and condition 2, 3, and 4 and 95% lower and upper confidence intervals were as follows: condition 2=0.71 (0.62, 0.80), condition 3=0.69 (0.60, 0.78), and condition 4=0.63 (0.54, 0.73). These results indicate good agreement between the outcome of condition 1 and conditions 2, 3, and 4. The sensitivities/specificities for 1, 2, 3, and 4 were as follows: 0.77/0.79, 0.74/0.75, 0.69/0.88, and 0.69/0.84, indicating that the test in all temperature conditions had a strong ability to detect the presence of BHBA in milk. In conclusion, the reliability of the Keto-Test strips was not dependent on the temperature of the milk or the test strips.

Molecular basis for enantioselectivity of lipase from Chromobacterium viscosum toward the diesters of 2,3-dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol.

2,3-Dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol, 1, is a chiral bisphenol useful for preparation of polymers. Previous screening of commercial hydrolases identified lipase from Chromobacterium viscosum (CVL) as a highly regio- and enantioselective catalyst for hydrolysis of diesters of 1. The regioselectivity was > or =30:1 favoring the ester at the 5-position, while the enantioselectivity varied with acyl chain length, showing the highest enantioselectivity (E = 48 +/- 20 S) for the dibutanoate ester. In this paper, we use a combination of nonsymmetrical diesters and computer modeling to identify that the remote ester group controls the enantioselectivity. First, we prepared nonsymmetrical diesters of (+/-)-1 using another regioselective, but nonenantioselective, reaction. Lipase from Candida rugosa (CRL) showed the opposite regioselectivity (>30:1), allowing removal of the ester at the 4'-position (the remote ester in the CVL-catalyzed reaction). Regioselective hydrolysis of (+/-)-1-dibutanoate (150 g) gave (+/-)-1-5-dibutanoate (89 g, 71% yield). Acylation gave nonsymmetrical diesters that varied at the 4'-position. With no ester at the 4'-position, CVL showed no enantioselectivity, while hindered esters (3,3-dimethylbutanoate) reacted 20 times more slowly, but retained enantioselectivity (E = 22). These results indicate that the remote ester group can control the enantioselectivity. Computer modeling confirmed these results and provided molecular details. A model of a phosphonate transition state analogue fit easily in the active site of the open conformation of CVL. A large hydrophobic pocket tilts to one side above the catalytic machinery. The tilt permits the remote ester at the 4'-position of only the (S)-enantiomer to bind in this pocket. The butanoate ester fits and fills this pocket and shows high enantioselectivity. Both smaller and larger ester groups show low enantioselectivity because small ester groups cannot fill this pocket, while longer ester groups extend beyond the pocket. An improved large-scale resolution of 1-dibutanoate with CVL gave (R)-(+)-1-dibutanoate (269 g, 47% yield, 92% ee) and (S)-(-)-1-4'-monobutanoate (245 g, 52% yield, 89% ee). Methanolysis yielded (R)-(+)-1 (169 g, 40% overall yield, >97% ee) and (S)-(-)-1 (122 g, 36% overall yield, >96% ee).

Patterns and predictors of employer risk-reduction activities (ERRAs) in response to a work-related upper extremity cumulative trauma disorder (UECTD): reports from workers' compensation claimants.

BACKGROUND: Despite being preventable, work-related upper extremity cumulative trauma disorders (UECTDs) remain problematic. This study is unique in its focus on predictors of employer risk-reduction activities (ERRAs) in response to a UECTD case. METHODS: Workers' compensation claimants (N = 537) completed a telephone survey about employer risk-reduction activities, workplace characteristics, safety programs, and physician recommendations for job modifications. RESULTS: Only 52% of respondents reported employer actions to investigate or reduce UECTD risk. Engineering and pace changes were prominent for keyboard workers and transfer to another job for manufacturing workers. Safety programs and physician recommendations increased the likelihood of risk-reduction activities. CONCLUSIONS: An opportunity to intervene post-injury to reduce risks for the injured worker and prevent new UECTD cases is being missed. Physician recommendations are strongly associated with specific ERRAs thought to be most effective. Educating employers and physicians about ergonomics could result in prevention of UECTDs.

The impact of occupational injury on injured worker and family: outcomes of upper extremity cumulative trauma disorders in Maryland workers.

BACKGROUND: Surveys have identified a dramatically rising incidence of work-related upper extremity cumulative trauma disorders (UECTDs). Outcome studies have addressed time lost from work and cost of compensation; omitting other significant consequences. We assess health, functional and family outcomes. METHODS: We identified 537 Workers' Compensation UECTD claimants. A computer-assisted telephone questionnaire was used to elicit symptom prevalence, functional impairment, depressive symptoms (CES-D scale), employment status. RESULTS: One to 4 years post-claim, respondents reported persistent symptoms severe enough to interfere with work (53%), home/recreation activities (64%) and sleep (44%). Only 64% of responses to the activities of daily living scale items indicated "normal" function. Job loss was reported by 38% of respondents, and depressive symptoms by 31%. CONCLUSIONS: Work-related UECTDs result in persisting symptoms and difficulty in performing simple activities of daily living, impacting home life even more than work. Job loss, symptoms of depression, and family disruption were common.

Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease.

We measured the eye movements of three sisters with Niemann-Pick type C disease who had a selective defect of vertical saccades, which were slow and hypometric. Horizontal saccades, and horizontal and vertical pursuit and vestibular eye movements were similar to control subjects. The initial movement of oblique saccades was mainly horizontal and most of the vertical component occurred after the horizontal component ended; this resulted in strongly curved trajectories. After completion of the horizontal component of an oblique saccade, the eyes oscillated horizontally at 10-20 Hz until the vertical component ended. These findings are best explained by models that incorporate separate feedback loops for horizontal and vertical burst neurons, and in which the disease selectively affects vertical burst neurons.

Evidence for an early inflammatory response in the central nervous system of mice with scrapie.

In Alzheimer's disease, the most prevalent of the neurodegenerative diseases, inflammation of the CNS contributes to the pathology and is a target for therapy. In contrast, the group of neurodegenerative conditions known as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many similarities between the pathologies of Alzheimer's Disease and Prion Diseases We have found evidence for an inflammatory component in mouse scrapie, characterized by microglial activation and T-lymphocyte recruitment, which appears long before any clinical signs of the disease and spreads along well-defined anatomical pathways. These observations emphasize the potential value of murine scrapie as a model for studying the inflammatory pathology of other neurodegenerative diseases.

Genetic engineering of carbohydrate biosynthetic pathways in transgenic mice demonstrates cell cycle-associated regulation of glycoconjugate production in small intestinal epithelial cells.

Proliferation, migration-associated differentiation, and cell death occur continuously and in a spatially well-organized fashion along the crypt-villus axis of the mouse small intestine, making it an attractive system for studying how these processes are regulated and interrelated. A pathway for producing glycoconjugates was engineered in adult FVB/N transgenic mice by expressing a human alpha 1,3/4-fucosyltransferase (alpha 1,3/4-FT; EC 2.4.1.65) along the length of this crypt-villus axis. The alpha 1,3/4-FT can use lacto-N-tetraose or lacto-neo-N-tetraose core chains to generate Lewis (Le) blood group antigens Le(a) or Le(x), respectively, and H type 1 or H type 2 core chains to produce Leb and Le(y). Single- and multilabel immunohistochemical studies revealed that expression of the alpha 1,3/4-FT results in production of Le(a) and Leb antigens in both undifferentiated proliferated crypt cells and in differentiated postmitotic villus-associated epithelial cells. In contrast, Le(x) antigens were restricted to crypt cells. Villus enterocytes can be induced to reenter the cell cycle by expression of simian virus 40 tumor antigen under the control of a promoter that only functions in differentiated members of this lineage. Bitransgenic animals, generated from a cross of FVB/N alpha 1,3/4-FT with FVB/N simian virus 40 tumor antigen mice, expand the range of Le(x) expression to include villus-associated enterocytes that have reentered the cell cycle. Thus, the fucosylations unveil a proliferation-dependent switch in oligosaccharide production, as defined by a monoclonal antibody specific for the Le(x) epitope. These findings show that genetic engineering of oligosaccharide biosynthetic pathways can be used to define markers for entry into, or progression through, the cell cycle and to identify changes in endogenous carbohydrate metabolism that occur when proliferative status is altered in a manner that is not deleterious to the system under study.

Supplementation of the human vestibulo-ocular reflex by visual fixation and smooth pursuit.

In studies over the past 30 years, D. A. Robinson and colleagues established that the dynamic characteristics of smooth pursuit eye movements (SP) are different at the onset from those at the cessation of the response. They proposed that cessation of SP was due to a separate fixation system. During head movements, both fixation and SP may contribute to gaze stabilization. We investigated the relative contributions of fixation and SP to the "visually enhanced" vestibulo-ocular reflex (VVOR) using a paradigm requiring a transition from VVOR to combined eye-head tracking (CEHT). We found, in four normal subjects, that ringing typical of SP generally did not occur during VVOR, but that it often appeared after the transition to CEHT. The findings were different in two patients with absent peripheral vestibular function; ringing typical of SP occurred always during VVOR but disappeared during the onset of CEHT. These results can be explained by a model in which an internal representation of target velocity serves as input to parallel SP and fixation systems, and as the determinant of which of the two systems will provide the command signal. Interpretation of our data using this model indicates that either fixation or SP systems may "visually enhance" the VOR, depending on the magnitude of retinal error velocity that remains after vestibular eye movements have been generated.

Processing of tumour necrosis factor-alpha precursor by metalloproteinases.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine. The processing enzyme(s) which cleave TNF-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.

The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis.

The expression of PECAM, ICAM-1, VCAM-1, and E-selectin was studied in 64 samples of human coronary arteries taken from 15 explanted hearts obtained within 5 min of transplantation. Normal artery (n = 12), predominantly fibrous plaques (n = 23), and plaques containing extracellular lipid (n = 26) and three segments showing recanalization channels were studied. All endothelial cells strongly and equally expressed PECAM; positive staining was used to check that artefactual denudation of the endothelial surface had not occurred. PECAM was also present in some lipid-filled macrophages. Normal arteries showed no VCAM-1 staining but focal segments of the endothelium were positive for ICAM-1 and E-selectin. ICAM-1 was strongly and constantly expressed by the endothelium over all types of plaques and in macrophages. E-selectin expression was confined to endothelial cells and occurred on the surface in 35 per cent of fibrous and 22 per cent of lipid-containing plaques. VCAM-1 staining of surface endothelium occurred in 39 per cent of fibrous and 20 per cent of lipid-containing plaques. A population of spindle-shaped cells of macrophage type (positive for EMB11 antigen) expressed VCAM-1 in lipid-containing plaques. Adventitial vessels adjacent to plaques showed endothelial expression of ICAM-1 and E-selectin. VCAM-1 staining of adventitial vessel endothelium was associated with local lymphoid aggregation. In conclusion, the expression of cell adhesion molecules is an important element in the inflammatory component of atherosclerosis and contributes to both monocyte and lymphocyte activation and recruitment from adventitial vessels and the arterial lumen.

Metalloproteinase inhibitors as therapeutics.

Matrix metalloproteinases (MMPs) are a family of enzymes which contain zinc at their active site and can degrade most of the matrix macromolecules found in connective tissues. These MMPs are secreted by connective tissue cells and infiltrating leucocytes in response to inflammatory mediators. There is now widespread recognition that MMPs are the major class of proteinases responsible for the excessive degradation of cartilage that leads to joint dysfunction in rheumatoid arthritis. The properties of the MMPs are reviewed and a therapeutic role for synthetic, zinc-binding pseudopeptide MMP inhibitors in the treatment of arthritis is proposed.

The effects of radiographic contrast media on myocardial contractility and coronary resistance: osmolality, ionic concentration, and viscosity.

With the ongoing development of new contrast agents, questions develop concerning the cardiac effects of these drugs. We used the perfused rat heart model to investigate the effects on cardiac and coronary function of hypertonic ionic (sodium chloride) and nonionic (glucose) solutions and conventional and low osmolality radiographic contrast media (RCM). We also evaluated the concurrent effects of RCM on prostacyclin and adenine nucleotide/nucleoside release. Hypertonic solutions of glucose had little effect on myocardial contraction (increase up to 7.7 +/- 0.9%), while NaCl solutions of similar osmolality were negatively inotropic (contractile force decreased up to 76.1 +/- 9.2%). Conventional RCM were negatively inotropic (decrease of 59.6 +/- 5.6% with Conray (Mallinckrodt Pharmaceuticals, St. Louis, MO), 32.2 +/- 3.2% with Angiovist 282 (Berlex Laboratories, Cedar Knolls, NJ]; two nonionic RCM, Iopamidol and Iotrol had little effect on myocardial contraction (reduction of 6.9 +/- 1.4% and increase of 12.0 +/- 2.9%, respectively). Hypertonic solutions of glucose and NaCl reduced coronary resistance in direct relationship to hyperosmolality. Conventional RCM also reduced coronary resistance, while the nonionic media caused minor alteration. None of the solutions tested altered prostacyclin or adenine nucleotide/nucleoside efflux from the heart. A solution of Ficoll 70 with a viscosity similar to that of RCM increased myocardial contraction by 9.6 +/- 3.6% and had no effect on coronary resistance, indicating that viscosity per se did not contribute to the negative inotropic effects or the reduction in coronary resistance. Hypertonic solutions, including conventional RCM, reduce coronary resistance as a result of their hyperosmolality Negative inotropic effects, however, are more related to high ionic concentration than to osmolality.