Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study

Abstract Background Statin intake is associated with muscular side effects, among which the unmasking of latent myopathies and of malignant hyperthermia (MH) susceptibility have been reported. These findings, together with experimental data in small animals, prompt speculation that statin therapy may compromise the performance of skeletal muscle during diagnostic in vitro contracture tests (IVCT). In addition, statins might reduce triggering thresholds in susceptible individuals (MHS), or exacerbate MH progression. We sought to obtain empirical data to address these questions. Methods We compared the responses of 3 different muscles from untreated or simvastatin treated MHS and non-susceptible (MHN) pigs. MHS animals were also invasively monitored for signs of impending MH during sevoflurane anesthesia. Results Muscles from statin treated MHS pigs responded with enhanced in vitro contractures to halothane, while responses to caffeine were unaltered by the treatment. Neither agent elicited contractures in muscles from statin treated MHN pigs. In vivo, end- tide pCO2, hemodynamic evolution, plasma pH, potassium and lactate concentrations consistently pointed to mild acceleration of MH development in statin-treated pigs, whereas masseter spasm and rigor faded compared to untreated MHS animals. Conclusions The diagnostic sensitivity and specificity of the IVCT remains unchanged by a short-term simvastatin treatment in MHS swine. Evidence of modest enhancement in cardiovascular and metabolic signs of MH, as well as masked pathognomonic muscle rigor observed under simvastatin therapy suggest a potentially misleading influence on the clinical presentation of MH. The findings deserve further study to include other statins and therapeutic regimes.

Download Full-text

Case study in 21 st century ecotoxicology: using in vitro aromatase inhibition data to predict short term in vivo responses in adult female fish

Environmental Toxicology and Chemistry ◽

10.1002/etc.4968 ◽

2020 ◽

Author(s):

Daniel L. Villeneuve ◽

Brett R. Blackwell ◽

Jenna E. Cavallin ◽

Wan‐Yun Cheng ◽

David J. Feifarek ◽

...

Keyword(s):

Adult Female ◽

Female Fish ◽

Aromatase Inhibition ◽

Short Term ◽

Inhibition Data

Download Full-text

A NEW NON-PROTEIN NITROGEN SOURCE FOR RUMINANTS

Canadian Journal of Animal Science ◽

10.4141/cjas69-022 ◽

1969 ◽

Vol 49 (2) ◽

pp. 135-141 ◽

Cited By ~ 2

Author(s):

L. P. Milligan ◽

A. R. Robblee ◽

J. C. Wood ◽

W. C. Kay ◽

S. K. Chakrabartty

Keyword(s):

Nitrogen Source ◽

Dietary Supplement ◽

Nitrogen Retention ◽

Feeding Trial ◽

Short Term ◽

Protein Nitrogen ◽

Rumen Microorganisms ◽

Production Of Ammonia

The preparation of a polymer of urea and furfural containing 23.2% nitrogen is described. This product was converted by rumen microorganisms in vitro to ammonia at a rate approximately one-seventh that of conversion of urea to ammonia. Use of the polymer as a dietary supplement in a feeding trial with lambs improved nitrogen retention over that of unsupplemented controls by 3.45 g of nitrogen retained per day, while an isonitrogenous quantity of supplemental urea improved nitrogen retention by 0.51 g of nitrogen retained per day. The blood urea pattern, throughout the day, of lambs adapted to control, urea-supplemented and urea–furfural polymer-supplemented rations indicated a slow, prolonged production of ammonia from the latter supplement and very rapid, short-term degradation of urea in vivo.

Download Full-text

4-Chloro-m-cresol Triggers Malignant Hyperthermia in Susceptible Swine at Doses Greatly Exceeding Those Found in Drug Preparations

Anesthesiology ◽

10.1097/00000542-199906000-00030 ◽

1999 ◽

Vol 90 (6) ◽

pp. 1723-1732. ◽

Cited By ~ 17

Author(s):

Paul A. Iaizzo ◽

Brooks A. Johnson ◽

Kaoru Nagao ◽

William J. Gallagher

Keyword(s):

Malignant Hyperthermia ◽

Blood Chemistry ◽

Response Curves ◽

End Tidal ◽

In Vivo Effects ◽

Higher Doses ◽

End Tidal Co2 ◽

Cardiovascular Reactions

Background Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. Methods Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. Results Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). Conclusions 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

Download Full-text

Studies on the functional activity of organotypically cultured mouse ovary

Development ◽

10.1242/dev.15.2.133 ◽

1966 ◽

Vol 15 (2) ◽

pp. 133-141

Author(s):

T. N. Chapekar ◽

G. V. Nayak ◽

Kamal J. Ranadive

Keyword(s):

Functional Activity ◽

Synthetic Medium ◽

Culture Conditions ◽

Short Term ◽

Plasma Clot ◽

Rat Ovary ◽

Old Mice ◽

Term Maintenance

Short-term maintenance of mouse and rat ovary in organotypic culture system is no longer a problem (Martinovitch, 1938; Gaillard, 1953; Trowell, 1959). Gaillard (1953) cultivated ovaries from 7- to 8-day-old and 21-day-old mice for a week on the plasma clot. Trowell (1959) maintained ovaries of 8-day-old mice on a synthetic medium in an O2-CO2 atmosphere for 9 days. He observed no histological differentiation in the tissues of the ovary. What needs confirmation and further investigation is the possibility of maintenance of functional activity of the ovary under culture conditions. A study was therefore undertaken to investigate if an ovary, cultivated in vitro for some time, shows hormonal activity when transplanted in vivo. In the present work cultured ovaries were grafted in the anterior eye-chamber of spayed female mice and the development of secondary sex organs such as mammary glands and uterus was studied.

Download Full-text

Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502014000200003 ◽

2014 ◽

Vol 50 (2) ◽

pp. 251-256

Author(s):

Igor Vivian de Almeida ◽

Giovana Domingues ◽

Lilian Capelari Soares ◽

Elisângela Düsman ◽

Veronica Elisa Pimenta Vicentini

Keyword(s):

Rattus Norvegicus ◽

Bone Marrow Cells ◽

Micronucleus Test ◽

Term Treatment ◽

Genotoxic Effects ◽

Short Term ◽

Short Term Treatment ◽

Chromosomal Aberration Test

Flunitrazepam (FNZ) is a sedative benzodiazepine prescribed for the short-term treatment of insomnia. However, there are concerns regarding possible carcinogenic or genotoxic effects of this medicine. Thus, the aim of this study was to evaluate the cytotoxic, clastogenic and aneugenic effects of FNZ in hepatoma cells from Rattus norvegicus (HTC) in vitro and in bone marrow cells of Wistar rats in vivo. These effects were examined in vitro following treatment with 0.2, 1.0, 5.0 or 10 μg/mL FNZ using a micronucleus test with a cytokinesis block or in vivo using a chromosomal aberration test following treatment with 7, 15 or 30 μg/mL/kg body weight. The results showed that the benzodiazepine concentrations tested were not cytotoxic, aneugenic or clastogenic. However, considering the adverse effects of using this benzodiazepine, more studies are required.

Download Full-text

Safety Evaluation of Multiple Strains ofLactobacillus plantarumandPediococcus pentosaceusin Wistar Rats Based on the Ames Test and a 28-Day Feeding Study

The Scientific World JOURNAL ◽

10.1155/2014/928652 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Cheng-Chih Tsai ◽

Sew-Fen Leu ◽

Quan-Rong Huang ◽

Lan-Chun Chou ◽

Chun-Chih Huang

Keyword(s):

Wistar Rats ◽

Clinical Chemistry ◽

Toxicity Study ◽

Bacterial Strains ◽

Oral Toxicity ◽

Short Term ◽

Mutagenic Potential ◽

Multiple Strains

Three lactic acid bacterial strains,Lactobacillus plantarum, HK006, and HK109, andPediococcus pentosaceusPP31 exhibit probiotic potential as antiallergy agents, both in vitro and in vivo. However, the safety of these new strains requires evaluation when isolated from infant faeces or pickled cabbage. Multiple strains (HK006, HK109, and PP31) were subject to a bacterial reverse mutation assay and a short-term oral toxicity study. The powder product exhibited mutagenic potential inSalmonellaTyphimurium strains TA98 and TA1535 (with or without metabolic activation). In the short-term oral toxicity study, rats received a normal dosage of 390 mg/kg/d (approximately9×109 CFU/kg/d) or a high dosage of 1950 mg/kg/d (approximately4.5×1010 CFU/kg/d) for 28 d. No adverse effects were observed regarding the general condition, behaviour, growth, feed and water consumption, haematology, clinical chemistry indices, organ weights, or histopathologic analysis of the rats. These studies have demonstrated that the consumption of multiple bacterial strains is not associated with any signs of mutagenicity ofS.Typhimurium or toxicity in Wistar rats, even after consuming large quantities of bacteria.

Download Full-text

Short-term Regulation of Resistin in vivo by Oral Lipid Ingestion and in vitro by Fatty Acid Stimulation

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0035-1555942 ◽

2015 ◽

Vol 123 (09) ◽

pp. 553-560 ◽

Cited By ~ 4

Author(s):

A. Schmid ◽

S. Leszczak ◽

I. Ober ◽

T. Karrasch ◽

A. Schäffler

Keyword(s):

Fatty Acid ◽

Short Term

Download Full-text

Phosphofructokinase activity and acidosis during short-term tetanic contractions

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-046 ◽

1991 ◽

Vol 69 (2) ◽

pp. 298-304 ◽

Cited By ~ 16

Author(s):

Lawrence L. Spriet

Keyword(s):

Glycolytic Enzyme ◽

Test Tube ◽

Mammalian Skeletal Muscle ◽

Short Term ◽

Short Supply ◽

In Vivo Experiments ◽

Anaerobic Energy

Anaerobic energy production is essential for the production of muscular tension when the demand for energy is greater than can be provided aerobically and when oxygen is in short supply. The largest source of anaerobic energy is from the glycolytic pathway. With sustained tetanic contractions, muscle glycolytic activity is high and hydrogen ions (H+) accumulate while tension production decreases. The increasing [H+] and decreasing tension led to the suggestion that H+ inhibits the activity of the regulatory glycolytic enzyme phosphofructokinase (PFK). Early in vitro work confirmed the H+ sensitivity of PFK in the test tube, indicating that little PFK activity should persist at a pH of 6.9–7.0. However, in situ and in vivo experiments suggested that significant PFK activity was maintained during intense contractions when muscle pH decreased to 6.4–6.6. There are several concerns associated with the application of in vitro findings to in vivo exercise situations: (i) there is little in vitro work in mammalian skeletal muscle with substrate and modulator concentrations representative of exercise, (ii) most in vitro analyses of PFK activity are performed following the dilution of the enzyme in mediums with low protein concentration, and (iii) do the modulators identified in vitro exist in high enough in vivo concentrations at rest and during exercise to contribute to the regulation of PFK? More recent in vitro and in situ PFK experiments have overcome some of these concerns. They confirm that during intense, short-term tetanic contractions, PFK activity is well matched to the ATP demand despite decreases in pH to ~6.4–6.5. A combination of decreased inhibitor (ATP) and increased substrate (fructose 6-phosphate) contents coupled with increases in the contents of several positive modulators may be responsible for the maintained PFK activity. This combination reduces the pH-dependent ATP inhibition of PFK and extends the physiological pH range of the enzyme to the range normally measured during this type of muscular activity.Key words: glycolysis, phosphofructokinase, anaerobic metabolism, acidosis.

Download Full-text