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PubMed2005

Oxidative susceptibility of unfractionated serum or plasma: response to antioxidants in vitro and to antioxidant supplementation.

BACKGROUND: The susceptibility of plasma lipids to oxidation is thought to be a factor contributing to atherogenic risk. Various groups have studied the in vitro oxidizability of isolated LDL and examined the effects of conventional antioxidants. The drawbacks associated with the isolation of LDL for evaluation of in vitro oxidizability, however, have limited the application of this measurement in large-scale studies. METHODS: We developed and evaluated an assay that can be used to directly assess the oxidative susceptibility of unfractionated serum or plasma lipids, obviating the need for isolation of lipoprotein fractions. Oxidative conditions were initiated in vitro with cuprous chloride and 2,2'-azobis(2-amidinopropane) hydrochloride. The effects of antioxidants added in vitro, and as an oral supplement, were monitored by conjugated diene formation. RESULTS: The addition of ascorbic acid (0-50 micromol/L) in vitro elicited a dose-dependent protective effect, increasing the lag time to oxidation (P < 0.001). In contrast, alpha-tocopherol demonstrated prooxidant behavior at increasing concentrations (0-50 micromol/L), although we observed a decrease in the maximum rate of oxidation. Our findings are supported by the results from plasma samples of participants in a randomized antioxidant (vitamins C and E) intervention study after acute ischemic stroke. The group receiving vitamins C and E for 14 days showed an increased lag time to plasma lipid oxidation in vitro compared with the nonsupplemented group (P < 0.05). CONCLUSION: The susceptibility of unfractionated plasma or serum lipids to oxidation in vitro offers an alternative to LDL for evaluating the efficacy of antioxidant regimens.

Acute Disease↗
PubMed2005

FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas.

OBJECTIVE: Non-functioning pituitary adenomas (NFPAs) are characterised by the lack of symptoms of hormone hypersecretory syndromes but in vitro studies have demonstrated that tumour cells may stain for gonadotrophins and/or their alpha- or beta-subunits. In this study, we aimed to examine the pattern of secretion of LH and FSH from a series of pituitary adenomas cultured in vitro and where data were available to relate the results to pre-operative serum gonadotrophin levels. METHODS: The in vitro secretion of LH and FSH was measured from 46 cultured NFPAs and compared with pre-operative serum gonadotrophin levels in 38 patients. Peritumorous 'normal' pituitary cell cultures from 20 additional pituitary tumour patients were used for comparison with the NFPA group. RESULTS: A median pre-operative LH:FSH ratio of 0.33:1 was found in 38 patients with NFPAs. Preferential secretion of FSH was also documented from media of 46 NFPAs cultured in vitro with a median LH:FSH ratio of 0.32:1. A significant correlation (r = 0.43, P < 0.01) was observed between serum and media levels of FSH but not LH. Peritumorous 'normal' pituitary cells released LH and FSH in a reversed ratio (median LH:FSH ratio = 3.6:1, P < 0.01 compared with NFPAs). CONCLUSIONS: This study has evaluated pre-operative serum gonadotrophin levels and in vitro release of hormones in cultures of surgically removed tissue from patients with NFPAs. The data suggest preferential secretion of FSH occurs both in vitro and in vivo. By demonstrating that NFPAs cultured in vitro reflect the in vivo situation of preferential secretion of FSH, it may be possible in future to perform functional studies using this system to elucidate the cellular and molecular mechanisms involved in the development of an imbalance in gonadotroph cells preferentially overproducing FSH in NFPAs.

Adenoma↗
PubMed1990

Morphology and proportion of inner cell mass of bovine blastocysts fertilized in vitro and in vivo.

The morphology and proportion of inner cell mass (ICM) of bovine blastocysts cultured in vitro or in vivo in rabbit oviducts after in-vitro fertilization of in-vitro matured follicular oocytes were compared with those of blastocysts fertilized in vivo by a differential fluorochrome staining technique. The delineation of each ICM cell was improved by the transfer of embryos derived from in-vitro fertilization to a rabbit oviduct although the cell-cell contacts of ICM cells were not as tight as those from in-vivo fertilization. The proportions (15.8 and 14.9%) of ICM in blastocysts cultured in vitro at early and expanded stages were significantly lower than those cultured in rabbit oviducts after in-vitro fertilization and fertilized in vivo. These results show that the transfer of bovine embryos derived from in-vitro fertilization to the rabbit oviduct increased the proliferation of ICM cells to the level of embryos fertilized in vivo although the cell-cell contact of ICM cell is not improved by the process.

Animals↗
PubMed1996

Expression of the gap junction gene connexin43 (Cx43) in preimplantation bovine embryos derived in vitro or in vivo.

In this study we have examined the presence of mRNA encoding connexin 43 (Cx43) in bovine embryos derived in vivo and in vitro. Cumulus-oocyte complexes, immature and matured oocytes liberated from cumulus cells, zygotes, 2-4-cell and 8-16-cell embryos, morulae, blastocysts and hatched blastocysts were produced in vitro from ovaries obtained from an abattoir using TCM 199 supplemented with hormones and 10% oestrous cow serum for maturation. Cumulus-oocyte complexes matured for 24 h were exposed to bull spermatozoa for 19 h and then cultured in TCM 199 supplemented with 10% oestrous cow serum to the desired developmental stage. Morulae and blastocysts derived in vivo were collected from superovulated donor cows. Total RNA was extracted from pools of 60-200 bovine oocytes or embryos using a modified phenol-chloroform extraction method and analysed by reverse transcriptase polymerase chain reaction. Before reverse transcription, aliquots of DNase-digested embryonic RNA were tested by polymerase chain reaction using bovine-specific primers to control for residual genomic DNA contamination. DNA-free, total RNA was reverse transcribed after preincubation with the Cx43 specific 3'primer. The resultant cDNA was amplified by polymerase chain reaction using Cx43 specific primers that define a 516 bp fragment of Cx43. The reverse transcriptase polymerase chain reaction product was verified by restriction enzyme analysis with Alu I and sequencing. Assays were repeated at least twice for each developmental stage and provided identical results between replicates. Cx43 transcripts were detected in bovine morulae and blastocysts grown in vivo. In contrast, whereas the early in vitro stages from cumulus-oocyte complexes to morulae expressed Cx43, blastocysts and hatched blastocysts did not have detectable concentrations of mRNA from this gene. Restriction enzyme cutting revealed three fragments of the predicted size (139, 177, 200 bp). The amplified product showed 100% identity with the published bovine genomic DNA sequence. Under our in vitro conditions the Cx43 gene either had never been activated, which would require that the maternal transcript was stable through early development, or embryonic gene expression that had been active was then terminated prematurely. The differences in transcription between bovine embryos derived in vivo or in vitro indicate that culture conditions affect gene expression. This affords a tool for the further optimization of in vitro production systems for bovine embryos and contributes towards physiological characterization by definition of transcription phenotype of bovine embryos produced in vitro.

Animals↗
PubMed2006

Suppressed expression of genes involved in transcription and translation in in vitro compared with in vivo cultured bovine embryos.

In vivo-derived bovine embryos are of higher quality than those derived in vitro. Many of the differences in quality can be related to culture environment-induced changes in mRNA abundance. The aim of this study was to identify a range of mRNA transcripts that are differentially expressed between bovine blastocysts derived from in vitro versus in vivo culture. Microarray (BOTL5) comparison between in vivo- and in vitro-cultured bovine blastocysts identified 384 genes and expressed sequence tags (ESTs) that were differentially expressed; 85% of these were down-regulated in in vitro cultured blastocysts, showing a much reduced overall level of mRNA expression in in vitro- compared with in vivo-cultured blastocysts. Relative expression of 16 out of 23 (70%) differentially expressed genes (according to P value) were verified in new pools of in vivo- and in vitro-cultured blastocysts, using quantitative real-time PCR. Most (10 out of 16) are involved in transcription and translation events, suggesting that the reason why in vitro-derived embryos are of inferior quality compared with in vivo-derived embryos is due to a deficiency of the machinery associated with transcription and translation.

Animals↗
PubMed1993

Technical note: forage in vitro dry matter digestibility as influenced by fiber source in the donor cow diet.

Objectives of this study were to determine the influence of five donor cow diets that differed in source of fiber on true in vitro DM digestibility of eight forages. Test forages included two alfalfa (31.2 and 38.3% NDF), corn silage (50.2% NDF), oat forage (48.2% NDF), perennial rye (62.1% NDF), two reed canarygrasses (55.9 and 68.1% NDF), and timothy (68.2% NDF). Sources of fiber in donor cow diets were alfalfa haylage or alfalfa haylage plus either corn cobs, cottonseed hulls, oat hulls, or soy hulls. In addition, the effect of filtering through sintered glass crucibles or filter paper (two replicates each) was evaluated. There were differences (P < .01) among feeds in in vitro DM digestibility, but there were no interactions (P > .05) between test forages and either source of fiber in donor diets or filtration method. There was an interaction between source of fiber in the donor diet and method of filtration (P < .01). Samples inoculated with ruminal fluid from cows fed diets with oat hulls or soy hulls had lower (P < .01) in vitro DM digestibility when filtered on crucibles than on filter paper. Filtration method did not affect (P > .05) in vitro DM digestibility of samples inoculated with ruminal fluid from other diets. The in vitro DM digestibility of samples inoculated with ruminal fluid from cows fed alfalfa haylage was less than the in vitro DM digestibility when other inocula were used. The source of fiber in the donor cow diet and filtration method can affect in vitro DM digestibility, but relative ranking of forages was unaffected by these variables.

Animal Feed↗
PubMed2005

A new in vitro bioassay system for discovery of novel human-use mosquito repellents.

A Klun & Debboun (K&D) test module, previously developed and used for quantitative measurement of the efficacy of mosquito repellents on human volunteers, was adapted for in vitro evaluation of repellents by coupling the module with a membrane-blood reservoir. Performance of Deet, Bayrepel, and SS-220 insect repellents in the new in vitro system was compared with their performance on humans against mosquitoes using our standard in vivo system. For each compound, in vitro dose-response assays were conducted with compounds applied to cloth positioned over blood reservoirs covered with Baudruche membrane against Aedes aegypti. The repellents were also tested in vitro against Anopheles stephensi and Ae. aegypti at a fixed dose of 24 nmol compound/cm2 cloth over the Baudruche and Edicol collagen membranes. Concurrently, the repellents were tested at the fixed dose using the K&D module on human volunteers. The observed proportions of both mosquito species deterred from biting in the fixed doses in the in vitro assays were similar to those obtained using humans, being clearly able to distinguish controls from repellents, and differing only in the ranking of the effectiveness of some of the repellents. Dose-response relationships of the in vitro and in vivo systems were also very similar, although not directly comparable because the data were not collected concurrently. This new in vitro assay system can be used in high throughput screening of compounds to identify new repellents having potential for use as topical mosquito repellents on humans.

Aedes↗
PubMed2005

Chemical and physical characteristics of corn silages and their effects on in vitro disappearance.

Estimating the available energy in corn silage provides a unique challenge because the silage contains variable proportions of grain and stover, each of which can differ in availability due to chemical composition and physical form. The objectives of this study were to investigate relationships among chemical components and their relationships with in vitro disappearance of ground and unground dried silages, and to quantify minimally fragmented starch in corn silage and investigate its impact and that of mean particle size (MPS) on in vitro disappearance of unground silages. Thirty-two corn silages were selected to provide diversity in dry matter, protein, fiber, and MPS. Detergent fibers were highly correlated with each other and with nonfiber carbohydrates, and were used to develop prediction equations between these constituents. Sieves with apertures > or =4.75 mm were used to isolate intact kernels and large kernel fragments, which were collected and analyzed to measure minimally fragmented starch (Starch>4.75). Dividing Starch>4.75 by total starch defined the proportion of minimally fragmented starch (Starch>4.75/Total), which ranged from 9 to 100% with a mean of 52%. Starch>4.75/Total was positively correlated with MPS (r = 0.46). The inverse of Starch>4.75/Total is an index of kernel fragmentation. Silages were prepared as whole material or ground to pass through a 4- or 1-mm screen of a cutter mill. In vitro dry matter disappearance (IVDMD) was greater for ground than for whole samples (71.7 and 61.2%, respectively). Increased IVDMD for ground samples was attributed to greater in vitro neutral detergent fiber (NDF) and neutral detergent solubles (NDS) disappearances. The IVDMD of ground samples was related to NDF and acid detergent lignin (R2 = 0.80). The IVDMD of whole corn silage was related to acid detergent lignin, Starch>4.75, MPS, and dry matter. When IVDMD was partitioned into in vitro digestible NDS (IVdNDS) and in vitro digestible NDF, the IVdNDS of whole was not uniform or completely fermented. The difference in IVdNDS between ground and whole was related to Starch>4.75/Total. In conclusion, the proportion of minimally fragmented starch provides a corn silage fragmentation index that is related to the in vitro digestion of whole silages that, if validated by in vivo trials, may be a useful quantitative substitute for the qualitative processing adjustment factor that is used currently in summative equations for estimating the total digestible nutrients of corn silages.

Carbohydrates↗
PubMed1990

Antibody response of mouse splenocytes using mixture of supernatants of thymocytes, adherent and non-adherent splenocytes: in-vitro immunization-II.

We adapted one of the in-vitro immunization methods to induce antibody responses and confirmed the success of the immunization by enzyme-linked immunosorbent assay (ELISA) without hybridization. We have previously reported several methods of in-vitro immunization using different conditioned media. Here we introduce another method of in-vitro immunization using a mixture of three types of supernatant (thymocytes, and adherent and non-adherent splenocytes of mouse). Splenocytes were immunized in-vitro by a recombinant human growth hormone (rhGH) with the above conditioned media, and the results by ELISA showed a much higher optical density than the other in-vitro immunization methods that we had previously reported. Humoral responses as a result of in-vitro immunization to soluble antigens were easily confirmed by ELISA using the above-conditioned media. This finding indicates that any other conditions thought to be critical by other researches may not be essential for in-vitro immunization.

Animals↗
PubMed1998

In vitro and skin testing for allergy: comparable clinical utility and costs.

Controversy exists concerning the appropriate use of skin testing and in vitro testing for the diagnosis of allergy, particularly inhalant allergy. Earlier comparisons of skin testing and in vitro testing concluded that skin testing had superior accuracy at lower expense. In light of new developments with in vitro allergy testing, however, this issue should be reconsidered. A review of the recent scientific literature indicates that in vitro and skin testing are highly correlated. However, without the existence of an independent gold standard for inhalant allergy, it is not possible to determine which test is more accurate. The accuracy of either test can be compromised if conducted using different protocols or having insufficient quality control. Given their respective trajectories for technological advancement, quantification, and quality control, in vitro testing may offer the more standardized approach. Although the cost per test of in vitro testing remains greater than that of skin testing, the per-patient costs of the two modalities appear to be comparable, given the greater number of allergens typically used in skin testing. In summary, both skin testing and in vitro testing are acceptable as frontline diagnostic tools.

Cost-Benefit Analysis↗
PubMed2001

An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant.

The ability of various human derived in vitro systems to predict various aspects of the in vivo metabolism and kinetics of almokalant have been investigated in a multicenter collaborative study. Although almokalant has been withdrawn from further clinical development, its metabolic and pharmacokinetic properties have been well characterized. Studies with precision-cut liver slices, primary hepatocyte cultures, and hepatic microsomal fractions fortified with UDP-glucuronic acid all suggested that almokalant is mainly glucuronidated to the stereoisomers M18a and M18b, which is in good agreement with the results in vivo. Both in vivo and in vitro studies indicate that the formation of M18b dominates over that of M18a, although the difference is more pronounced with the in vitro systems. Molecular modeling, cDNA-expressed enzyme analysis, correlation analysis, and inhibition studies did not clearly indicate which P450 enzymes catalyze the oxidative pathways, which may indicate a problem in identifying responsible enzymes for minor metabolic routes by in vitro methods. All of the in vitro systems underpredicted the metabolic clearance of almokalant, which has previously been reported to be a general problem for drugs that are cleared by P450-dependent metabolism. Although few studies on in vivo prediction of primarily glucuronidated drugs have appeared, in vitro models may consistently underpredict in vivo metabolic clearance. We conclude that in vitro systems, which monitor phase II metabolism, would be beneficial for prediction of the in vivo metabolism, although all of the candidate liver-derived systems studied here, within their intrinsic limitations, provided useful information for predicting metabolic routes and rates.

Anti-Arrhythmia Agents↗
PubMed2001

In vitro fertilization and embryo development in pigs.

Considerable progress has been made in the in vitro production of pig embryos using improved methods for in vitro maturation (IVM) and fertilization (IVF). Despite the progress, polyspermic penetration remains a problem for in vitro-matured oocytes. Variation among boars, ejaculates and IVF protocols used in different laboratories appears to influence the incidence of polyspermy. Recent studies indicate that oviduct cells and their secretions play a role in reducing polyspermy. Very early attempts to culture in vivo-derived pig embryos met with little success and most were arrested at the four-cell stage. At present, many culture media are available that can overcome the four-cell block and support development to the blastocyst stage. In contrast, blastocyst development of in vitro-produced (IVP) embryos in these culture media varies significantly. Significant differences in morphology and numbers of cells have been observed in in vitro-produced blastocysts compared with in vivo-derived blastocysts. Surgical transfer of in vitro-produced embryos to recipient animals has resulted in acceptable pregnancy rates with moderate litter sizes. Although several systems are available for the generation of in vitro-produced embryos, the problems of polyspermy and poor embryo survival prevent large-scale production of embryos. Further research should be directed to improve oocyte and embryo quality, and to develop methods to minimize polyspermy through development of better IVM, IVF and embryo culture techniques.

Animals↗
PubMed2001

In vitro development of pig preantral follicles.

A limiting factor to realizing the full potential of many of the new reproductive techniques is the lack of abundant numbers of fertilizable oocytes. This problem could be addressed by using the large source of oocytes available from preantral and primordial follicles by developing systems for in vitro growth. In vitro systems that use early growing follicles as a source of oocytes have been developed for laboratory species and these have been successful in producing live young. If successful, in vitro growth in association with in vitro maturation (IVM) and cryopreservation would optimize in vitro production systems. In vitro growth systems that support the growth of pig preantral follicles have been developed and have been successful in producing meiotically competent oocytes but, to date, no live young have been produced. However, these systems remain to be characterized and their main application is as experimental models to study the processes of early oocyte and follicle development. This review provides an overview of culture systems that have been developed for domestic species and discusses how these are furthering our basic knowledge of early follicular development, as well as considering the benefits and potential problems associated with in vitro growth systems.

Animals↗
PubMed1976

In vitro labeling and gold activation autoradiography for determination of labeling index and DNA synthesis times of solid tumors.

In vitro labeling and gold activation autoradiography were used to determine the [3H]thymidine ([3H]TdR)-labeling indices and DNA synthesis times for C3H/He spontaneous mammary tumors. Three variations of the [3H]TdR, [14C]thymidine ([14C]TdR) double-labeling method, together with double-emulsion autoradiography, were used to determine the DNA synthesis times (TS). Tumors labeled totally in vivo (in vivo-in vivo method) and tumors labeled with [3H]TdR in vivo and subsequently labeled with [14C]TdR in vitro showed similar TS values. DNA synthesis times for tumors determined totally in vitro by double labeling (in vitro-in vitro method) were significantly longer than those observed in vivo; however, identical samples subjected to Hypaque-Ficoll gradient separation after double labeling showed TS's similar to those found in vivo. Furthermore, the interval between [3H]TdR and [14C]TdR administration had no effect on TS estimates in vitro. Gold activation autoradiography was used in the present experiments to reduce autoradiographic exposure times. This method, together with in vitro labeling, permits [3H]TdR labeling index and TS determinations after 6-hr and 7-day exposures, respectively.

Animals↗
PubMed1992

In vitro methods: their relevance and complementarity in ocular safety assessment.

Ocular irritation includes a wide variety of mechanisms some of which can be explored by in vitro methods. For example, the effects on epithelial cells that constitute the outer layers of both the conjunctiva and the cornea may result in direct cytotoxicity or impairment of cellular functions -such as impermeability-, phenomena that can be explored in vitro. Irritancy may also involve inflammation of the conjunctival connective tissue and of the corneal stroma with its vascular and cellular features; effects on the stroma can lead to the opacification of the cornea; this last phenomenon may be the consequence of mechanisms such as modification of the structure of proteins or changes in stroma hydration which in particular is closely related to corneal endothelium metabolic activity. Recovery after eye injury depends partly on the extent of ocular damage and on the residual mitotic activity of the remaining cells. We have studied 41 surfactants, lotions and shampoos in 6 to 8 in vitro methods each one exploring one or two endpoints that could be linked to the ocular irritancy phenomena described above. In vivo ocular irritancy data for these materials from previous studies were compared to in vitro results. The results obtained show that -among the techniques that were investigated and for the categories of substances that were studied- the Het-CAM test and more particularly the endpoint that is related to vascular effects gives the best assessment of acute ocular irritancy (Spearman's rho coefficients between in vivo and in vitro data greater than 0.90); however, cell culture methods, especially one based on short contact time between cells and products and on evaluation of early toxic effects, also proved interesting (Spearman's rho coefficients between in vivo and in vitro data greater than 0.85). Moreover, the isolated cornea opacity and permeability test gave complementary information more related to recovery from surfactant-induced damage. These encouraging results lead us to consider in vitro ocular safety assessment with optimism for the categories of products investigated.

Allantois↗
PubMed1992

[Evaluation of environmental factors affecting embryo development in vitro].

Human in vitro fertilization and embryo transfer (IVF-ET) became an indispensable modality for treating infertile patients. The principle of this method is simple: that is, recovery of gametes from the gonads of men and women and transfer of the embryos into the uterus. This method can be expected, therefore, to be applied to many patients with a variety of causes of infertility. Unfortunately, the success rates are not satisfactory in the majority of clinics in the 14 years since the first report of a test tube in 1978. In view of improving the success rate, one major issue is the protocol used for ovulation induction, which may influence the quality of eggs as well as the environmental conditions in the endometrium at the time of embryo replacement. Another major issue should be the technique for embryo culture because, in general, mammalian embryos, including humans', are known to exhibit developmental retardation in vitro. In a significant number of embryos, cleavage is arrested at the first or second cell cycle when cultured under the conventional culture conditions. This phenomenon in rodents is known as "block to development in vitro" or "two-cell block in vitro". Recently, the mouse two-cell block was found to be attenuated by the addition of superoxide dismutase (SOD) to the culture medium. SOD is the enzyme that catalyzes the dismutation reaction of superoxide anion radicals: 2O2- + 2H(+)----H2O2 + O2. This suggests that developmental retardation in vitro may be related to the potential oxygen toxicity that embryos encounter in vitro. Following to this finding, a variety of culture conditions have been found to attenuate blocking phenomenon and to increase blastulation rate in the mouse embryos. By the addition of chemicals to the culture medium such as L-Cysteine, L-Ascorbic acid, EDTA, DTPA or thiredoxine, blastulation rates could be increased overcoming blocking phenomenon. From these findings, it seemed possible to hypothesize that developmental retardation is caused by the oxidative stress that embryos encounter in vitro. Oxidative stress is defined as an increased intracellular concentration of the active oxygen species in a stead-state condition. To make the hypothesis validated, intracellular generation of active oxygen species was measured by using DCHF-DA, a fluorescence dye precursor. The results showed that the fluorescent emissions of embryos were lowest in embryos cultured under 5% O2 and highest under 40% O2. L-Cysteine and thioredoxin, both of which have been shown to promote the embryo development, decreased the fluorescence emissions of embryos.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Short report: lack of prediction of amodiaquine efficacy in treating Plasmodium falciparum malaria by in vitro tests.

Amodiaquine (AQ) is currently a major candidate for new antimalarial combinations, although in vivo and in vitro tests have been rarely simultaneously investigated. The efficacy of AQ was assessed at the dose of 30 mg/kg in treating Plasmodium falciparum malaria attacks in 74 children from southeast Gabon, and the in vitro activity of monodesethylamodiaquine (MdAQ), the main metabolite of AQ, was measured against P. falciparum parasites isolated from these children. Treatment failures were observed in 40.5% of the children, while 5.4% of the isolates showed in vitro resistance to MdAQ. No relationship was observed between in vivo and in vitro susceptibility. The in vitro activities of MdAQ and chloroquine were correlated. The reasons for such disparities between in vivo and in vitro AQ activities are discussed and the issue of the validity of in vitro tests to measure AQ efficacy is raised.

Amodiaquine↗
PubMed2004

Effects of flecainide on atrial and ventricular refractoriness in rabbits in vitro and in vivo.

This study compared the in vitro versus in vivo effects of flecainide on effective refractory period (ERP) in atrial and ventricular tissue in rabbits. Flecainide (a class 1c agent) was chosen, on the basis of its known pharmacological profile and antiarrhythmic actions, to provide a reference compound for investigating models that suitably predict the clinical effects of antiarrhythmics. The rabbit models used were those previously described by Lowe et al. (2002) and Leung et al. (2003). ERP was measured as the shortest S1-S2 interval that elicited a second contraction (in vitro) or electrogram (in vivo). Flecainide (1-10 microM) in vitro produced a concentration-dependent increase in ERP. The greatest drug-induced change from pre-drug values in vitro occurred with the highest concentration in atria and ventricles at 4 Hz. The change was 30+/-4 msec (33+/-7%) in atria versus 53+/-8 msec (46+/-10%) in ventricles. In vivo, flecainide (1 - 4 micromol/kg) dose-dependently increased atrial ERP at 2 and 6 Hz. The biggest change was 28+/-17 msec (29+/-16%). However, there was no effect at 4 Hz. In the ventricles, a dose-related increase in ERP was only seen at 4 Hz (26+/-6 msec). Flecainide showed no frequency dependence of action on ERP in any preparation. Flecainide produced adverse effects both in vitro and in vivo. A concentration and frequency-dependent negative inotropic effect was seen in vitro, and dose-related hypotension in vivo. The highest dose (8 micromol/kg i.v.) of flecainide was lethal. Flecainide produced the expected electrophysiological and toxicity profile, both in vitro and in vivo. Despite such findings, the drug is used to terminate and prevent atrial arrhythmias clinically. In conclusion our rabbit models for determining ERP may not be useful in predicting the clinical usefulness of a drug like flecainide.

Animals↗