Effects of three warm-up regimens of equal distance on VO2 kinetics during supramaximal exercise in Thoroughbred horses.

REASONS FOR PERFORMING STUDY: Several studies have indicated that even low-intensity warm-up increases O(2) transport kinetics and that high-intensity warm-up may not be needed in horses. However, conventional warm-up exercise for Thoroughbred races is more intense than those utilised in previous studies of equine warm-up responses. OBJECTIVES: To test the hypothesis that warm-up exercise at different intensities alters the kinetics and total contribution of aerobic power to total metabolic power in subsequent supramaximal (sprint) exercise in Thoroughbred horses. METHODS: Nine well-trained Thoroughbreds ran until fatigue at 115% of maximal oxygen consumption (VO2max) 10 min after warming-up under each of 3 protocols of equal running distance: 400 s at 30% VO2max (LoWU), 200 s at 60% VO2max (MoWU) and 120 s at 100% VO2max (HiWU). Variables measured during exercise were rates of O(2) and CO(2) consumption/production (VO2,VO2), respiratory exchange ratio (RER), heart rate, blood lactate concentration and accumulation rate and blood gas variables. RESULTS: VO2 was significantly higher in HiWU than in LoWU at the onset of the sprint exercise and HR was significantly higher in HiWU than in LoWU throughout the sprint. Accumulation of blood lactate, RER, P(a)CO(2) and PvCO2 in the first 60 s were significantly lower in HiWU than in LoWU and MoWU. There were no significant differences in stroke volume, run time or arterial-mixed venous O(2) concentration. CONCLUSIONS: These results suggest HiWU accelerates kinetics and reduces reliance on net anaerobic power compared with LoWU at the onset of the subsequent sprint.

Comparison of net anaerobic energy utilisation estimated by plasma lactate accumulation rate and accumulated oxygen deficit in Thoroughbred horses.

REASONS FOR PERFORMING STUDY: Accumulated O(2) deficit (AOD) and plasma lactate accumulation rate (PLAR) are alternative methods for estimating net anaerobic energy utilisation (NAEU) in exercising horses. How they compare or their accuracy is unknown. OBJECTIVES: We hypothesised net anaerobic energy utilisation calculated by PLAR (NAUE(PLAR)) is equivalent to NAUE estimated by AOD (NAUE(AOD)). METHODS: Six Thoroughbred horses ran at identical supramaximal speeds (118% aerobic capacity) until exhaustion for 2 runs while breathing normoxic (NO, 21% O(2)) or hyperoxic (HO, 26% O(2)) gas. Jugular blood was sampled at 15 s intervals to measure plasma lactate concentration. Horses also ran at incremental submaximal speeds from 1.7-11.0 m/s to determine the linear relationship between speed and O(2) consumption to estimate O(2) demand for AOD calculations. RESULTS: Maximum O(2) consumption of horses increased 11.6 ± 2.3% in HO and NAEU(PLAR) and NAUE(AOD) decreased 38.5 ± 8.0% and 46.2 ± 17.7%, respectively. The NAEU(PLAR) in NO was 114.5 ± 27.4 mlO(2) (STPD) equivalent/kg bwt contributing 23.5 ± 3.7% to total energy turnover and in HO was 70.9 ± 19.8 mlO(2) (STPD) equivalent/kg bwt contributing 14.6 ± 3.8% to total energy turnover. The NAUE(AOD) in NO was 88.6 ± 24.3 mlO(2) (STPD) equivalent/kg bwt contributing 19.9 ± 2.1% to total energy turnover and in HO was 56.2 ± 19.1 mlO(2) (STPD) equivalent/kg bwt contributing 10.9 ± 4.3% to total energy turnover. Overall, NAEU(AOD) was systematically biased -23.5 ± 16.8 mlO(2) (STPD) equivalent/kg bwt below NAEU(PLAR). Total energy demand estimated by PLAR was 11.1 ± 5.4% greater than that estimated by AOD and was higher in every horse. CONCLUSIONS: The NAUE(PLAR) estimates average 40.0 ± 29.6% higher than NAUE(AOD) and are highly correlated (r(2) = 0.734), indicating both indices are sensitive to similar changes in NAEU. Accuracy of the estimates remains to be determined. Multiple considerations suggest NAUE(AOD) may underestimate total energy cost during high-speed galloping, thus biasing low the AOD estimate of NAEU.

Use of an implantable transducer to measure force in the superficial digital flexor tendon in horses at walk, trot and canter on a treadmill.

REASONS FOR PERFORMING STUDY: Although the main cause of injury to the superficial digital flexor tendon (SDFT) is assumed to be high intensity loading of the tendon, to date the forces exerted on the SDFT during cantering have never been measured. OBJECTIVE: To measure the force exerted on the SDFT at walk, trot and canter on a treadmill. METHODS: Arthroscopically implantable force probes (AIFP) were implanted in the SDFT of the left and right forelimbs of 8 Thoroughbred horses (480-565 kg). The output of the AIFP was calibrated using the SDFT force calculated by inverse dynamics and an in vitro model of the lower forelimb at trot. The AIFP output was recorded at 1000 Hz at the walk, trot and canter (9 m/s) on a flat treadmill. RESULTS: AIFP data were analysed successfully in 13 measurement sessions at the walk and trot, in the leading forelimb in 8 sessions at canter and in the trailing forelimb in 5 sessions at canter. The mean ± s.d. maximal force in the SDFT was 3110 ± 1787 N at the walk, 5652 ± 2472 N at the trot, 7030 ± 2948 N in the leading forelimb and 6453 ± 2940 N in the trailing forelimb at canter. CONCLUSIONS: The force in the SDFT increases with running speed from the walk to the canter. The force in the SDFT could not be measured at the gallop. Further study is needed to determine the force in the SDFT at high speed, because it is important for preventing injuries to the SDFT to limit overloading of this tendon.

Utilisation of the time constant calculated from heart rate recovery after exercise for evaluation of autonomic activity in horses.

REASONS FOR PERFORMING STUDY: Heart rate (HR) recovery immediately after exercise is controlled by autonomic functions and the time constant (T) calculated from HR recovery is thought to be an index of parasympathetic activity in man. OBJECTIVES: To investigate whether it is possible to evaluate autonomic function using the time constant in horses. METHODS: Five Thoroughbred horses were subjected to a standard exercise test. Following pre-medication with saline, atropine and/or propranolol, the horses ran for 2.5 min at a speed of 8 m/sec at a 10% incline and T was calculated from HR after the exercise. Secondly, 7 Thoroughbred horses were then trained for 11 weeks and T and maximal oxygen uptake (VO2max) measured at intervals of 1 or 2 weeks. In 6 horses, T with atropine pre-medication was also measured before and after the whole training period. Furthermore, the HR variability at rest was evaluated by power spectral analysis at intervals of 3 or 4 weeks. RESULTS: Time constant was increased by atropine and/or propranolol pre-medication, decreased with the progress of training and inversely correlated with VO2max during training (r = 0.43, P<0.005). Parasympathetic blockade significantly decreased T only after and not before, the training; however, T was lower in post training than in pretraining, irrespective of parasympathetic blockade. On the other hand, parasympathetic activity at rest was attenuated and sympathetic activity became predominant following the training. CONCLUSION: Heart rate recovery is affected by sympathetic withdrawal and parasympathetic reactivation in horses and suggests that physical training hastened HR recovery by improving the parasympathetic function after exercise with aerobic capacity. However, the effects of other factors need to be considered because the training effect appeared on T even under parasympathetic blockade. The parasympathetic activity at rest is in contrast to that after exercise, suggesting that T does not reflect parasympathetic activity at rest. POTENTIAL RELEVANCE: If demonstrated how HR recovery is controlled after exercise, its analysis will be important in the evaluation of physical fitness in horses.

Effect of detraining on cardiorespiratory variables in young thoroughbred horses.

REASONS FOR PERFORMING STUDY: Thoroughbred racehorses often experience interruptions to their training. Identifying the effects of these changes and how they alter athletic performance might provide an insight on to how to prevent these changes from occurring. HYPOTHESIS: Training and detraining young Thoroughbreds alters their aerobic capacities with correlated changes in circulatory capacities; if horses remained spontaneously active in a pasture during their detraining period, their decreases in aerobic capacity during detraining would be reduced. METHODS: We trained 6 Thoroughbred yearlings for 6 months using a conventional yearling race training programme. They were then detrained for 10 weeks with free range on pasture for 8 h/day and stall rest at night. Treadmill measurements of O2 transport variables were made before training (PRE), after training (TR) and after detraining (DT). A step-test protocol identified each horse's aerobic capacity (VO2max) and speed to attain it, and a steady-state run at VO2max was used to quantify 02 transport variables at each time period. RESULTS: The mass-specific and whole-body VO2max, cardiac output (Q) and stroke volume (Vs) increased from PRE to TR. All mass-specific values decreased significantly from TR to DT; however, because body mass increased by 8.3% from TR to DT, none of the variables changed significantly from TR to DT on a whole-body basis. CONCLUSIONS: Changes in aerobic capacity are highly correlated with changes in Vs and circulatory capacity during training and detraining. Exercise activity of trained young horses free at pasture for 8 h/day is sufficient to maintain VO2max, (Q and Vs during 10 weeks of DT. POTENTIAL RELEVANCE: Aerobic and cardiovascular fitness may be maintained in young Thoroughbred horses during at least 10 weeks of detraining by maintaining modest spontaneous exercise activity.

Energetic cost of locomotion on different equine treadmills.

REASON FOR PERFORMING STUDY: Human athletes run faster and experience fewer injuries when running on surfaces with a stiffness 'tuned' to their bodies. We questioned if the same might be true for horses, and if so, would running on surfaces of different stiffness cause a measurable change in the amount of energy required to move at a given speed? HYPOTHESIS: Different brands of commercial treadmills have pans of unequal stiffness, and this difference would result in different metabolic power requirements to locomote at a given speed. METHODS: We tested for differences in stiffness between a Mustang 2200 and a Säto I commercial treadmill by incrementally loading each treadmill near the centre of the pan with fixed weights and measuring the displacement of the pan as weights were added or removed from the pan. We trained six 3-year-old Thoroughbreds to run on the 2 treadmills. After 4 months the horses ran with reproducible specific maximum rates of O2 consumption (VO2max/kg bwt, 2.62 +/- 0.23 (s.d.) mlO2 STPD/sec/kg) at 14.2 +/- 0.7 (s.d.) m/sec. They were alternately run on the 2 treadmills at identical grade (0.40 +/- 0.02%) and speeds (1.83 (walk), 4.0 (trot) and 8.0 (canter) m/sec, all +/- 0.03 m/sec) while wearing an open-flow mask for measurement of VO2. RESULTS: The Mustang treadmill was over 6 times stiffer than the Säto. The VO2/kg bwt increased by approximately 4-fold over the range of speeds studied on both treadmills. Oxygen consumption was significantly lower at all speeds for the Mustang treadmill compared to the Säto. The fractional difference in energy cost decreased by a factor of 6 with increasing speed, although absolute difference in cost was relatively constant. CONCLUSIONS: We suggest it costs less energy for horses to walk, trot or canter on a stiffer treadmill than on a more compliant treadmill, at least within the ranges of stiffness evaluated. POTENTIAL RELEVANCE: It may be possible to define a substrate stiffness 'tuned' to a horse's body enabling maximal energetic economy when running. The differences between treadmills allows more accurate comparisons between physiological studies conducted on treadmills of different stiffness, and might help to identify an ideal track stiffness to reduce locomotor injuries in equine athletes.

Method for quantifying net anaerobic power in exercising horses.

REASON FOR PERFORMING STUDY: There is no good method for measuring net anaerobic power in exercising horses to allow accurate estimates of total metabolic power. HYPOTHESIS: The increase in VO2max when breathing hyperoxic (HO) gas should be accompanied by a stoichiometrically equal (in terms of ATP turnover, i.e. energy equivalents) decrease in plasma lactate accumulation rate (Mlactate). METHODS: Six 3-year-old Thoroughbreds were trained on an equine treadmill wearing a semi-open flow mask for measurement of VO2. After 4 months the horses ran with reproducible specific VO2max (VO2max/kg bwt). The mask design allowed mixing of O2 or N2 with the inward bias flow of gas so that inspired O2 concentration of the horse could be controlled. While the horse breathed either HO (25.1% O2), normoxic (NO, 21% O2) or hypoxic (LO, 19.5% O2) gas, it ran at a speed sufficient to elicit VO2max in NO while jugular venous blood was drawn at 15 sec intervals over a period of 2 min to determine Mlactate. RESULTS: VO2max/kg bwt was not significantly different between LO and NO conditions, and LO data could not be used in the comparison. The VO2max/kg bwt increased from 2.59 +/- 0.24 (s.d.) to 2.86 +/- 0.24 mlO2 (STPD)/sec/kg in NO and HO, respectively, while Mlactate decreased from 11.5 +/- 4.2 to 9.0 +/- 3.9 mmol/min as VO2 increased. CONCLUSIONS: The ratio of delta Mlactate to delta VO2max/kg bwt suggests that Mlactate of approx 11.1 +/- 6.7 mmol/min is associated with net anaerobic power approximately equivalent to 1.0 mlO2 (STPD)/sec/kg of aerobic power (20.1 W/kg(-1)). The high variability in VO2max/kg bwt observed in data from some runs, particularly in LO, suggests that caution must be used when comparing data from the same horse during different runs. POTENTIAL RELEVANCE: This study provides a tool for estimating net anaerobic power and, more accurately, evaluating total metabolic power of horses exercising at or above their aerobic capacities.

Effect of amino acid and glucose administration following exercise on the turnover of muscle protein in the hindlimb femoral region of thoroughbreds.

REASONS FOR PERFORMING STUDY: In man, muscle protein synthesis is accelerated by administering amino acids (AA) and glucose (Glu), because increased availability of amino acids and increased insulin secretion, is known to have a protein anabolic effect. However, in the horse, the effect on muscle hypertrophy of such nutrition management following exercise is unknown. OBJECTIVES: To determine the effect of AA and Glu administration following exercise on muscle protein turnover in horses. We hypothesise that administration of AA and Glu after exercise effects muscle hypertrophy in horses, as already shown in man and other animals. METHODS: Measurements of the rate of synthesis (Rs) and rate of degradation (Rd) of muscle protein in the hindlimb femoral region of thoroughbred horses were conducted using the isotope dilution method to assess the differences between the artery and iliac vein. Six adult Thoroughbreds received a continuous infusion of L-[ring-2H5]- phenylalanine during the study, the stable period for plasma isotope concentrations (60 min), resting periods (60 min), treadmill exercise (15 min) and recovery period (240 min). All horses were given 4 solutions (saline [Cont], 10% AA [10-AA], 10% Glu [10-Glu] and a mixture with 10% AA and 10% Glu [10-Mix]) over 120 min after exercise, and the Rs and Rd of muscle protein in the hindlimb measured. RESULTS: The average Rs during the 75-120 min following administration of 10-Mix was significantly greater than for the other solutions (P<0.05). The second most effective solution was 10-AA, and there was no change in Rs after 10-Glu. CONCLUSIONS: Administration of AA following exercise accelerated Rs in the hindlimb femoral region, and this effect was enhanced when combined with glucose, because of increasing insulin secretion or a decreased requirement for AA for energy. POTENTIAL RELEVANCE: Further studies are required regarding the effect on muscle hypertrophy of supplementing amino acids and glucose in the feed of exercising horses.

Physiological responses of young Thoroughbreds during their first year of race training.

Yearling horses are typically trained for more than a year before they begin racing; therefore, we questioned how relevant analyses of the initial responses to training are compared to physiological responses that occur over a year of training, and whether young horses with no history of training would respond the same as older horses that had been trained previously. We hypothesised that changes in O2 transport over the last months of a year of training would be different than at the beginning. We trained 5 yearling Thoroughbreds and evaluated metabolism, O2 transport and echocardiograms. Measurements were made before breaking (T1), after 6 months of training (T2) and following an additional 4 months of training (T3). We compared 5 trained horses (TR) with 5 untrained (UT) sex-, size- and age-matched yearlings kept at pasture and in boxes. Satellite telemetry indicated UT moved less total daily distance than TR during winter and more during summer, but UT walked for 80% of their distance, TR only 25%. The UT increased body mass (Mb) after T1 by 13% and were significantly heavier and fatter than TR. Specific aerobic capacity (VO2max/Mb) increased by 16% in both groups at T2, but by T3 was not different from T1 in UT, but was higher in TR (19%>T1, 15%>UT). In TR, specific cardiac output (Q/Mb) increased by 13% at T2, and specific stroke volume (V(S)/Mb) were larger at T2 and T3 than T1 and UT at the same times both by physiological (15-16%) and echocardiographical (22-23%) estimates. Increased Vs was a primary correlate of the sustained increase in VO2max/Mb in TR. The large increases in V(S) and VO2max had occurred by T2 and changed only slightly by T3.

Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies.

Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with hematological malignancies receiving chemotherapy. We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase >ten times the normal upper limit and total bilirubin >5 mg/dl) during chemotherapy in 268 patients with hematological malignancies. Eight patients (3.0%) were infected with HBV and 22 patients (8.2%) were infected with HCV. One patient (0.4%) was infected with both HBV and HCV. HBV- or HCV-infected patients showed severe liver dysfunction at a significantly higher incidence than non-infected patients (11/31 (35.5%) vs. 0/237 (0%), p<0.0001). Furthermore, the incidence of severe liver dysfunction in HBV-infected patients was significantly higher than in HCV-infected patients (6/8 (75.0%) vs. 4/22 (18.2%), p<0.01). Three of eight HBV-infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV-DNA by polymerase chain reaction (PCR). Although post-transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Since HBV-infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV-infected patients before chemotherapy for hematological malignancies, it is recommended that HBV-DNA should be tested by PCR to detect HBV marker-negative carriers and liver function tests should be carefully monitored.

Determination of oral dosage and pharmacokinetic analysis of flecainide in horses.

To determine oral dosage and to evaluate the pharmacokinetics in horses of orally administered flecainide, an antiarrhythmic drug, the correlations between its plasma concentration and PR, QRS and QT intervals in equine electrocardiograms (ECG) were investigated. Six healthy horses were administered a randomly ordered dose of 4 or 6 mg/kg of flecainide acetate. The ECG was monitored (heart rate (HR), PR, QRS, and QT intervals) and blood was taken at timed intervals to measure the plasma flecainide concentrations pre- and post-administration. The maximum plasma concentration reached 1014+/-285 (SD) ng/m/ in 45+/-13 min and 1301+/-400 ng/ m/l in 60+/-37 min for doses of 4 and 6 mg/kg flecainide, respectively. From the pharmacokinetic analysis, clearance rates were 14.6+/-6.4 and 11.7+/-5.2 ml/kg/min and terminal elimination half-lives were 228+/-53 and 304+/-87 min. The QRS and QT intervals increased significantly for both doses following administration, though HR and PR intervals did not change. Plasma flecainide concentrations were significantly correlated with QRS (r=0.935, P<0.001) and QT intervals (r=0.753, P<0.001). In conclusion, plasma concentrations of flecainide for treating equine atrial fibrillation were obtained by oral administration of 4 and 6 mg/kg, and the drug was rapidly eliminated from plasma in horses.

Asymmetric catalytic ene-cyclization approach to 2-fluoro-19-nor-1,25-dihydroxyvitamin D(3) A-ring analog with significant transactivation activity.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)2D3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for the treatment of cancer and psoriasis. However, little information has been available on the binding conformation of the 1alpha,25(OH)2D3 molecule and its analogs with the vitamin D receptor (VDR). Therefore, we synthesized 2alpha-fluorinated A-ring analogs of 19-nor-1alpha,25(OH)2D3 in order to investigate the VDR-binding conformation of the A-rings on the basis of the (19)F NMR analysis. The 2alpha-fluoro-19-nor-1alpha,25-dihydroxyvitamin D3 A-ring analog thus synthesized via a asymmetric catalytic carbonyl-ene cyclization, shows significant activity in transactivation.

Frequency of and risk factors for epistaxis associated with exercise-induced pulmonary hemorrhage in horses: 251,609 race starts (1992-1997).

OBJECTIVE: To determine the frequency of epistaxis during or after racing among racehorses and identify factors associated with development of epistaxis. DESIGN: Retrospective study. SAMPLE POPULATION: 247,564 Thoroughbred and 4,045 Anglo-Arab race starts. PROCEDURE: Race start information (breed, age, sex, racing distance, and race type) was obtained for Thoroughbred and Anglo-Arab horses racing in Japan Racing Association-sanctioned races between 1992 and 1997. All horses that raced were examined by a veterinarian within 30 minutes of the conclusion of the race; any horse that had blood at the nostrils was examined with an endoscope. If blood was observed in the trachea, epistaxis related to exercise-induced pulmonary hemorrhage (EIPH) was diagnosed. RESULTS: Epistaxis related to EIPH was identified following 369 race starts (0.15%). Frequency of EIPH-related epistaxis was significantly associated with race type, age, distance, and sex. Epistaxis was more common following steeplechase races than following flat races, in older horses than in horses that were 2 years old, following races < or =1,600 m long than following races between 1,601 and 2,000 m long, and in females than in sexually intact males. For horses that had an episode of epistaxis, the recurrence rate was 4.64%. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that frequency of EIPH-related epistaxis in racehorses is associated with the horse's age and sex, the type of race, and the distance raced. The higher frequency in shorter races suggests that higher intensity exercise of shorter duration may increase the probability of EIPH.

Potentially protective effects of the Ser447-Ter mutation of the lipoprotein lipase gene against the development of coronary artery disease in Japanese subjects via a beneficial lipid profile.

Several DNA variants at the lipoprotein lipase (LPL) gene locus have been found to be associated with the plasma lipid levels and the prevalence of coronary artery disease (CAD). In particular, the Ser447-termination (Ter) mutation at the exon 9 of the LPL gene has the potential to elevate the plasma high-density lipoprotein (HDL) levels, but it remains unknown in the Japanese population. The present study investigated 93 CAD patients and 96 age- and sex-matched healthy controls. The Ser447-Ter mutation was determined by polymerase chain reaction restriction fragment length polymorphism method. The allelic frequency of the Ser447-Ter mutation was 0.103 in all subjects. The Ser447-Ter (GG and CG) group was associated with significantly higher levels of plasma HDL-cholesterol (p<0.001) and lower levels of plasma triglyceride than the CC group (p<0.02). The peak particle size of low-density lipoprotein (LDL) was significantly larger in the Ser447-Ter (GG and CG) group than in CC group (p<0.05). The frequency of the Ser447-Ter genotype in GG and CG was significantly lower in CAD than in the controls (11.9% vs 26%, odds ratio = 0.38; 95% confidence interval, 0.18-0.81; p<0.02). These results suggest that the Ser447-Ter mutation of the LPL gene is associated with high plasma HDL-cholesterol levels, low plasma triglyceride levels and a larger LDL particle size. This mutation may have a protective effect against the development of CAD via its favorable lipoprotein profile.

Effects of repeated atropine injection on heart rate variability in Thoroughbred horses.

To investigate the effects of repeated atropine injection on heart rate (HR) variability in resting Thoroughbred horses, two microg/ kg of atropine as parasympathetic nervous blockade was injected intravenously every 6 min to a total of 8 microg/kg after intravenous administration of 0.2 mg/kg of propranolol as sympathetic nervous blockade. We recorded electrocardiograms and obtained the HR, then evaluated variation in HR from the power spectrum in terms of low frequency (LF, 0.01-0.07 Hz) power and high frequency (HF, 0.07-0.6 Hz) power. Administration of atropine decreased parasympathetic nervous activity in a dose-dependent manner, affecting first the LF power, then the HF power and finally HR. These responses may provide valuable information for evaluating autonomic nervous activity in Thoroughbred horses.

Safe and efficacious dosage of flecainide acetate for treating equine atrial fibrillation.

To determine a safe and efficacious dose of flecainide acetate for treating equine atrial fibrillation (Af), the safe dosage level was determined by injecting 1, 2, or 3 mg/kg i.v. of 1% flecainide acetate solution at a rate of 0.2 mg/kg/min to five clinically healthy horses. Clinical signs and the ECG were monitored (HR, PR, QRS, and QT intervals) and blood was taken to measure the plasma flecainide concentration pre- and post-administration. No abnormal signs were observed in the 1- or 2-mg/kg groups, while agitation was observed in three of five horses in the 3-mg/kg group. The QRS, and QT intervals for the 3-mg/kg group increased significantly. The peak plasma flecainide concentrations were 1.316 +/- 358 (SD) ng/ml, 1,904 +/- 314 ng/ml, and 2,251 +/- 387 ng/ml for the 1-, 2-, and 3-mg/kg groups, respectively. To evaluate the efficacy of flecainide, Af was induced by right atrial pacing in six clinically healthy horses, and 1% flecainide acetate solution was then administered until they converted to sinus rhythm. All horses with induced Af converted. For the conversion, a total dose of 1.40 +/- 0.63 mg/kg flecainide was required, the duration of administration was 7.00 +/- 3.15 min and plasma flecainide concentration at conversion was 1,303 +/- 566 ng/ml. In conclusion, flecainide acetate is a safe and effective antiarrhythmic agent for equine Af, and the clinically effective dosage is 1 to 2 mg/kg.

Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance.

Insulin resistance is associated with atherogenic lipoprotein phenotype, including small dense LDL particle, hypertriglycemia and low HDL cholesterol levels. Troglitazone, a novel insulin sensitizing agent, may improve the associated lipid profile in patients with insulin resistance. We examined the effects of troglitazone (400 mg daily for 12 weeks) in 12 non-diabetic coronary patients (60+/-10 years), all of whom had hyperinsulinemic response to an oral glucose load. Troglitazone markedly reduced the insulin response. After the treatment, plasma triglycerides decreased by 32% (P<0.05), HDL cholesterol increased by 11%, (P<0.05) and LDL peak particle diameter increased from 24.7+/-0.3 to 25.5+/-0.5 nm (P<0.01). These lipidic improvements were associated with a significant rise in postheparin lipoprotein lipase levels (175+/-52 to 217+/-69 ng/ml, P<0.01). In patients with insulin resistance syndrome, troglitazone improved the atherogenic lipoprotein phenotype as well as hyperinsulinemia. Our data suggest that troglitazone therapy could reduce the atherosclerotic risk due to insulin resistance even in non-diabetic patients.

Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm.

Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.