Anesthetized Beagle Dogs Research Articles

Evaluation of a novel, low-cost, 3D printed video laryngoscope with borescope in anesthetized Beagle dogs

ObjectiveTo develop and evaluate a low-cost three-dimensional (3D)-printed video laryngoscope (VLVET) for use with a commercial borescope. Study designInstrument development and pilot study. AnimalsA total of six adult male Beagle dogs. MethodsThe VLVET consisted of a laryngoscope handle and a Miller-type blade, and a detachable camera holder that attached to various locations along the blade. The laryngoscope and camera holder were 3D-printed using black polylactic acid filament. Dogs were premedicated with intravenous (IV) medetomidine (15 μg kg−1) and anesthesia induced with IV alfaxalone (1.5 mg kg−1). The VLVET, combined with a borescope, was used for laryngeal visualization and intubation. Performance was evaluated by comparing direct and video-assisted views in sternal recumbency. The borescope camera was sequentially positioned at 2, 4, 6, 8 and 10 cm from the blade tip (distanceLARYNX-CAM), which was placed on the epiglottis during intubation or laryngoscopy. At the 10 cm distanceLARYNX-CAM, laryngeal visualization was sequentially scored at inter-incisor gaps of 10, 8, 6, 4 and 2 cm. Laryngeal visualization scores (0–3 range, with 0 = obstructed and 3 = unobstructed views) were statistically analyzed using the Friedman’s test. ResultsUnder direct visualization, the 2 cm distanceLARYNX-CAM had a significantly lower score compared with all other distanceLARYNX-CAM (all p = 0.014) because the view was obstructed by the camera holder and borescope camera. With both direct and camera-assisted views, visualization scores were higher at inter-incisor gaps ≥ 4 cm compared with 2 cm (all p < 0.05). Conclusions and clinical relevanceDuring laryngoscopy and intubation, the VLVET and borescope facilitated both direct and video laryngoscopy at distanceLARYNX-CAM in Beagle dogs when inter-incisor gaps were ≥ 4 cm.

Cardiopulmonary and recovery effect of intravenous caffeine in anesthetized Beagle dogs

Cardiopulmonary and recovery effect of intravenous caffeine in anesthetized Beagle dogs

The impact of anaphylaxis on the absorption of intranasal epinephrine in anaesthetized non-naive beagle dogs.

Epinephrine delivery via an intranasal spray (neffy) is being evaluated as an additional option to treat severe allergic reaction and may provide clinical benefit by reducing the time to dosing in community settings by avoiding needles. Given that hypotension is a hallmark symptom of severe allergic reactions, a preclinical study was conducted to evaluate the impact of this factor on epinephrine absorption via neffy. The objective of this study was to evaluate the absorption of epinephrine via neffy in a dog model of anaphylaxis with severe hypotension. Epinephrine absorption via neffy was evaluated in anesthetized beagle dogs under both normal conditions and hypotension associated with anaphylaxis. Atotal of 14 dogs (10 males and 4 females) were dosed with neffy, 1.0 mg, under normal conditions, followed by neffy, 1.0 mg, under conditions of anaphylaxis. The mean maximum concentration of epinephrine was higher during anaphylaxis than under normal conditions (2,670± 2,150 pg/mL and 1,330± 739 pg/mL [P< .05]). Relative to normal conditions, anaphylaxis resulted in higher overall epinephrine exposure (area under the curve from 0 to 45 minutes= 54,400± 18,100 min×pg/mL and 34,300± 21,500 minutes×pg/mL [P< .05]), which is likely due to the increase in vascular permeability commonly observed during severe allergic reactions. Taken together with real-world evidence from nasal naloxone treatment for opioid overdose demonstrating that the reduced blood flow or hypotension associated with overdose does not appear to suppress naloxone's efficacy, the current findings demonstrate that epinephrine is well absorbed following neffy delivery during the hypotension associated with severe anaphylaxis reactions.

Volumetric evaluation of fluid responsiveness using a modified passive leg raise maneuver during experimental induction and correction of hypovolemia in anesthetized dogs

ObjectiveTo demonstrate if modified passive leg raise (PLRM) maneuver can be used for volumetric evaluation of fluid responsiveness (FR) by inducing cardiac output (CO) changes during experimental induction and correction of hypovolemia in healthy anesthetized dogs. The effects of PLRM on plethysmographic variability index (PVI) and pulse pressure variation (PPV) were also investigated. Study designProspective, crossover study. AnimalsA total of six healthy anesthetized Beagle dogs. MethodsDogs were anesthetized with propofol and isoflurane. They were mechanically ventilated under neuromuscular blockade, and normothermia was maintained. After instrumentation, all dogs were subjected to four stages: 1, baseline; 2, removal of 27 mL kg–1 circulating blood volume; 3, after blood re-transfusion; and 4, after 20 mL kg–1 hetastarch infusion over 20 minutes. A 10 minute stabilization period was allowed after induction of each stage and before data collection. At each stage, CO via pulmonary artery thermodilution, PVI, PPV and cardiopulmonary variables were measured before, during and after the PLRM maneuver. Stages were sequential, not randomized. Statistical analysis included repeated measures anova and Tukey’s post hoc test, considering p < 0.05 as significant. ResultsDuring stage 2, PLRM at a 30° angle significantly increased CO (mean ± standard deviation, 1.0 ± 0.1 to 1.3 ± 0.1 L minute–1; p < 0.001), with a simultaneous significant reduction in PVI (38 ± 4% to 21 ± 4%; p < 0.001) and PPV (27 ± 2% to 18 ± 2%; p < 0.001). The PLRM did not affect CO, PPV and PVI during stages 1, 3 and 4. Conclusions and clinical relevanceIn anesthetized dogs, PLRM at a 30° angle successfully detected FR during hypovolemia, and identified fluid nonresponsiveness during normovolemia and hypervolemia. Also, in hypovolemic dogs, significant decreases in PVI and PPV occurred in response to PLRM maneuver.

Utility of Real-Time Three-Dimensional Echocardiography for the Assessment of Right Ventricular Morphology and Function in Large Animal Models.

Real-time three-dimensional echocardiography (RT3DE) enables a noninvasive assessment of right ventricular (RV) morphology. However, no study has evaluated the relationship between RV function obtained by RT3DE and RV pressure-volume loops. This hypothesis-driven, experimental study aimed to assess the utility of RT3DE in the evaluation of RV morphology and function. Ten anesthetized beagle dogs sequentially underwent dobutamine infusion, acute infusion of lactated Ringer’s solution, and furosemide administration to alter RV contractility and loading conditions. RV pressure-volume loop-derived hemodynamic measurements and echocardiography, including two-dimensional speckle-tracking echocardiography and RT3DE, were performed in each study protocol. Bland–Altman analysis showed strong agreement in RV volume, ejection fraction, and stroke volume obtained by right heart catheterization and RT3DE. Multiple regression analyses revealed that the peak myocardial velocity of the lateral tricuspid annulus (RV s’) and global RV longitudinal strain rate were significantly associated with end-systolic elastance (adjusted r2 = 0.66, p < 0.001). RV s’, RV free wall longitudinal strain, and RT3DE-derived stroke volume/end-systolic RV volume ratio were associated with RV pressure-volume loops-derived end-systolic/arterial elastance ratio (adjusted r2 = 0.34, p < 0.001). RT3DE could detect the changes in catheterization-derived RV volume with a strong agreement and might be useful in estimating RV-pulmonary arterial coupling.

Evaluation of the use of various formula for correction of the QT interval (QTc) and ECG reference intervals in anesthetized beagle dogs

Evaluation of the use of various formula for correction of the QT interval (QTc) and ECG reference intervals in anesthetized beagle dogs

Evaluation of the tongue for oscillometric measurement of arterial pressure in anesthetized Beagle dogs

ObjectiveTo evaluate the agreement between oscillometric blood pressure (OBP) measured from the tongue and invasive blood pressure (IBP), and to compare OBPs measured from the tongue with OBPs measured from the pelvic limb and tail. Study designProspective experimental study. AnimalsA total of eight adult Beagle dogs weighing 11.1 ± 1.2 kg. MethodsAnimals were premedicated with intravenous (IV) acepromazine (0.005 mg kg–1). Anesthesia was induced with alfaxalone (3 mg kg–1) IV and maintained with isoflurane. The dorsal pedal artery was catheterized for IBP measurements. Systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressure were simultaneously measured from the tongue, pelvic limb and tail. Based on invasive SAP, hypertension (>140 mmHg), normotension (90–140 mmHg) and hypotension (<90 mmHg) were induced by controlling end-tidal isoflurane concentrations and/or dobutamine/dopamine administration. Agreement between paired IBP and OBP measurements was analyzed with reference standards for noninvasive blood pressure devices used in small animals and humans. ResultsRegardless of cuff placement, the mean bias ± standard deviation between IBP and OBP met veterinary (≤10 ± 15 mmHg) and human (<5 ± 8 mmHg) standards for MAP and DAP. SAP measurements provided by the OBP device showed unacceptable agreement with IBP, and the bias between methods increased at higher blood pressures, regardless of cuff site. During hypotension, tongue OBP showed the largest percentage of absolute difference <10 mmHg in relation to IBP for SAP (90%), MAP (97%), and DAP (93%), compared with pelvic limb (60%, 97% and 82%, respectively) and tail OBP (54%, 92% and 77%, respectively). Conclusions and clinical relevanceThe tongue is a clinically useful site for measuring OBP in anesthetized Beagle dogs, providing reliable estimates of MAP and DAP. The tongue could replace other cuff placement sites and may be a relatively suitable site for assessing hypotension.

The effects of maxillary nerve block, ethmoidal nerve block and their combination on cardiopulmonary responses to nasal stimulation in anesthetized Beagle dogs

ObjectiveTo describe an approach for ethmoidal nerve block (EBLOCK) and to compare the effects of a maxillary nerve block (MBLOCK), EBLOCK and their combination (M-EBLOCK) on heart rate (HR), systolic (SAP), mean (MAP), diastolic (DAP) arterial pressures and respiratory rate (fR) during nasal stimulation in dogs. Study designProspective, blinded, randomized, crossover placebo-controlled study. AnimalsBeagle dogs (five cadavers, nine live dogs), with a median (interquartile range) weight of 10.5 (10.3–11.0) kg. MethodsThe accuracy of iohexol injections (each 1 mL) at the maxillary and ethmoidal foramina in cadavers was evaluated using computed tomography. Then, anesthetized dogs were administered four bilateral treatments separated by 1 week, saline or 2% lidocaine 1 mL per injection: injections of saline at the maxillary and ethmoidal foramina (Control), injections of lidocaine at the maxillary foramina and saline at the ethmoidal foramina (MBLOCK), injections of saline at the maxillary foramina and lidocaine at the ethmoidal foramina (EBLOCK) and injections of lidocaine at all foramina (M-EBLOCK). The ventral nasal meatus was bilaterally stimulated using cotton swabs, and HR, SAP, MAP, DAP and fR were continuously recorded. Values for each variable were compared before and after stimulation using Wilcoxon signed-rank test. Changes in variables among treatments were analyzed using Mann–Whitney U and Kruskal–Wallis tests (p ≤ 0.05). ResultsComputed tomography revealed iohexol distribution around the openings of the target foramina in all cadavers. In living dogs, HR, SAP, MAP, DAP and fR significantly increased after stimulation within each treatment (p < 0.03). Physiologic responses were significantly attenuated, but not absent, in the M-EBLOCK [HR (p = 0.019), SAP, MAP, DAP and fR (all p ≤ 0.001)] compared with those in the Control. Conclusions and clinical relevanceConcurrent injections of lidocaine at the maxillary and ethmoidal foramina attenuated HR, arterial pressure and fR responses to nasal stimulation in Beagle dogs.

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Indole alkaloids extract (IAAS) was prepared from leaves of Alstonia scholaris (L.) R. Br., an evergreen tropical plant widely distributed throughout the world. This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases. This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use. The bacterial reverse mutation (Ames) test, in vitro mammalian chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus (MN) test were performed to evaluate genotoxicity. Mice were administered IAAS (240, 480, or 960 mg/kg bw) once orally to observe adverse central nervous system effects. Furthermore, beagle dogs were administered IAAS (10, 30, 60 mg/kg bw) once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems. IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500 μg/plate, in the mammalian chromosomal aberration test up to 710 μg/mL, or in the MN test up to 800 mg/kg bw. No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS. Moreover, blood pressure, heart rate, electrocardiogram parameters, and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group. These data indicated that IAAS did not induce mutagenicity, clastogenicity, or genotoxicity, and no pharmaco-toxicological effects were observed in the respiratory, cardiovascular, or central nervous systems. Our results increased understanding of safety considerations associated with IAAS, and may indicate that IAAS is a possible drug candidate.Graphic

Simultaneous Quantitation of a Novel α₁/β₁-Blocker TJ0711 and Its Two Metabolites in Dog Plasma Using LC-MS/MS and Its Application to a Pharmacokinetic Study after Intravenous Infusion.

TJ0711∙HCl, which is a novel α1/β1 adrenoceptor blocking agent with a ratio of 1:1 for α1/β1, is designed to treat and prevent perioperative hypertension. M1 and M3 were identified as important metabolites in vitro for either antihypertension activity or the major metabolite production. In order to obtain a pharmacokinetic profile of both TJ0711 and its metabolites, a rapid, selective, and reliable LC-MS/MS method was developed and validated for simultaneous determination of TJ0711 and two metabolites in beagle dog plasma via efficiently separating two interferential metabolites M16 and M4 from M1 and M3, respectively. Chromatographic separation was achieved on a Waters CORTECS C18+ column (2.1 × 100 mm, 2.7 μm). The mass spectrometric detection was carried out in positive ion MRM mode with ESI+ source. Protein precipitation was used in sample preparation and provided good recovery without a matrix effect. Good linearity was observed at the ranges of 0.5–100 ng/mL for TJ0711 and M3, 0.1–20 ng/mL for M1. Additional validation results were within the acceptance limits followed U.S. FDA guidelines for bioanalytical method validation. This method was successfully applied to an intravenous infusion pharmacokinetic study of TJ0711 at dosing rates of 3, 6, and 12 µg/kg/min in anesthetized beagle dogs for the first time. TJ0711 and its two metabolites exhibited effective proportionality in the dosage of 3 to 12 µg/kg/min. Neither TJ0711 nor its metabolites showed significant differences in pharmacokinetic parameters such as t1/2, CL, and Vss among three dose groups.

Effect of ethmoidal versus maxillary nerve block for nasal sensation in anesthetized Beagle dogs

Effect of ethmoidal versus maxillary nerve block for nasal sensation in anesthetized Beagle dogs

Changes in endotracheal tube intracuff pressure and air leak pressure over time in anesthetized Beagle dogs

ObjectiveTo evaluate endotracheal tube intracuff pressure (Pcuff) changes over time and the effect of these changes on air leak pressure (Pleak). Study designProspective experimental study. AnimalsA group of nine healthy adult Beagle dogs. MethodsIn part I, in vitro measurements of Pcuff were recorded for 1 hour in eight endotracheal tubes subjected to four treatments: room temperature without lubricant (RT0L), room temperature with lubricant (RTWL), body temperature without lubricant (BT0L), and body temperature with lubricant (BTWL). In part II, nine dogs were endotracheally intubated and Pleak was evaluated at Pcuff of 25 mmHg. Subsequently, Pcuff was reset to 25 mmHg (baseline) and Pcuff measurements were recorded every 5 minutes for 1 hour. Subsequently, a second Pleak measurement was recorded at the current Pcuff. The data were analyzed using Wilcoxon signed-rank test, repeated measures anova and Mann–Whitney U test. ResultsIn part I, Pcuff differed significantly between the RT0L and RTWL treatments at 5–60 minutes, and between the BT0L and BTWL treatments at 5–35, 55 and 60 minutes (p < 0.05). In part II, compared with baseline pressures, mean Pcuff decreased to <18 mmHg at 10 minutes and significant decreases were recorded at 15–60 minutes (Pcuff range: 10.0 ± 4.9 to 13.4 ± 6.3 mmHg, mean ± standard deviation). Significant differences were observed between the first and second Pleak measurements (p = 0.034). Pleak decreased in six of nine dogs, was not changed in two dogs and increased in one dog. Conclusions and clinical relevanceSignificant decreases in Pcuff over time were measured. Pleak may decrease during anesthesia and increase the risk for silent pulmonary aspiration. The results indicate the need for testing Pcuff more than once, especially at 10 minutes after the onset of anesthesia.

Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs

Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs.

Contrast enhanced ultrasonography of kidney in conscious and anesthetized beagle dogs.

Contrast enhanced ultrasound (CEUS) is useful to evaluate tissue perfusion in the kidney. In veterinary medicine, sedation or anesthesia may be required in uncooperative or panting patients. The aim of this study was to evaluate and compare the normal kidney perfusion patterns in conscious and anesthetized dogs using CEUS. Eight healthy beagles were used in this study. Scanning was performed in conscious dogs using manual restraint (conscious group), or under general anesthesia using tiletamine-zolazepam and medetomidine (TZM group) or medetomidine (M group). The contrast agent (Sonovue®) was administered as an IV bolus. The peak intensity (PI), time to peak enhancement from injection (TTP0) and the time to peak enhancement from the initial rise (TTPup), upslope, downslope and area under the curve (AUC) were analyzed. Compared to the cortical values in the conscious group, TTP0 was significantly delayed in the TZM group, and upslope, TTP0 and TTPup were significantly different in the M group. The AUCs in the TZM and M groups were not different from those in the conscious group. The upslope of renal medullary perfusion was significantly decreased in the TZM and M groups. TTP0 and TTPup were also significantly delayed in these groups. The AUC of the medulla was significantly decreased in the M group. Therefore, TZM is useful as an anesthetic protocol when performing CEUS, and the obtained data may serve as reference values in the evaluation of renal perfusion using CEUS in dogs under anesthesia.

Differences between acceleromyography and electromyography during neuromuscular function monitoring in anesthetized Beagle dogs

ObjectiveQuantitative neuromuscular monitoring is essential for studies of potency and duration of neuromuscular blocking agents, and for detecting residual paralysis in anesthetized patients. This investigation evaluates whether there are systematic differences between acceleromyography (AMG) and electromyography (EMG); two quantitative methods for monitoring neuromuscular block. Study designProspective. AnimalsTen healthy Beagle dogs. MethodsDogs were anesthetized with isoflurane and dexmedetomidine. Both ulnar nerves were stimulated with a train-of-four (TOF) pattern every 15 seconds. The magnitude of the first twitch (T1) and the TOF ratio (magnitude of T4/T1; TOFR) were quantified simultaneously with AMG and EMG, applied randomly to each extremity. The extent of maximal block (T1 depression) and onset time were measured by AMG and EMG during TOF monitoring after the administration of cisatracurium (0.05 mg kg−1). In addition, recovery of T1 to 25% and 75%, the recovery index (time between T1 of 25% and 75%), and recovery of the TOFR to 0.9 were used to characterize recovery from cisatracurium and were compared between monitors. Regression and Bland-Altman plots for T1 and TOFR were also created. ResultsMaximal block and onset time were not different between monitors. Time to recovery of T1 to 25% and 75%, and time to TOF ratio 0.9 was significantly shorter with AMG. The recovery index was not different between monitors. When the TOFR returned to 0.9 with AMG, EMG still measured considerable residual block (TOFR 0.47). Conclusions and clinical relevanceElectromyography consistently detected residual NMB when recovery from NMB was complete as assessed by AMG.

Guiding intramuscular diaphragm injections using real‐time ultrasound and electromyography

We describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals. Ultrasound was used to visualize the diaphragm on each side of spontaneously breathing, anesthetized beagle dogs and cynomolgus macaques. An electromyography (EMG) needle was introduced and directed by ultrasound to confirm that the needle entered the muscular portion of the diaphragm, and methylene blue was injected. Injection accuracy was confirmed upon necropsy by tracking the spread of methylene blue. All methylene blue injections were confirmed to have been placed appropriately into the diaphragm. This study demonstrates the feasibility and accuracy of using ultrasound and EMG to guide injections and to reduce complications associated with conventional blind techniques. Ultrasound guidance can be used for clinical EMG of the diaphragm. Future applications may include targeted diaphragm injections with gene replacement therapy in neuromuscular diseases.

Interventricular Differences in β‐Adrenergic Responses in the Canine Heart: Role of Phosphodiesterases

BackgroundRV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β‐adrenergic (β‐AR) responsiveness is unknown. In this study, we examine whether β‐AR response and signaling differ in right (RV) versus left (LV) ventricles.Methods and ResultsSarcomere shortening, Ca2+ transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRET‐based sensors. Isoproterenol increased sarcomere shortening ≈10‐fold and Ca2+‐transient amplitude ≈2‐fold in LV midmyocytes (LVMs) versus ≈25‐fold and ≈3‐fold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2‐fold higher β‐AR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, β‐AR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the β‐AR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmax≈5‐fold versus 3‐fold in LV.ConclusionCanine RV and LV differ in their β‐AR response due to intrinsic differences in myocyte β‐AR downstream signaling. Enhanced β‐AR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV.

Comparison of invasive and noninvasive blood pressure measurements in the anesthetized beagle dog

Comparison of invasive and noninvasive blood pressure measurements in the anesthetized beagle dog

Negative impact of melatonin ingestion on the photopic electroretinogram of dogs

Melatonin follows a circadian rhythm entrained by the light/dark cycle and plays a role in promoting light sensitivity at night. It has been suggested that melatonin and dopamine reciprocal inhibition may contribute to the switch between day and night vision. The purpose of this study was to investigate the impact of a high dose of melatonin administration on the photopic and scotopic electroretinogram (ERG) of dogs in the daytime, when it is not thought to be present. Photopic and scotopic ERG luminance response functions were obtained from 7 anaesthetized beagle dogs (3 males and 4 females), once without melatonin (control) and once after oral administration of melatonin (90mg/dog). Vmax (maximal b-wave amplitude achieved) and logK (retinal sensitivity) were calculated from the derived luminance response function. Photopic flicker ERG was also recorded. In photopic condition, a-wave amplitude (control: −126.90μV; with melatonin: −49.64μV; p<0.001) and Vmax (control: 252.50μV; with melatonin: 115.40μV; p<0.001) were decreased. A significant reduction of the photopic flicker ERG amplitude was observed after melatonin ingestion. In scotopic condition, an overall difference was reported before and after melatonin ingestion for the a- and b-wave amplitude, but no change was significant for Vmax. Melatonin ingestion at a high dose during the day decreases the photopic amplitude of a- and b-wave, but has no impact on implicit time. This negative impact of melatonin on photopic system may serve to promote night vision.

Effects of AL 107, a novel semisynthetic cardiac glycoside, on the cardiovascular system in anaesthetized beagle dogs with pentobarbital-induced cardiac insufficiency.

The inotropic efficacy, arrhythmogenicity and cardiohaemodynamic properties of AL 107 (3-alpha-methyl-digitoxigenin glucoside, CAS 62190-59-4), a novel cardiac glycoside, were studied in anaesthetized dogs with pentobarbital-induced acute cardiac insufficiency. Three groups of dogs received AL 107, ouabain or verhicle. The cardiac glycosides were infused intravenously in eight increasing dose levels which where given cumulatively. Slope of left ventricular pressure rise (LVdp/dtmax) increased in the AL 107- and ouabain-treated groups. At the end of the 6th dose level ouabain caused a significantly higher LVdp/dtmax (137 +/- 15% of the baseline value taken before induction of insufficiency) than AL 107 (94 +/- 9%). Further increase of the dose resulted in a reduction of LVdp/dtmax in ouabain-treated dogs, whereas AL 107 continuously increased LVdp/dtmax up to the highest dose infused, where 130 +/- 16% of the baseline value was reached. In ouabain-treated dogs, ECG abnormalities accompanied the decrease of LVdp/dtmax whereas ECG-changes did not interfere with the development of left ventricular contractility in AL 107-treated dogs. The 6th dose of ouabain provoked a maximal increase of cardiac output (CO) (up to 107 +/- 8% of baseline values) and stroke volume (SV) (up to 122 +/- 6% of baseline values) which decreased upon further dose elevation. In the dose-range studied AL-107 induced a continuous increase of both parameters which, however, hardly reached the baseline values. ECG abnormalities occurred in both substance-treated groups and showed quantitative but not qualitative differences. The ECG showed rapid recovery after cessation of AL 107 infusion but did not normalize during a postinfusional recovery period of 1 h after treatment with ouabain. In conclusion, AL 107 increased cardiac performance in an acute canine model of cardiac insufficiency. It was slightly less active than ouabain. However, the ECG disorders were more moderate in AL 107--than in ouabain-treated dogs, a difference which was most pronounced with respect to reversibility in the postinfusional period.