Efficacy of a mephentermine-based product as a vasopressor and a cardiac performance enhancer when given intramuscularly to cattle.

The goal of this study was to confirm the vasopressor and cardiac effects of POTENAY® INJETÁVEL (POT), a mephentermine-based product, given to cattle with induced vascular/cardiac depression. Ten healthy Holstein cattle (206 ± 13 kg) followed a randomized-complete-block design (RCBD) utilizing crossover study design. Each animal randomly received (1 ml/25 kg, IM) of either POT (n = 10) or volume-matched placebo control (0.9%NaCl, CP, n = 10). A subset of animals (n = 5) received POT first (day 0) while the remaining (n = 5) received CP; after a six-day washout period, cattle received the opposite compound. Animals were anesthetized and catheterized for systemic/left ventricular hemodynamic monitoring. Myocardial dysfunction/hypotension was induced by increasing the end-tidal isoflurane concentration until arterial blood pressure was 20% lower than at baseline and remained stable. Once the animal was determined to be hypotensive and hemodynamically stable, steady-state hypotensive baseline data (BL2) were acquired, and treatment with either POT or CP was given. Data were acquired post-treatment at every 15 min for 90 min. POT improved cardiac output (+68 L/min, ±14%, p < 0.05), MAP (+14 mmHg, ±4%, p < 0.05), HR (+22 bpm, ±8%, p < 0.05), and peak rates of ventricular pressure change during both systole (dP/dtmax : +37 mmHg/s ±13%, p < 0.05) and diastole (dP/dtmin : +31 mmHg/s, ±7%, p < 0.05). No improvements were noted following placebo-control administration. Results indicate that POT improves cardiac performance and systemic hemodynamics in cattle with induced cardiovascular depression when given as single intramuscular injection.

An overview of the safety pharmacology career of Dr. C.R. Hassler.

Each year the Safety Pharmacology Society (SPS) recognizes an investigator who has had a marked impact upon the discipline. The 2016 recipient of the SPS Distinguished Service Award (DSA) was Dr. Craig R. Hassler. Dr. Hassler is one of the founding members of the SPS and has been actively engaged in physiological research for over 46years. Dr. Hassler delivered a talk entitled "My 43Years at Battelle Memorial Institute" to meeting attendees. In this article an overview is provided of the illustrious career of Dr. Hassler along with an account of the numerous animal models that were developed at Battelle under his guidance over the years.

Insulin-like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity.

AIMS: Insulin-like growth factor 1 (IGF-1)-dependent signalling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here, we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy. METHODS: Rats were perfused with isoproterenol via osmotic pump (1 mg kg(-1) per day) and treated with 2 mg kg(-1) IGF-1 (2 mg kg(-1) per day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analysed for fibrosis and apoptosis, and relevant biochemical signalling cascades were assessed. RESULTS: After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax) and structural remodelling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signalling and activated Akt are selectively upregulated in Iso+IGF-1-treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups; however, tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. CONCLUSION: IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies.

The safety of high-dose buprenorphine administered subcutaneously in cats.

The safety of a proprietary formulation of buprenorphine hydrochloride administered subcutaneously (SC) to young cats was investigated in a blinded, randomized study. Four cohorts of eight cats aged approximately 4 months were administered saline, 0.24, 0.72 or 1.20 mg/kg/day buprenorphine SC for nine consecutive days, representing 0×, 1×, 3× and 5× of the intended dose. Cats were monitored daily for evidence of clinical reactions, food and water intake and adverse events (AEs). Physical examinations, clinical pathology, vital signs and electrocardiograms (ECGs) were evaluated at protocol-specified time points. Complete necropsy and histopathologic examinations were performed following humane euthanasia. Four buprenorphine-treated cats experienced AEs during the study, two unrelated and two related to study drug administration. The two cats with AEs considered related to drug administration had clinical signs of hyperactivity, difficulty in handling, disorientation, agitation and dilated pupils in one 0.24 mg/kg/day cat and one 0.72 mg/kg/day cat. All of these clinical signs were observed simultaneously. There were no drug-related effects on survival, injection response, injection site inspections, body weight, food or water consumption, bleeding time, urinalysis, respiration rate, heart rate, ECGs, blood pressures, body temperatures, macroscopic examinations or organ weights. Once daily buprenorphine s.c. injections at doses of 0.24, 0.72 and 1.20 mg/kg/day for 9 consecutive days were well tolerated in young domestic cats.

Obesity trends in the surgical population at a large academic center : a comparison between 1989-1991 to 2006-2008 epochs.

BACKGROUND: Changes in the prevalence of obesity of surgical patients overtime and in relation to the general population have not been well characterized. METHODS: Height, weight, age and gender data of adult patients who underwent general anesthesia at our institution were abstracted. Reliable data was available for the years 1989-1991 and 2006-2008, and comparisons were made between these epochs. Additional comparisons were made between our Minnesota surgical patients and the general Minnesota population. RESULTS: Substantial changes in patient weight occurred with a decline in normal weight patients (body mass index [BMI] < or =25.0) from 41.6% to 30.9% (P <0.001), while the prevalence of obesity (BMI 30-34.9) increased from 14.9% to 20.6% (P <0.001) and morbidly obesity (BMI > 35) from 7.1% to 14.8% (P <0.001). Minnesota surgical patients had a higher prevalence of obesity in every demographic category (P <0.001) compared to the general population. CONCLUSION: A substantial increase in the prevalence of obesity and morbid obesity among surgical patients at our institution occurred and the prevalence of obesity in our contemporary practice is higher than the general population. These observations most likely have profound implications on healthcare delivery resources, though its impact has yet to be determined.

Measuring high pressure baroreceptor sensitivity in the rat.

INTRODUCTION: The high pressure baroreceptor reflex rapidly buffers changes in systemic arterial pressure in response to postural changes, altered gravitational conditions, diseases, and pharmacological agents. Drug-induced exaggeration of changes in heart rate and in systemic arterial pressure is a leading cause of adverse events and of patients terminating use of drugs, particularly in the aging population. This paper presents a facile method for monitoring the high pressure baroreceptor reflex in rats, and presents an alternative to quantifying the magnitude of this reflex using 2 dependent variables, heart rate and systemic arterial pressure, rather than merely change in heart rate. METHODS: Twenty-four rats were allocated to 3 groups: group I anesthetized with 100mg/kg thiopental, group II anesthetized with 2% isoflurane given by inhalation, group III anesthetized with thiopental but pretreated for 2weeks with 2µg/kg aldosterone given SQ bid. After induction to anesthesia, hair was clipped from the ventral aspect of the neck, and petrolatum was applied to the skin to permit an air-tight seal with a glass funnel attached to a source of variable and controllable negative pressure. Systemic arterial pressure, ECG, heart rate, and a force of suction applied to the neck were all recorded continuously. RESULTS: After baseline recordings, a force of -20mmHg was applied for 20s over the carotid artery. In rats receiving thiopental, the average changes in heart rate and systemic arterial pressure following the application of -20mmHg neck suction were 30±11bpm and 45±14mmHg, respectively. The ratios of change in heart and change in systemic arterial pressure to application of negative force over the carotid sinus are 1.5±0.6bpm/mmHg and 0.7±04mmHg/mmHg, respectively. Mean values for heart rate and for mean systemic arterial pressure during baseline and after application of neck suction for 20s showed little to no decrease (i.e., blunting) in rats anesthetized with isoflurane or pretreated with aldosterone. DISCUSSION: Thus this methodology was able to detect, in rats, blunting of baroreceptor function for at least 2 perturbations of this important homeostatic control system.

Estimation of left ventricular filling pressure by Doppler echocardiography in dogs with pacing-induced heart failure.

BACKGROUND: Congestive heart failure (CHF) is a common clinical syndrome characterized by elevated filling pressure. HYPOTHESIS: Doppler echocardiographic (DE) variables of left ventricular (LV) filling can predict a decline of LV end-diastolic pressure (LVEDP) induced by acute preload reduction in dogs with compensated CHF. ANIMALS: Five male hound dogs. METHODS: Dogs previously instrumented with a transvenous cardiac pacemaker and a LV pressure gauge were paced at 160-180 bpm to induce mild CHF characterized by LVEDP > 20 mmHg. LVEDP and 9 DE variables of LV filling derived from diastolic time intervals, transmitral and pulmonary venous flow, and tissue Doppler imaging were measured simultaneously at baseline and 30, 60, 120, and 240 minutes after furosemide (4 mg/kg, IV) or placebo (0.9% saline, IV). Repeated measures analysis of variance and correlation analysis were used to determine the association between the decline of LVEDP after furosemide and DE measures of LV filling pressure (LVFP). RESULTS: Furosemide but not placebo decreased LVEDP (P < .001). The ratio of early transmitral flow velocity to LV isovolumic relaxation time (E : IVRT) predicted LVEDP best (R(2)= .50; P < .001). Correlations were also found between LVEDP and IVRT, E, ratio between E and late diastolic transmitral flow velocity (E : A), and early diastolic velocity of the mitral annulus (Ea). The ratio of E to Ea (E : Ea) was not useful in the prediction of LVEDP in this model. CONCLUSION AND CLINICAL IMPORTANCE: E : IVRT can be used to predict LVFP in dogs with mild left-sided CHF induced by rapid pacing.

The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization.

BACKGROUND AND PURPOSE: I(Kur) (Ultra-rapid delayed rectifier current) has microM sensitivity to 4-aminopyridine (4-AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes I(Kur) and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with microM sensitivity to 4-AP is present in canine ventricle. EXPERIMENTAL APPROACH: We used established voltage clamp protocols and used 4-AP (50 and 100 microM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid-myocardium. KEY RESULTS: Action potential recordings in the presence of 4-AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P<0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial I(Kur), in approximately 70% of left ventricular myocytes. The IC(50) of 4-AP for this current was 24.2 microM. The concentration of 4-AP used in our experiments resulted in selective blockade of an outward current that was not I(to) or I(Kr). Beta-adrenergic stimulation with isoprenaline significantly increased the 4-AP sensitive outward current density (P<0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. CONCLUSIONS AND IMPLICATIONS: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4-AP and its constitutive role in ventricular repolarization.

n-3 (omega-3) polyunsaturated fatty acids prevent acute atrial electrophysiological remodeling.

BACKGROUND AND PURPOSE: Recent reports suggest that n-3 (omega-3) polyunsaturated fatty acids (PUFAs) may reduce atrial fibrillation (AF). Reduction of the atrial effective refractory period (ERP) is believed to be an important early remodeling event that favors the development and perpetuation of AF. We hypothesized that n-3 PUFAs would attenuate early atrial electrophysiolgical remodeling in a canine model of acute atrial tachypacing. EXPERIMENTAL APPROACH: Adult dogs of either sex received n-3 PUFAs (n=6), n-6 PUFAs (n=6), or saline (n=6) infused over 1 h. After a stable ERP was established, treatment was initiated concurrently with 6 h of rapid atrial pacing (400 b.p.m.). Serial right atrial ERPs were measured during rapid atrial pacing, and induction of atrial tachyarrhythmias was attempted at the conclusion of each study. KEY RESULTS: There was no change in P wave duration or in the PQ, QRS, QT or QTc intervals in any of the treatment groups. N-3 PUFA treatment significantly reduced the shortening of atrial ERP, compared to both control groups (P<0.05). In separate experiments, the same n-3 PUFA infusion was given to dogs remaining in normal sinus rhythm. During sinus rhythm, n-3 PUFA infusion did not alter any electrocardiogram (ECG) parameter or the atrial ERP. CONCLUSIONS AND IMPLICATIONS: We conclude that acute n-3 PUFA treatment prevents acute atrial electrophysiological remodeling during high rate activity, which may minimize the self-perpetuation of AF.

Assessment of drug-induced QT interval prolongation in conscious rabbits.

INTRODUCTION: Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the RR interval on the QT interval of conscious rabbits. This study was also conducted to validate the use of conscious, sling-trained rabbits to assess the QTc interval, and to evaluate the reliability and accuracy of this preparation in predicting drug-induced QTc prolongation in humans. METHODS: ECGs were recorded via bipolar transthoracic ECG leads in 7 conscious rabbits previously trained to rest quietly in slings. The heart rate was slowed with 2.0 mg/kg zatebradine to assess the effects of heart rate on the QT interval. The same ECG and sling preparation was used to evaluate the effects in of three drugs known to be torsadogenic in humans (cisapride, dofetilide and haloperidol), two drugs known to be non-torsadogenic in humans (propranolol and enalaprilat) and a control article (vehicle). All of the test articles were administered intravenously to 4 rabbits, and both RR and QT intervals were measured and the corrected QT values were calculated by an investigator blinded to the test article, utilizing our own algorithm (QTc=QT/(RR)(0.72)) which permitted the least dependency of QTc on RR interval. RESULTS: The following regression equations were obtained relating QT to RR: QT=2.4RR(0.72), r(2)=0.79, with RR intervals varying between 210 and 350 ms. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide and haloperidol (p<0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat. DISCUSSION: Results indicate that a bipolar transthoracic ECG recorded in conscious, sling-trained rabbits may provide an easy and economical methodology useful in predicting QTc lengthening of novel pharmacological entities.

Sensitivity and specificity of isolated perfused guinea pig heart to test for drug-induced lengthening of QTc.

INTRODUCTION: The purpose of this study was to determine the sensitivity and specificity for predicting the liability of a compound to lengthen QTc using isolated, perfused guinea pig hearts (Langendorff preparation). METHODS: QTc (Fridericia correction) was calculated from bipolar transventricular electrograms. Hearts were exposed to escalating concentrations of 26 compounds thought to lengthen, and 13 compounds thought not to lengthen, QTc in humans. RESULTS: In this preparation, QTc was found to lengthen in 26 of 26 compounds thought to be positive (sensitivity 1.00) and not to lengthen or to lengthen insignificantly in 13 of 13 compounds thought to be negative (specificity 1.0) in man. Probucol and ontazolast could not be studied because of limited solubility. Successful experiments were conducted on over 98% of guinea pigs anesthetized. DISCUSSION: We believe that the isolated perfused guinea pig heart is an in vitro preparation that could be utilized early in preclinical testing for identifying a liability to lengthen QTc in humans, but we do not believe--as is true also for other in vitro methods--that the concentration at which the liability is demonstrated in vitro necessarily predicts the concentration at which a liability exists in man.

A study and comparative analysis of managerial and leadership effectiveness in the National Health Service: an empirical factor analytic study within an NHS Trust hospital.

The research described in this article was concerned primarily with identifying the criteria of managerial/leadership effectiveness applying at the middle and front line levels of management within an NHS Trust Hospital using critical incident technique and factor analysis methods. The findings suggest that the self-perceptions of managers and the perceptions of superiors and subordinates are very similar, and only differ on a limited number of criteria. This challenges the 'perspective-specific' models of managerial effectiveness advocated by some researchers. The results are compared against those from a near identical study carried out by the author within one part of the British Civil Service, and the results from a different but comparable factor analytic study carried out by other researchers elsewhere in the NHS. The results suggest the existence of generalized criteria of managerial effectiveness, which lend considerable support to the notion of the 'universally effective manager'. This challenges the 'contingent models' of managerial effectiveness advocated by various expert commentators. In addition, the research supports the new model of transformational leadership offered by Alimo-Metcalfe and Alban-Metcalfe for application within both the NHS and local government, and adds to the empirical base supporting the current drive towards evidence-based practice in management within the healthcare sector.

Acute effects of escalating doses of amiodarone in isolated guinea pig hearts.

Cardiac effects of escalating concentrations of amiodarone were determined on isolated perfused guinea pig hearts (Langendorff preparations). Spontaneously beating hearts were instrumented for the measurement of RR, PQ, QRS, QT and QTc durations (from a bipolar electrogram), and dP/dtmax and dP/dtmin from an isovolumetric left ventricular pressure curve. Ten hearts were exposed to escalating concentrations of amiodarone (10-7, 10-6, 10-5 and 10-4 M) in dimethyl sulfoxide (DMSO)/Krebs-Henseleit or to DMSO/Krebs-Henseleit (vehicle). Measurements were collected during the last minute of a 15-min concentration. Means of all parameters were compared by ANOVA with repeated measures design. When compared with vehicle, amiodarone prolonged QT and QTc durations at concentrations >10-6 M. The apparent lengthening of RR, PQ and QRS at concentrations >10-6 M did not achieve statistical significance. Similarly, the apparent decreases in dP/dtmax and dP/dtmin at concentrations >10-6 M did not achieve statistical significance. The putative therapeutic concentration of amiodarone is between 2 and 4 x 10-6 M. In this study, at a concentration of 10-6 M, only RR and dP/dtmin tended to change, but they were not different from vehicle. Thus, amiodarone in this preparation has little potential for cardiac toxicity at therapeutic concentrations.

Negative affect and interpersonal rejection among prison inmates in a therapeutic community: a social relations analysis.

The authors used D. A. Kenny's social relations model to examine J. C. Coyne's interpersonal theory of depression among a clinical sample of well-acquainted prison inmates. Members of 12 therapy groups (N = 142) diagnosed with a substance abuse disorder completed a self-report measure of depression and anxiety and indicated their desire to interact with other group members. There was both consensus about which group members were rejected and individual differences in the participants reported desire for future interaction with other group members. Those reporting high levels of depressive negative affect were most likely to be rejected. Those lowest in positive affect indicated the least desire for future interaction with others.

A semi-immobilization of a partial auricle induces hypertrophy and ultrastructural alteration of cardiomyocytes.

Semi-immobilization of a partial area of the ventral edge, lateral epicardium of the left auricle (ventrolateral of left auricle), by using quick adhesion glue induces moderate hypertrophy of myocytes with an average increase of 34% in cross-sectional area. Intercellular connective tissues increased, and cellular sizes varied markedly. The ultrastructure of immobilized (semi-immobilized) myocytes commonly exhibited degenerating features in myofibrils, various cytoplasmic organelles including mitochondrial cristae and sarcoplasmic reticulum (SR) were disrupted, and T-tubules disappeared. Z-line streaming and widening (hypertrophic Z-line, rod bodies) and increase of metabolic particle deposition are typical phenomena in addition to intercalated disc (Id) disorganization. The results suggest that semi-immobilization of the auricle induces hypertrophy of myocytes in association with degeneration and disruption of myofibrils and other cytoplasmic organelles, and an increase of intercellular connective tissues, rather than increase of myofibril mass. This is the first study to immobilize only a part of the heart rather than the whole animal. Our results using artificial immobilization of cardiac myocytes were extremely significant since the structural alterations obtained were similar to that observed in cardiomyopathies. This suggests that myocytes progressing to heart failure are also subjected to inhibition of movement. Therefore, this experiment may prove very useful as a model for studying the functional effect of heart failure observed in cardiomyopathy.

Electrophysiologic and hemodynamic effects of apomorphine in dogs.

Apomorphine is a dopamine receptor agonist used as an emetic, for Parkinson's disease, and for treating erectile dysfunction. This study was conducted to monitor cardiovascular function in dogs given the standard emetic dose (0.05 mg/kg) or 10 times that. Measurements were made during baseline and at 1, 5, 15, 30, 45, and 60 min after iv administration. There were no changes produced by the 0.05 mg/kg dose of apomorphine except for a decrease in mean systemic arterial pressure (AoPm) at the 1 through 15 min recordings. For the 0.5 mg/kg dose, there were reductions in systemic vascular resistance at the 1 and 5 min recordings and in AoPm at the 1 through 60 min recordings. Although not significant, when AoPm fell, heart rate, stroke volume, and cardiac output tended to increase. Action potentials were recorded from superfused Purkinje and endocardial ventricular fibers while exposed to 10(-9) to 10(-5) M apomorphine (10(-10) M is considered therapeutic and 10(-7) M is considered lethal). There were no changes in action potential characteristics of Purkinje fibers, but action potential duration at 90% repolarization prolonged approximately 10-12% in endocardium at concentrations of 10(-6) M and greater. At the usual emetic dose (0.05 mg/kg) apomorphine resulted in no signs of cardiovascular toxicity and, at 0.5 mg/kg, cardiovascular changes were minimal. The emetic dose is higher than that for Parkinson's disease or erectile dysfunction; thus apomorphine appears to be a safe compound for clinical use in dogs and by extrapolation to man.

Afferent baroreceptor discharge in pregnant rats.

The baroreflex function curve is shifted to lower operating pressures, efferent sympathoexcitatory responses are attenuated, and sympathoinhibitory responses are potentiated in pregnant compared with virgin rats. It has been proposed that during pregnancy, elevated levels of 3 alpha-hydroxy-dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, may contribute to this difference, because acute intravenous administration of 3 alpha-OH-DHP to virgin female rats mimics the effects of pregnancy on the baroreflex. To determine whether changes in the afferent limb might contribute to these baroreflex responses, the effects of pregnancy and 3 alpha-OH-DHP on aortic depressor nerve activity were assessed in the current study. Baroreceptor discharge curves were obtained in Inactin-anesthetized rats by recording aortic nerve activity during ramp increases and decreases in mean arterial pressure (MAP) [intravenous phenylephrine and nitroprusside infusion] before [(control, C) 15 min (E1), and 30 min (E2) after 3 alpha-OH-DHP (220 microg/kg bolus + 22 microg x kg(-1) x min(-1) infusion iv)]. Baseline blood pressure was significantly lower in pregnant (109 +/- 4.4 mmHg) compared with virgin (122 +/- 2.8 mmHg) rats. The only significant difference in the baroreceptor discharge curves was a decrease in curve midpoint in pregnant rats (virgin = 140 +/- 2.7 vs. pregnant = 124 +/- 3.6 mmHg). 3 alpha-OH-DHP had no effect on afferent baroreceptor discharge curves in either virgin or pregnant groups. These results suggest that pressure-dependent baroreceptor resetting may contribute to a shift in the baroreflex curve to lower operating pressures, but cannot completely explain differences in baroreflex function between virgin and pregnant animals.