The effect of glycopyrrolate on heart rate and intestinal motility in conscious horses

Glycopyrrolate (GLY) is a synthetic quaternary ammonium anticholinergic compound which offers a number of advantages over atropine, including less arrhythmogenic influence and lack of significant effect upon the central nervous system, eyes and foetus. Five healthy horses (7.4 ± 2.2 years, 462 ± 31.7 kg) were administered 2.5, 5 and 10 μg/kg doses of GLY iv in a randomised and blinded manner with at least 48 h between treatments. The electrocardiogram and heart rate were recorded on an oscilloscopic and chart recorder while gastrointestinal (GIT) motility was assessed by auscultation of 4 abdominal quadrants, assigning a subjective score from 0 (no motility) to 4 (normal motility). Heart rate, which was observed at baseline, 2, 5, 10, 15, 30 min, and 1, 2, 3, 4, 6, 9, 12, 18 and 24 h post GLY, revealed no change with the 2.5 μg/kg dose, and an increase with 5 μg/kg (59%) and 10 μg/kg (109%) for up to 1 h. The 2.5 and 5 μg/kg doses did not prevent the development of second degree atrioventricular block in some horses for up to 15 min, while the 10 μg/kg dose eliminated any pre-existing block within 5 min. There was a complete loss of GIT motility with the 5 and 10 μg/kg doses and partial loss with the 2.5 μg/kg dose. Subsequent return of motility was apparently dose-dependent with 50% of baseline motility score returning in 2.4, 6.4 and 11.5 h with 2.5, 5 and 10 μg/kg doses, respectively. Two horses receiving a 10 μg/kg dose developed abdominal discomfort. Passage of faeces and appetite were not significantly different with any dose. Glycopyrrolate did not induce any change in the pupillary response to a light source at any stage of observation. The results of this study indicate that 5 μg/kg induces a reasonable increase in heart rate without affecting GIT motility for an excessive length of time in awake, healthy, adult, unsedated horses.     

Effects of a muscarinic type-2 antagonist on cardiorespiratory function and intestinal transit in horses anesthetized with halothane and xylazine

OBJECTIVE: To evaluate the cardiorespiratory and intestinal effects of the muscarinic type-2 (M2) antagonist, methoctramine, in anesthetized horses. ANIMALS: 6 horses. PROCEDURE: Horses were allocated to 2 treatments in a randomized complete block design. Anesthesia was maintained with halothane (1% end-tidal concentration) combined with a constant-rate infusion of xylazine hydrochloride (1 mg/kg/h, i.v.) and mechanical ventilation. Hemodynamic variables were monitored after induction of anesthesia and for 120 minutes after administration of methoctramine or saline (0.9% NaCl) solution (control treatment). Methoctramine was given at 10-minute intervals (10 microg/kg, i.v.) until heart rate (HR) increased at least 30% above baseline values or until a maximum cumulative dose of 30 microg/kg had been administered. Recovery characteristics, intestinal auscultation scores, and intestinal transit determined by use of chromium oxide were assessed during the postanesthetic period. RESULTS: Methoctramine was given at a total cumulative dose of 30 microg/kg to 4 horses, whereas 2 horses received 10 microg/kg. Administration of methoctramine resulted in increases in HR, cardiac output, arterial blood pressure, and tissue oxygen delivery. Intestinal auscultation scores and intestinal transit time (interval to first and last detection of chromium oxide in the feces) did not differ between treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Methoctramine improved hemodynamic function in horses anesthetized by use of halothane and xylazine without causing a clinically detectable delay in the return to normal intestinal motility during the postanesthetic period. Because of their selective positive chronotropic effects, M2 antagonists may represent a safe alternative for treatment of horses with intraoperative bradycardia.     

Methoctramine, a cardioselective muscarinic cholinergic antagonist, prevents fentanyl-induced bradycardia in the dog

A controlled study examining the effects of the cardioselective muscarinic cholinergic antagonist methoctramine on fentanyl-induced bradycardia was performed in six dogs. Five doses of methoctramine (6, 10, 20, 30 and 60 |ig/kg) followed by fentanyl (20 μg/kg) were administered randomly on separate days. Fentanyl caused a significant reduction in heart rate from baseline values. Moreover, fentanyl produced a variety of arrhythmogenic actions indicative of vagal hyper-activity, including sinus bradycardia, second-degree atrioventricular block and ventricular and supraventricular escape beats. Administration of methoctramine 5 min before fentanyl injection prevented the bradycardic effects of fentanyl in a dose-dependent manner, with high doses of methoctramine causing sinus tachycardia. Using regression analysis, the dose of methoctramine necessary to prevent fentanyl-induced bradyarrhythmias without causing tachycardia was calculated as 14.4 μg/kg. The study confirmed that fentanyl administration in the conscious dog causes profound bradycardia with bradyarrhythmias. The cardioselective muscarinic antagonist agent methoctramine prevented the bradycardic effects of fentanyl.     

Effects of clomipramine hydrochloride on heart rate and rhythm in healthy dogs

OBJECTIVE: To determine the effects of clomipramine hydrochloride on heart rate and rhythm in dogs. ANIMALS: 17 healthy Beagles. PROCEDURES: In experiment 1, 8 dogs received placebo or clomipramine (20 mg/kg of body weight, q 24 h, PO) for 7 days in a 2-way crossover design. In experiment 2, 9 dogs were evaluated for 48 hours before and 24 hours after oral administration of clomipramine (4 or 12 mg/kg) in a 2-way crossover design. Electrocardiogram and heart rate were monitored continuously by use of telemetry. RESULTS: A significant diurnal rhythm in heart rate was detected; minimum values were recorded at night. Administration of 20 mg of clomipramine/kg induced a significant reduction in heart rate, with peak effect achieved approximately 12 hours after dosing. Administration of 4 or 12 mg of clomipramine/kg did not result in significant changes in heart rate. Sinoatrial and second-degree atrioventricular block and ventricular escape beats were observed during periods of slow heart rate in more dogs that received clomipramine (3 to 4 of 8 dogs), compared with dogs that received placebo (1 to 2 of 8 dogs), but this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of clomipramine induced benign cardiovascular effects in dogs rather than the potentially dangerous arrhythmias or tachycardia reported following administration of tricyclic antidepressants to humans. Precautions regarding cardiovascular effects may not be needed for the use of clomipramine in healthy dogs.     

Bronchodilator activity of the selective muscarinic antagonist revatropate in horses with heaves

Bronchodilators are frequently used to attenuate airway obstruction in equine heaves (or recurrent airway obstruction). This study evaluated the selective (M₃ and M₁) muscarinic antagonist revatropate, which offers potential advantages over non-specific antimuscarinic agents such as ipratropium. Protocol 1 assessed the response to inhaled revatropate (1, 2 and 7 mg) using a blinded, negative (inhaled saline) and positive (inhaled ipratropium bromide; 0.3, 0.7 and 2 mg) controlled, dose escalation study, with six heaves horses. The lowest doses of revatropate and ipratropium induced a rapid (within 1 h) and significant improvement in airway function. The highest doses of both drugs had no significant effect on gastrointestinal sound score or iris function, but resulted in tacky mucous membranes and reduced gastrointestinal sound score in some horses.In Protocol 2, a cross-over design comparing the duration of action of inhaled revatropate (1 mg), ipratropium (0.3 mg) and saline, some indices of airway function were improved for between 5 and 6 h after revatropate administration, and for between 6 and 24 h after ipratropium administration. Inhaled revatropate and ipratropium had similar effects on airway function, with no significant difference between their efficacies. Importantly, however, only revatropate significantly improved clinical scores of breathing effort, improving combined clinical score at the 1 h time point and abdominal score at the 1–3 h time points. No significant adverse events were observed in Protocol 2, although some horses had reduced gastrointestinal sound scores. Inhaled revatropate is therefore a safe and effective bronchodilator for treating airway obstruction in heaves.     

Effects of medetomidine on intestinal and colonic motility in the dog

The motor responses of the jejunum and colon to stimulation of α₂-adrenoceptors by medetomidine and clonidine were investigated in four dogs. In fasting dogs, medetomidine, at a dose rate of 30 μg/kg i.v., disrupted the migrating myoelectric complex (MMC) pattern of the small intestine for about 2 h. Similar, but shorter-lasting effects were also induced by clonidine (30 μg/kg i.v.) on the jejunum. The administration of α₂-agonists inhibited colonic motility in fasting dogs, although medetomidine-induced inhibition was preceded by a short period of increased muscle tone. All these effects were reversed by the α₂-antagonists atipamezole (0.15 mg/kg i.v.) and yohimbine (0.20 mg/kg i.v.). In fed dogs, medetomidine (30 μg/kg i.v.) induced a strong increase of the tone on the proximal colon, while the activity of the medium and distal colon was completely suppressed. Yohimbine (0.50 mg/kg i.v.) immediately restored the activity of the colon and induced a propagated giant contraction and defaecation by the animal. These data confirm the importance of a₂-adrenergic receptors in the control of intestinal and colonic motility in the dog.     

Validation of heart rate spot-check protocol to measure circadian variation and heart rate in healthy dogs and dogs with atrial fibrillation

IntroductionAlternatives for out-of-clinic heart rate (HR) measurement are required to optimise the management of atrial fibrillation (AF) in dogs. Additionally, the presence of circadian variation (CV) in HR in pet dogs remains unknown.We aimed to identify the number and duration of spot-checks required for an accurate estimation of 24-hour HR in canine AF. Circadian variation in HR was examined in healthy dogs and dogs with AF, and spot-check-derived HR was compared with a CV-derived gold standard.Materials and methodsAmbulatory electrocardiogram data from healthy dogs and dogs with AF were retrospectively analysed. Heart rate was calculated from the entire recording and pre-defined periods (spot-checks) of one hour to 30 and 60 s in duration. Circadian variation in HR was determined by cosinor analysis. Bias and limits of agreement of means and median HR with mesor HR were determined by correlation and Bland–Altman analysis.ResultsCircadian variation in HR was identified not only in 18/22 healthy dogs and 14/21 AF dogs but only on ambulatory electrocardiogram recordings.Four-hourly spot-checks provided the most accurate estimate of mesor HR in healthy dogs (bias of the median over 30 s 7.70, limits of agreement 7.48), whereas, in dogs with AF, four, six and eight-hourly spot-checks provided reliable estimates of mesor HR (bias within −1.29 and −29.5).ConclusionsFour, six and eight-hourly HR spot-checks can estimate 24-hourly HR in dogs with AF. There was CV in HR in most healthy pet dogs and dogs with AF. Spot-check protocols cannot identify CV in HR.     

The effect of anesthesia and surgery on heart rate variability in dogs

Heart rate variability (HRV) may be useful for objective assessment of stress and pain in animals. The objective of this study was to describe the effect of anesthesia and surgery on HRV in dogs. We hypothesized that surgery would decrease HRV to a greater degree and for a longer duration than anesthesia alone. Four healthy male dogs (29 ± 2 kg) were instrumented for ambulatory ECG monitoring. Continuous ECG data was obtained for 1 day prior to, and 6 days following anesthesia alone (ANES) or anesthesia plus unilateral stifle arthrotomy (ANSX). The anesthetic protocol included xylazine (0.5 mg kg^–1 IM), morphine (0.5 mg kg^–1 IM), atropine (0.04 mg kg^–1 IM), thiopental (10 mg kg^–1 IV) and isoflurane in oxygen. A single dose of morphine (0.5 mg kg^–1 IM) was administered at extubation. Time domain analysis of HRV was performed on 5 minutes epochs of artefact‐ and arrhythmia‐free ECG data obtained at 12 noon and 12 midnight on each of the seven experimental days. Mean RR interval, standard deviation of normal R‐R intervals (SDNN), and the standard deviation of successive differences in RR intervals (SDSD) were compared to baseline for ANES and ANSX. Pain scores obtained during the day were also evaluated. Significance was set at p < 0.01. There were no differences between groups for any baseline data. Mean RR interval did not differ from baseline on days 1–6 in ANES or ANSX. SDNN and SDSD values at noon were not different from baseline on days 1–6 in ANES or ANSX. At midnight on days 1 and 2, SDNN was significantly decreased from baseline in ANSX, and on day 1 a significant difference between groups existed. ANSX values of SDSD at midnight were significantly decreased from baseline and ANES on day 1. Pain scores for ANSX were significantly greater than baseline on days 1–3, and different from ANES on days 1–5. These results suggest that HRV is decreased following anesthesia plus surgery, and that changes in HRV may be associated with pain.     

Pre-operative stress in dogs - a preliminary investigation of behavior and heart rate variability in healthy hospitalized dogs

OBJECTIVE: To assess pre-operative behavioral and physiological characteristics of healthy dogs hospitalized for elective surgery. STUDY DESIGN: Open clinical observational study. ANIMALS: Forty-one bitches hospitalized for elective ovariohysterectomy. METHODS: While undisturbed in a hospital cage, the behavior of the dog was recorded using a video camera and recorder. From the video recordings, various behavioral variables were registered. Simultaneous measurements were made on heart rates and heart rate variability (HRV) by use of an ambulatory electrocardiogram. In addition, the dog's response to human approach was noted. RESULTS: Different behavioral patterns were found in the dogs studied. Thirteen individuals were regarded as highly active, and were seen to bark or howl, manipulate the environment or attempt to flee vigorously. In 13 dogs (passive dogs) none of these activities occurred. Panting and displacement behaviors, such as snout licking, were observed in nearly all the animals monitored. In general, heart rates were higher and HRV lower with the most active individuals; however, the presence of physiological arousal could not be excluded in two animals with passive behaviors. To some extent, the behavior of the dog while undisturbed in the cage was reflected in the responses to a person entering the cage. CONCLUSIONS AND CLINICAL RELEVANCE: The different individual responses detected in this study raise an important question concerning their role and existence throughout the entire peri-operative period, especially during the post-anesthetic recovery phase when behavioral characteristics are commonly used to assess patient welfare. The results also emphasize the need for further investigations to explore the effects of pre-operative stressors on canine surgical patients, and the factors contributing to them.     

The effect of autonomic manipulation on heart rate variability in dogs

Beat‐to‐beat variation of heart rate is reflective of autonomic balance and has been used to assess pain and stress in human beings. The purpose of this investigation was to pharmacologically manipulate the autonomic nervous system and to determine the effect of these manipulations on heart rate variability (HRV) in dogs. Four adult male hound dogs (27 ± 1 kg) were used in the investigation. Each dog was given five treatments: Parasympathetic blockade (glycopyrrolate; 0.01 mg kg^–1 IV and 0.01 mg kg^–1 IM), parasympathetic stimulation (phenylephrine; 0.005 mg kg^–1 IV + 0.05 mg kg^–1hour^–1), sympathetic blockade (propranolol; 0.11 mg kg^–1 IV), sympathetic stimulation propranolol; 0.01 μg kg^–1 minute^–1), and saline control. At least 48 hours were allowed between treatments. ECG recordings were obtained using an ambulatory ECG monitor. A 5‐minutes period of continuous recording obtained ~30 minutes after initiation of drug administration was used for data analysis. Changes in HRV were evaluated by time and frequency‐domain analysis. The standard deviation of normal R‐R intervals (SDNN), as well as the standard deviation of successive differences in RR intervals (SDSD) were assessed for each treatment. Low frequency (LFP; 0.05–0.15 Hz), high frequency (HFP; 0.15–0.35 Hz), and total (TP; 0.017–0.5 Hz) spectral power were also determined. The LFP:HFP ratio was also evaluated. A two‐way anova with a Tukey's test was used to detect differences (p < 0.05). Administration of glycopyrrolate or isoproterenol increased HR and decreased SDNN and SDSD below control levels. Phenylephrine or propranolol administration were without effect. LFP was diminished by glycopyrrolate and isoproterenol, but was unaffected by phenylephrine and propranolol. HFP, TP, and LFP:HFP were unaffected by treatment. Both branches of the autonomic nervous system influence SDNN and LFP. SDSD, in contrast, is altered primarily by parasympathetic activity. Thus, it appears that parasympathetic activity modulates HRV in the resting dog, as either withdrawal of parasympathetic influence or accentuated sympathetic activity led to significant changes in these measures of HRV. Conversely, augmentation of parasympathetic activity or withdrawal of sympathetic tone minimally affected HRV.     

Effects of mechanical and pharmacologic manipulations on portal pressure, central venous pressure, and heart rate in dogs

Central venous pressure (CVP), portal pressure (PP), and heart rate (HR) were monitored in 6 female, sexually intact, middle-age Beagles during temporary portal vein obstruction, anesthetic recovery, abdominal bandaging, and propranolol administration. Intraoperative baseline PP was 7.3 mm of Hg (+/- 1.7 SD). Portal pressure was significantly increased throughout portal vein occlusion, but returned to baseline values 2 minutes after release of the ligature. Central venous pressure was significantly decreased throughout portal vein occlusion, but did not differ significantly from baseline values 3 minutes after release of the portal vein ligature. Portal pressure increased significantly (8 +/- 3.3 mm of Hg) over baseline values after application of an abdominal bandage; however, CVP did not change significantly. During postoperative monitoring, CVP and PP did not change significantly from respective 18-hour mean postoperative values in resting dogs. At 60 and 75 minutes after surgery, heart rate was significantly increased over the 18-hour mean. Portal pressure and CVP, respectively, were significantly increased over intraoperative baseline values in the first hour and the first 8 hours after surgery. Postoperative CVP and HR were significantly correlated. Individual measurements of PP in dogs that were abdominal pressing during barking or defecation were significantly increased (9 +/- 3 mm of Hg) above measurements taken after cessation of abdominal press. Portal pressure measurements in standing dogs decreased 7.5 +/- 2 mm of Hg, compared with measurements of the same dog in lateral recumbency. Central venous pressure was inaccurate in dogs performing abdominal press. Portal pressure did not decrease significantly from baseline after injection of propranolol (2 mg/kg, IV).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiorespiratory effects of a cardioselective muscarinic antagonist in anesthetized horses

Treatment of bradycardia in horses has been historically ignored because of the motility depressant effects of nonselective antimuscarinics. This study evaluated the cardiopulmonary effects of a cardioselective (M2) muscarinic antagonist, methoctramine (MET), in anesthetized horses. In a previous in vitro study, we determined that supraphysiological doses of MET were necessary to inhibit acetylcholine‐induced longitudinal jejunal smooth muscle contractions in this species. Six adult horses were allocated to two treatments in a randomized complete block design. Anesthesia was induced with xylazine/ketamine, and maintained with halothane (1% end‐tidal) and a constant infusion of xylazine (1 mg kg^?1 hour^?1) under mechanical ventilation. Invasive hemodynamic variables were monitored at baseline (approximately 45 minutes after induction) and for 120 minutes after MET or saline (control) had been injected. MET was titrated at 10‐minute intervals (10 µg kg^?1 IV) until the heart rate (HR) increased at least 30% above the baseline, or a maximum cumulative dose of 30 µg kg^?1 had been injected. A person blinded to the treatment evaluated recovery scores and monitored intestinal auscultation until 24 hours after the end of anesthesia using previously published methods. Cardiovascular parameters were analyzed by anova followed by a Dunnet's test, and nonparametrical data were analyzed by a Mann–Whitney U‐test (p < 0.05). Values were mean ± SEM unless otherwise stated. MET significantly increased HR from baseline to 120 minutes post‐injection (from 29 ± 1 to 36 ± 2 beats minute^?1 at 20 minutes). Thermodilution cardiac output (CO) and mean arterial pressure (MAP) were increased from baseline to 75 minutes post‐MET injection (from 13.9 ± 0.8 to 19.4 ± 2.0 L minute^?1 for CO at 20 minutes, and from 82 ± 3 to 103 ± 5 mm Hg for MAP at 20 minutes). Recovery characteristics and bowel auscultation scores did not differ among the groups. The return to at least 75% of the maximum auscultation score occurred at 10 (8–18) hours [median (range)] for controls and at 9 (8–12) hours for MET. It was concluded that MET increased HR and improved hemodynamic function during halothane/xylazine anesthesia with no apparent effect on return to full‐bowel motility, as assessed by auscultation. Accordingly, M2 muscarinic antagonists might be represented as a safer alternative to treat intraoperative bradycardia in horse.     

The influence of spasmolytic agents on heart rate variability and gastrointestinal motility in normal horses

The effects of hyoscine-N-butylbromide (hyoscine) and propantheline-bromide (propantheline) on heart rate (HR), HR variability (HRV) and gastrointestinal tract (GIT) contractions in the normal horse were determined. Five adult horses had ECG recordings for 180min after treatment with propantheline (100mg), hyoscine (120mg) or saline. Both propantheline and hyoscine reduced GIT sounds, with propantheline having a longer duration of effect (?120min). Both drugs elevated HR relative to the control baseline period (P<0.05), with the effects of propantheline again being of longer duration. HRV analysis indicated that propantheline suppressed Total Power (P<0.05), and both the high frequency (HF) and low frequency (LF) components of the power spectral analysis for up to 60-90min post treatment. Hyoscine had no effect on HRV Total Power but reduced the HF component for 30min after drug injection. Time domain variables correlated with Total Power and HF data (P<0.01). The marked effect of these compounds on parasympathetic control of cardiac and GIT function in normal horses should be taken into consideration when evaluating a clinical response to these agents.     

The influence of spasmolytic agents on heart rate variability and gastrointestinal motility in normal horses

The effects of hyoscine-N-butylbromide (hyoscine) and propantheline-bromide (propantheline) on heart rate (HR), HR variability (HRV) and gastrointestinal tract (GIT) contractions in the normal horse were determined. Five adult horses had ECG recordings for 180 min after treatment with propantheline (100 mg), hyoscine (120 mg) or saline. Both propantheline and hyoscine reduced GIT sounds, with propantheline having a longer duration of effect (⩾120 min). Both drugs elevated HR relative to the control baseline period (P < 0.05), with the effects of propantheline again being of longer duration. HRV analysis indicated that propantheline suppressed Total Power (P < 0.05), and both the high frequency (HF) and low frequency (LF) components of the power spectral analysis for up to 60–90 min post treatment. Hyoscine had no effect on HRV Total Power but reduced the HF component for 30 min after drug injection. Time domain variables correlated with Total Power and HF data (P < 0.01). The marked effect of these compounds on parasympathetic control of cardiac and GIT function in normal horses should be taken into consideration when evaluating a clinical response to these agents.     

Effects of age, body weight, and heart rate on transmitral and pulmonary venous flow in clinically normal dogs

OBJECTIVE: To determine the influence of age, body weight (BW), heart rate (HR), sex, and left ventricular shortening fraction (LVSF) on transmitral and pulmonary venous flow in clinically normal dogs. ANIMALS: 92 client-owned dogs 3 months to 19 years old. PROCEDURE: Transthoracic Doppler echocardiography recordings of transmitral flow and pulmonary venous flow were obtained in conscious unsedated dogs. Influence of age, BW, HR, sex, and LVSF on diastolic variables was assessed, using statistical methods such as ANOVA on ranks and univariate and multivariate forward stepwise linear regression analyses. RESULTS: Age significantly influenced isovolumic relaxation time (IVRT, r = 0.56), ratio between peak velocity of the early diastolic mitral flow wave-to-peak velocity of late diastolic mitral flow wave (E:A; r = -0.44), deceleration time of early diastolic mitral flow (DTE; r = 0.26), and peak velocity of atrial reversal pulmonary venous flow wave (AR-wave; r = 0.37). Significant changes of mitral inflow and pulmonary venous flow variables were evident only in dogs > 6 and > 10 years old, respectively. Body weight significantly influenced DTE (r = 0.63), late diastolic flow duration (r = 0.60), and AR duration (r = 0.47), whereas HR significantly affected DTE (r = -0.34), IVRT (r = -0.33), and peak velocity of AR (r = 0.24). Sex or LVSF (range 22 to 48%) did not influence any echocardiographic variables. CONCLUSIONS AND CLINICAL RELEVANCE: Age, BW, and HR are important factors that affect filling of the left atrium and left ventricle in clinically normal dogs.