Pentobarbital-anesthetized Dogs Research Articles

The evaluation of drug-induced changes in left ventricular function in pentobarbital-anesthetized dogs

IntroductionThe goal of this study was to determine whether assessment of myocardial contractility and hemodynamics in an anesthetized dog model, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. MethodsDerived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end-diastolic LVP, and LVdP/dtmax as the primary contractility index. ResultsThese results demonstrate that statistically significant increases (amrinone and pimobendan) and decreases (atenolol and itraconazole) in left ventricular dP/dtmax were observed at clinically relevant exposures. DiscussionThe analysis from the current study supports the strategic use of the anesthetized dog model early in the drug Discovery process for a comprehensive cardiovascular evaluation that can include left ventricular dP/dtmax with good translation to human.

Leptin injection into the left stellate ganglion augments ischemia-related ventricular arrhythmias via sympathetic nerve activation

Leptin is a peptide hormone produced by adipose tissue whose basic function is regulating energy balance and sympathetic outflow. Previous studies have shown that increased nerve activity of the left stellate ganglion (LSG) promotes ventricular arrhythmia (VA). The purpose of this study was to investigate whether leptin could facilitate VA through activation of the LSG. Sixteen pentobarbital-anesthetized dogs were divided into a control group (saline; n = 8) and a leptin group (leptin; n= 8). Microinjections of either 0.1 mL saline or leptin (18 μg) were injected into the LSG. Action potential duration (APD) of the myocyte and the function and neural activity of the LSG were measured at different time points. VA induced by occlusion of the left anterior descending branch was continuously measured for 1 hour. At the end of the experiment, the LSG tissues were collected for molecular detections. Compared with the control group, leptin microinjection resulted in (1) significant enhancement in the incidence of VA; (2) significant decrease in APD and increase in APD dispersion; and (3) significant increase in the function and neural activity of the LSG. Mechanistically, the leptin receptor was found in the LSG, and its signaling was significantly activated in the leptin-injected group. Additionally, leptin microinjection markedly increased the expression of proinflammatory cytokines. LSG activation induced by leptin microinjection promotes ischemia-induced VAs. Activated leptin receptor signaling and up-regulation of proinflammatory cytokines in the LSG may be responsible for these effects.

Epinephrine for Cardiac Arrest

Epinephrine for Cardiac Arrest: Are We Doing More Harm Than Good? Vijay Krishnamoorthy;Monica Vavilala;Michael Fettiplace;Guy Weinberg; Anesthesiology

Metánbelélegzés gyulladáscsökkentő hatásának vizsgálata ischaemia-reperfusio alatt

Gastrointestinal methane generation has been demonstrated in various conditions, but it is not known whether it has any impact on the mammalian physiology or pathophysiology. Our aim was to characterize the effects of exogenous methane on the process of inflammatory events induced by reoxygenation in a canine model of ischemia-reperfusion. Sodium pentobarbital-anesthetized inbred beagle dogs (n = 18) were randomly assigned to sham-operated or ischemia-reperfusion (I/R) groups. I/R was induced by occluding the superior mesenteric artery for 1 h, and the subsequent reperfusion was monitored for 3 h. For 5 min before reperfusion, the animals were mechanically ventilated with normoxic artificial air with or without 2.5% methane. The macrohemodynamics and small intestinal pCO2 gap changes were recorded and tissue superoxide and nitrotyrosine levels and myeloperoxidase activity changes were determined in intestinal biopsy samples. Structural mucosal damage was measured via light microscopy and HE staining. Methane inhalation positively influenced the macrohemodynamic changes, significantly reduced the intestinal pCO2 gap changes and the magnitude of the tissue damage after reperfusion. Further, the intestinal myeloperoxidase activity, the superoxide and nitrotyrosine levels were reduced. These data demonstrate the anti-inflammatory profile of methane. The study provides evidence that exogenous methane modulates leukocyte activation and affects key events of I/R-induced oxidative and nitrosative stress.

The atrial neural network as a substrate for atrial fibrillation

Previously, we showed that the ganglionated plexi (GP) on the atrium can play a critical role in the initiation and maintenance of atrial fibrillation (AF). We tested the role of the atrial neural network as a substrate for AF without the influence of the GP. In pentobarbital-anesthetized open-chest dogs, two barriers across the left/right atrial appendage (AA) divided the AA into smaller and larger areas of approximately similar size, 2 cm². Electrical stimulation of the superior left and right GP allowed measurement of the greatest percent slowing of the heart rate prior to atrial excitation (n = 7). Acetylcholine (Ach; 1, 10, and 100 mM) was applied to the smaller and then to the larger area. In 22 dogs, the effects on AF duration in response to Ach applied to the atria were tested after GP ablations and atropine applied to the atria. GP function was unchanged by various concentrations of Ach applied to the smaller or larger areas of the atria. However, AF duration was significantly longer for each Ach concentration when applied to the larger versus the smaller area (p ≤ 0.01). AF was attenuated by GP ablations and atropine, but the differences between small and large areas were maintained. Ach on a larger area of the atria significantly increased the induced AF duration compared to an area half the size without changes in GP function suggesting that recruiting a larger area of the atrial neural network provided more of an AF substrate.

Antiarrhythmic Effects of Vasostatin‐1 in a Canine Model of Atrial Fibrillation

We examined the antiarrhythmic effects of vasostatin-1, a recently identified cardioregulatory peptide, in canine models of atrial fibrillation (AF). In 13 pentobarbital-anesthetized dogs bilateral thoracotomies allowed the attachment of multielectrode catheters to superior and inferior pulmonary veins and atrial appendages (AA). Rapid atrial pacing (RAP) was maintained for 6 hours. Each hour, programmed stimulation was performed to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 hours, vasostatin-1, 33 nM, was injected into the anterior right (AR) ganglionated plexus (GP) and inferior right (IR) GP every 30 minutes (n = 6). Seven dogs underwent 6 hours of RAP only (controls). At baseline, acetylcholine, 100 mM, was applied on the right AA and AF duration was recorded before and after injection of vasostatin-1, 33 nM, into the ARGP and IRGP. In separate experiments (n = 8), voltage-sinus rate response curves (surrogate for GP function) were constructed by applying high-frequency stimulation to the ARGP with incremental voltages with or without vasostatin-1. Vasostatin-1 significantly decreased the duration of acetylcholine-induced AF (11.0 ± 4.1 vs 5.5 ± 2.6 min, P = 0.02). The cumulative WOV (the sum of individual WOVs) significantly increased (P < 0.0001) during the first 3 hours and decreased toward baseline in the presence of vasostatin-1 (P < 0.0001). Cumulative WOV in controls steadily increased. Vasostatin-1 blunted the slowing of sinus rate with increasing stimulation voltage of ARGP. Vasostatin-1 suppresses AF inducibility, likely by inhibiting GP function. These data may provide new insights into the role of peptide neuromodulators for AF therapy.

Effects of dibutyryl cyclic adenosine monophosphate on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs

Background: Hypercapnia is associated with diaphragm muscle dysfunction that causes a reduction of diaphragmatic force generated for a constant elective myographic activity. No published data are available concerning hypercapnic depression of diaphragmatic contractility during dibutyryl cyclic adenosine monophospate (DBcAMP) administration. Objective: The aim of this study was to assess the effects of DBcAMP on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs. Methods: This experimental study was conducted from July to December 2008 at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Adult (aged >5 years) mongrel dogs weighing 10 to 15 kg were randomly divided into 3 equal groups. Hypercapnia (80–90 mm Hg) was induced with 10% carbon dioxide added to the inspired gas. When hypercapnia was established, group 1 was infused with low-dose DBcAMP (0.05 mg/kg/min); group 2 was infused with high-dose DBcAMP (0.2 mg/kg/min); and group 3 received placebo (saline). Study drug was administered intravenously for 60 minutes. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at baseline, induction of hypercapnia, and study drug administration. Results: Twenty-one dogs were divided into 3 groups of 7. There were no significant differences observed at baseline. In the presence of hypercapnia, Pdi (mean [SD], cm H 2O) at low- (20-Hz) and high-frequency (100-Hz) stimulation was significantly decreased from baseline in each group (all, P = 0.001). In groups 1 and 2, Pdi at both stimuli was significantly increased during DBcAMP administration compared with hypercapnia-induced values (group 1: 20-Hz, 13.5 [2.2] vs 15.0 [2.4], respectively, P = 0.001, 100-Hz, 21.2 [1.6] vs 22.5 [1.6], P = 0.001; group 2: 20-Hz, 13.7 [1.4] vs 19.2 [1.7], P = 0.001, 100-Hz, 21.0 [2.4] vs 27.2 [2.5], P = 0.001). The Pdi at both stimuli during DBcAMP administration was significantly higher in group 2 than in group 1 (20-Hz, 19.2 [1.7] vs 15.0 [2.4], P = 0.001, 100-Hz, 27.2 [2.5] vs 22.5 [1.6], P = 0.003). In group 3, Pdi did not significantly change in regard to either stimulus from hypercapnia-induced values. Conclusion: DBcAMP, in a dose-dependent manner, was associated with improved hypercapnic depression of diaphragmatic contractility in these pentobarbital-anesthetized dogs.

Cardiovascular Effects of Torcetrapib in Conscious and Pentobarbital-anesthetized Dogs

Torcetrapib is a cholesteryl ester transfer protein inhibitor with an undesired response of increasing arterial pressure in humans. Pressor responses to torcetrapib have been demonstrated in multiple preclinical species. However, these studies have not related plasma concentrations to observed effects. Our purpose was to 1) characterize the cardiovascular responses of torcetrapib in conscious and anesthetized dogs with measured plasma concentrations; and 2) characterize the hemodynamic effects contributing to hypertension using comprehensively instrumented anesthetized dogs. Torcetrapib was dosed orally (3, 30 mg/kg) and intravenously (0.01, 0.33, 0.1 mg/kg) in conscious and anesthetized dogs, respectively. Mean arterial pressure and heart rate were monitored in both models; additional parameters were measured in anesthetized dogs. Plasma drug concentrations were assessed in both models. In conscious and anesthetized dogs, torcetrapib increased mean arterial pressure 25 and 18 mm Hg and heart rate 35 and 21 beats/min, at 2.94 and 3.99 microg/mL, respectively. In anesthetized dogs, torcetrapib increased pulmonary arterial pressure, both systemic and pulmonary hypertension driven by increases in vascular resistance. The compound increased rate pressure product and myocardial contractility while decreasing time to systolic pressure recovery and ejection time. Thus, torcetrapib-induced pressor responses are mediated by systemic and pulmonary vasoconstriction and are associated with increased myocardial oxygen consumption and positive inotropy.

Nonspecific inhibition of nitric oxide synthesis evokes endothelin-dependent increases in myocardial contractility

The role of endogenous nitric oxide (NO) in modulating myocardial contractility is still unclear, in part because of unknown, secondary effects of blocking NO release. We hypothesized that the nonspecific inhibition of nitric oxide synthase (NOS) enhances endothelin-1 (ET-1) effects, which can play a role in ET-A receptor-dependent myocardial contractile responses. The myocardial contractility was estimated from the slope of the left ventricular end-systolic pressure–diameter relationship in closed-chest, pentobarbital-anesthetized dogs. Group 1 ( n = 7) was the saline-treated control, while in groups 2 ( n = 7) and 3 ( n = 7) N-nitro- l-arginine (NNA, 4 mg kg −1), a nonselective NOS blocker, was administered with or without pretreatment with the ET-A receptor antagonist ETR-P1/fl peptide (100 nmol kg −1 iv). Plasma ET-1, nitrite/nitrate (NO x ) and blood superoxide levels were measured, and myocardial ET-1 content and xanthine oxidoreductase (XOR) activity were determined from myocardial biopsies. The infusion of NNA over 120 min decreased the plasma NO x , significantly elevated the plasma ET-1 and blood superoxide levels, and in parallel greatly increased the left ventricular contractility as compared with the untreated controls [47.5 vs 30 mm Hg mm −1]. The myocardial ET-1 content decreased simultaneously, while the XOR activity and blood superoxide level were significantly elevated. These effects, including NNA-induced positive inotropy, were significantly suppressed by pretreatment with ETR-P1/fl peptide. These results demonstrate that a diminished NO synthesis leads to a preponderant ET-1 effect, which increases myocardial contractility through an ET-A receptor-dependent mechanism.

Modulation of cardiac contractility through endothelin-1 release and myocardial mast cell degranulation

The aim of this study was to outline the consequences of a hypertonic saline-dextran-40 (HSD) infusion-induced peripheral flow stimulus on the ventricular function in closed-chest, pentobarbital-anesthetized dogs. We hypothesized that HSD-induced elevation in endothelin-1 (ET-1) and nitric oxide (NO) release can have a role in myocardial contractile responses; and that cardiac mast cells (MC) degranulation may be involved in this process. The consequences of disodium cromoglycate (a MC stabilizer) or ETR-p1/fl peptide (an endothelin-A receptor antagonist) treatment were evaluated. A 4 ml/kg iv HSD40 infusion significantly increased cardiac index and myocardial contractility, and resulted in a decreased peripheral resistance. The postinfusion period was characterized by significant plasma NO and ET-1 elevations, these hemodynamic and biochemical changes being accompanied by a decreased myocardial ET-1 content, NO synthase activity and enhanced myocardial MC degranulation. Disodium cromoglycate treatment inhibited the HSD40-induced elevations in myocardial contractility and MC degranulation, and similar hemodynamic changes were noted after treatment with ETR-p1/fl peptide, together with a normalized myocardial myocardial ET-1 content, NO synthesis and a significant reduction in MC degranulation. These results indicate that peripheral NO and ET-1 release modulates the cardiac contractility through myocardial ET-A receptor activation and MC degranulation.

Dose-related effects of olprinone on hypercapnia-Induced impairment of diaphragmatic contractility in pentobarbital-anesthetized dogs

Background: In a previous study, olprinone was found to be more effective than milrinone in improving hypercapnic depression of diaphragmatic contractility in dogs. Objective: The purpose of this experimental study was to assess the doserelated effects of olprinone on hypercapnia-induced impairment of diaphragmatic contractility. Methods: This study was conducted at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Hypercapnia (partial pressure of carbon dioxide [C0 2] in arterial blood 80-90 mm Hg) was induced in pentobarbital-anesthetized dogs by adding 10% C0 2 to their inspired gas. When hypercapnia was established, the dogs were randomly assigned to 1 of 4 groups: (all dogs were administered a bolus dose of olprinone 10 mg/kg) group 1 was maintained with olprinone 0.1 μg/kg · min -1; group 2 was maintained with olprinone 0.3 μg/kg · min -1; group 3 was maintained with olprinone 0.5 μg/kg min -1; and group 4 received no study drug. The study drug was administered IV for 60 minutes. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi). The study investigator was not blinded to treatment assignment. Results: Twenty-four healthy adult mongrel dogs were used in the study; 6 dogs were assigned to each treatment group. In the presence of hypercapnia in each group, Pdi (mean [SD], cm H 2O) at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation significantly decreased from baseline (all, P = 0.001). During study drug administration in groups 1, 2, and 3, Pdi at both stimuli levels increased significantly from hypercapnia-induced values (all, P = 0.001); in group 4, Pdi to each stimulus did not change significantly from hypercapnia-induced values. There was a significant correlation between olprinone dose and Pdi at both stimuli (all, P = 0.001). The regression equations were: Pdi at 20-Hz stimulation (cm H 2O) = 24.97 × olprinone dose (μg/kg · min -1) + 13.54 ( r = 0.887; n = 24) and Pdi at 100-Hz stimulation (cm H 2O) = 29.18 × olprinone dose (μg/kg · min -1) + 20.55 ( r = 0.911; n = 24). Conclusion: Olprinone was associated with a dose-dependent improvement of hypercapnia-induced impairment of diaphragmatic contractility in these pentobarbital-anesthetized dogs.

Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs

Because degranulation of brain mast cells activates adrenocortical secretion (41, 42), we examined whether activation of such cells increases renin and vasopressin (antidiuretic hormone: ADH) secretion. For this, we administered compound 48/80 (C48/80), which liberates histamine from mast cells, to pentobarbital-anesthetized dogs. An infusion of 37.5 microg/kg C48/80 into the cerebral third ventricle evoked increases in plasma renin activity (PRA), and in plasma epinephrine (Epi) and ADH concentrations. Ketotifen (mast cell-stabilizing drug; given orally for 1 wk before the experiment) significantly reduced the C48/80-induced increases in PRA, Epi, and ADH. Resection of the bilateral splanchnic nerves (SPX) below the diaphragm completely prevented the C48/80-induced increases in PRA and Epi, but potentiated the C48/80-induced increase in ADH and elevated the plasma Epi level before and after C48/80 challenge. No significant changes in mean arterial blood pressure, heart rate, concentrations of plasma electrolytes (Na+, K+, and Cl-), or plasma osmolality were observed after C48/80 challenge in dogs with or without SPX. Pyrilamine maleate (H1 histaminergic-receptor antagonist) significantly reduced the C48/80-induced increase in PRA when given intracerebroventricularly, but not when given intravenously. In contrast, metiamide (H2 histaminergic-receptor antagonist) given intracerebroventricularly significantly potentiated the C48/80-induced PRA increase. A small dose of histamine (5 microg/kg) administered intracerebroventricularly increased PRA twofold and ADH fourfold (vs. their basal level). These results suggest that in dogs, endogenous histamine liberated from brain mast cells may increase renin and Epi secretion (via the sympathetic outflow) and ADH secretion (via the central nervous system).

The Effects of Different Dobutamine Infusion Rates on Hypercapnic Depression of Diaphragmatic Contractility in Pentobarbital-Anesthetized Dogs

Previously, we demonstrated that dobutamine was more effective than dopamine for the improvement of diaphragmatic contractility during hypercapnia. Here, we studied the effects of different dobutamine infusion rates on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs. Animals were divided into four groups of six each. In each group, hypercapnia (80-90 mm Hg) was produced by adding 10% CO2 to inspired gas. When hypercapnia was established, group Dob 0 received no study drug; group Dob 5 was induced with dobutamine 5 microg x kg(-1) x min(-1); group Dob 10 was induced with dobutamine 10 microg x kg(-1) x min(-1); group Dob 15 was induced with dobutamine 15 microg x kg(-1) x min(-1). Study drugs were administered IV for 60 min. Diaphragmatic contractility was assessed by measurement of transdiaphragmatic pressure (Pdi). In the presence of hypercapnia, in each group, Pdi at low-frequency (20 Hz) and high-frequency (100 Hz) stimulation decreased from baseline (P < 0.05). In group Dob 0, Pdi to each stimulus did not change from hypercapnia-induced values. In groups Dob 5, Dob 10 and Dob 15, during the study drug administration, Pdi at both stimuli increased from hypercapnia-induced values (P < 0.05). There was a significant positive correlation between dobutamine infusion rates and Pdi at both stimuli (P = 0.0001). Dobutamine effectively improves hypercapnic depression of diaphragmatic contractility in an infusion rate-dependent manner in pentobarbital-anesthetized dogs.

Effects of milrinone and olprinone on hypercapnic depression of diaphragmatic contractility in pentobarbital-anesthetized dogs

Abstract. Hypercapnia is associated with diaphragm muscle dysfunction that is a reduction of diaphragmatic force generated for stable electric myographic activity. The purpose of this study was to test the effects of milrinone and olprinone on decreased diaphragmatic contractility induced by hypercapnia in pentobarbital-anesthetized dogs. This experimental study was conducted at the Department of Anesthesiology, University of Tsukuba, Institute of Clinical Medicine, Tsukuba, Japan. Hypercapnia (partial pressure of carbon dioxide [CO2] in arterial blood 80-90 mm Hg) was induced by adding 10% CO2 to the inspired gas. When hypercapnia was established, group 1 received no study drug, group 2 was infused with milrinone (50 g/kg initial dose plus 0.5 g/kg · min(-1) thereafter), and group 3 was infused with olprinone (10 g/kg initial dose plus 0.3 g/kg · min(-1) thereafter). Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi). Twenty-four, healthy, adult mongrel dogs were used in the study; 8 dogs were assigned to each treatment group. In the presence of hypercapnia, in each group, Pdi (mean [SD], cm-H2O) at low-frequency (20 Hz) and highfrequency (100 Hz) stimulation significantly decreased from baseline (group 1: 20 Hz, 15.1 [2.4] vs 13.3 [2.7]; 100 Hz, 23.1 [2.7] vs 20.6 [2.5], both, P = 0.001; group 2: 20 Hz, 15.2 [2.0] vs 13.2 [2.5]; 100 Hz, 23.0 [2.5] vs 20.5 [2.5], both, P = 0.001; group 3: 20 Hz, 15.0 [2.2] vs 13.2 [2.1]; 100 Hz, 23.0 [2.5] vs 20.5 [2.7], both, P = 0.001). In group 1, the change in Pdi with regard to each stimulus was not significant when compared with the hypercapnia-induced values. In groups 2 and 3, during study-drug administration, Pdi increased significantly in response to both stimuli compared with hypercapnia-induced values (group 2: 20 Hz, 13.2 [2.5] vs 18.8 [2.2]; 100 Hz, 20.5 [2.5] vs 27.7 [2.3], both, P = 0.001; group 3: 20 Hz, 13.2 [2.1] vs 22.3 [3.5]; 100 Hz, 20.5 [2.7] vs 30.8 [2.2], both, P = 0.001). The increase in Pdi with both stimuli was significantly greater in group 3 than in group 2 (20 Hz, 22.3 [3.5] vs 18.8 [2.2], P = 0.035; 100 Hz, 30.8 [2.2] vs 27.7 [2.3], P = 0.046). The results of this experimental study of the effects of milrinone and olprinone on hypercapnic depression of diaphragmatic contractility in these pentobarbital-anesthetized dogs suggest that olprinone and milrinone significantly improved diaphragm muscle dysfunction induced by hypercapnia. The effects of olprinone were significantly greater than those of milrinone. Further studies are needed to determine the optimal dose of the study drugs.

Olprinone/dopamine combination for improving diaphragmatic fatigue in pentobarbital-anesthetized dogs

Background: Diaphragmatic fatigue might contribute to the development of respiratory failure. In particular, the spontaneous, natural rate of phrenic nerve discharge occurs mainly in low-frequency ranges making low-frequency fatigue clinically important in both humans and animals. Olprinone, a phosphodiesterase 3 inhibitor, improves contractility in fatigued diaphragm, but is also associated with hypotension. Dopamine might be used concomitantly for treating related hypotension. Objective: The purpose of the study was to assess the effect of olprinoneplus dopamine on diaphragmatic fatigue in pentobarbital-anesthetized dogs. Methods: This nonblinded study was conducted at the Department ofAnesthesiology, Institute of Clinical Medicine, Tsukuba, Japan. Diaphragmatic fatigue (assessed by a decrease in diaphragmatic contractility) was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 minutes. Immediately after the fatigue-producing period, groups 2, 3, and 4 received an initial 10 μg/kg dose of olprinone. Group 2 then received maintenance olprinone of 0.3 μg/kg · min; group 3 received maintenance olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min; and group 4 received maintenance olprinone 0.3 μg/kg · min plus dopamine 5 μg/kg · min. Group 1 received no study drug. Olprinone and dopamine were administered IV for 30 minutes. Diaphragmatic contractility was assessed by measuring the maximal transdiaphragmatic pressure (Pdi) generated by test stimuli after airway occlusion at functional residual capacity. Hypotension induced by the study drugs was defined as a >10 mm Hg decrease in mean arterial pressure (MAP), calculated by diastolic pressure plus ⅓ pulse pressure, from baseline. Results: Twenty-eight mongrel dogs (18 males and 10 females, weighing 10-15 kg)were used in the study; 7 dogs were randomly assigned to each treatment group. When fatigue was established in each group, mean (SD) Pdi at low-frequency (20 Hz) stimulation decreased significantly from baseline in all groups (group 1: 15.6 [2.2] vs 11.7 [2.4] cm H 2O, P = 0.008; group 2: 15.4 [1.5] vs 11.6 [1.3] cm H 2O, P= 0.005; group 3:15.5 [2.0] vs 11.6 [1.8] cm H 2O, P= 0.006; group 4: 15.7 [1.4] vs 12.0 [1.4] cm H 2O, P= 0.008), while no significant change existed in Pdi at high-frequency (100 Hz) stimulation ( P = NS). After study drug administration, Pdi in groups 2, 3, and 4 increased significantly from fatigued values at both 20 Hz stimulation (group 2: 11.6 [1.3] vs 21.8 [2.0] cm H 2O, P = 0.001; group 3: 11.6 [1.8] vs 22.2 [1.8] cm H 2O, P = 0.001; group 4: 12.0 [1.4] vs 25.9 [1.9 ] cm H 2O, P = 0.001) and 100 Hz stimulation (group 2: 22.0 [2.2] vs 29.0 [1.9] cm H 2O, P = 0.002; group 3: 22.1 [2.0] vs 29.3 [2.2] cm H 2O, P = 0.002; group 4: 21.8 [2.2] vs 31.7 [2.4] cm H 2O, P= 0.001). The increase in Pdi was significantly larger in group 4 compared with the other 3 groups (all, P < 0.05). Hypotension was not observed in group 4. MAP did not change significantly in group 1 or group 4 compared with baseline or fatigued MAP values ( P = NS). Groups 2 and 3 had significant decreases in MAP with treatment compared with values in group 1 and with baseline and fatigued MAP values (all, P < 0.05). The MAP of group 4 was significantly greater than the MAP of groups 2 and 3 with treatment (both, P < 0.05). Conclusions: Olprinone 0.3 μg/kg sd min plus dopamine 5 μg/kg · min improved contractility in fatigued diaphragms and was not associated with hypotension in these pentobarbital-anesthetized dogs. Olprinone monotherapy and olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min might improve contractility significantly. However, it was also associated with significant decreases in MAP.

Hemodynamic effects of bupropion in anesthetized dogs

Bupropion is a non-nicotinic drug used in smoking cessation therapy. However, its acute effects remain unclear. In this study, we investigated the effects of bupropion on hemodynamic parameters in pentobarbital-anesthetized mongrel dogs. Bupropion administered either in bolus injections (3 or 6 mg/kg, i.v.) or in cumulative doses of 0.01, 0.1, 1, 3 and 10 mg/kg showed, in both studies, a significant increase of mean pulmonary arterial pressure and pulmonary vascular resistance index. These results show that bupropion can elevate the pulmonary pressure. Further investigations should be done to test this effect in smokers with chronic obstructive pulmonary disease.

S-wave in lead III is helpful for the early detection of bupivacaine-induced cardiac depression in dogs

Unintentional intravascular bupivacaine injection is known to be associated with treatment-resistant cardiovascular collapse. Therefore, it is important for safe anesthetic management to establish an early sign of bupivacaine-induced cardiac depression with available monitoring. We hypothesized that bupivacaine induced-cardiac depression in dogs could be detected early by analyzing the electrocardiogram (ECG). We performed this study to investigate changes of ECG and ultimately find a variable reflecting cardiac output (CO) changes in dogs with bupivacaine-induced cardiac depression.Bupivacaine was infused into pentobarbital-anesthetized dogs (n = 9) at a rate of 0.5 mg x kg(-1) x min(-1) for 30 min. R-wave, S-wave and T-wave amplitudes in leads I, II and III were measured every five minutes after the start of bupivacaine infusion, and electrical axes of the heart were calculated at each time. The PR interval, QRS complex duration and corrected QT interval were also measured. CO, mean arterial blood pressure and heart rate were recorded at five-minute intervals. The relationships between CO and ECG wave parameters and of CO vs the hemodynamic variables were compared by correlation coefficients and regression analysis.The electrical mean axis of the heart was deviated to the left by the bupivacaine infusion. S-wave in lead III increased approximately twice within the first five minutes and showed the closest correlation with CO (r = 0.751, P < 0.001) during 30 min bupivacaine infusion.Close monitoring of an ECG, and especially the S-wave amplitude in lead III can be helpful for the early detection of bupivacaine-induced cardiac depression in dogs.

Effects of diazepam on diaphragmatic functionand recovery in pentobarbital-anesthetized dogs: An open-label, dose-finding, pharmacologic study

Background: Diazepam, a highly lipid-soluble benzodiazepine, is commonly used as a sedative agent during and after surgery. Based on a literature search, no published data are available concerning diaphragmatic function (as measured by contractility and electrical activity) during and after the administration of diazepam. Objective: The purpose of this study was to assess the effects of diazepam use on diaphragmatic function and recovery in pentobarbital-anesthetized dogs. Methods: This open-label, dose-finding, pharmacologic study was conductedat the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Healthy adult mongrel dogs weighing 10 to 15 kg were assigned to 1 of 3 study groups: low dose (0.2-mg/kg) diazepam, high-dose (0.5-mg/kg) diazepam, or control (no study drug). Each dog was anesthetized with pentobarbital 2 mg/kg · h IV Study drug was administered IV for 1 hour. Diaphragmatic function was assessed before (baseline) and at 0 (immediately after), 1, and 2 hours after the end of study drug administration, using measurement of transdiaphragmatic pressure (Pdi), defined as the difference between gastric and esophageal pressures, and by integrated electrical activity (20- and 100-Hz stimulation) of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm. The percentage changes from baseline in Edi-cru (%Edi-cru) and Edi-cost (%Edi-cost) were calculated. Results: Twenty-four mongrel dogs were used in the study; 8 dogs were assigned to each treatment group. During diazepam administration in the low-dose group, significant decreases from baseline in Pdi were found with 20-Hz stimulation (15.6 [1.7] vs 13.3 [1.9] cm H 2O; P < 0.05) and 100-Hz stimulation (22.0 [2.1] vs 19.6 [1.8] cm H 2O; P < 0.05). In the high-dose group, the decreases in Pdi were significant with 20-Hz stimulation (15.5 [1.8] vs 10.0 [2.0] cm H 2O; P < 0.05) and 100-Hz stimulation (22.2 [1.9] vs 16.2 [ 2.0 ] cm H 2O; P < 0.05). In the low-dose group at 100-Hz stimulation, mean (SD) %Edi-cru and %Edi-cost were significantly lower compared with baseline (88.8% [6.6%] and 88.5% [5.9%], respectively; both, P < 0.05). In the high-dose group at 100-Hz stimulation, mean (SD) %Edi-cru and %Edi-cost were significantly lower compared with baseline (77.5% [4.3%] and 78.0% [5.0%], respectively; both, P < 0.05). The decreases in Pdi, %Edi-cru, and %Edi-cost were significantly greater in the high-dose group compared with the low-dose group (all, P < 0.05). Conclusion: The results of this experimental study of the effects of diazepamon diaphragmatic function and recovery in pentobarbital-anesthetized dogs suggest that diazepam inhibits diaphragmatic function in a dose-related manner and delays recovery.

The effect of insulin on the resuscitation of bupivacaine-induced severe cardiovascular toxicity in dogs.

Resuscitation after bupivacaine-induced cardiovascular collapse is difficult and often resistant to conventional treatment. We tested the hypothesis that insulin treatment would effectively reverse bupivacaine-induced cardiovascular collapse in pentobarbital-anesthetized dogs. Bupivacaine was administered at 0.5 mg. kg(-1). min(-1) until mean arterial blood pressure decreased to 40 mm Hg or less. In the insulin-glucose-potassium (IGK) group (n = 7), an IV bolus of regular insulin (2 U/kg) was given, followed by a glucose infusion (2 mL/kg of 50% dextrose in water) for 30 min and a potassium infusion (1-2 mmol. kg(-1). h(-1)). In the control group (n = 7), glucose infusion was given as in the IGK group. In contrast to the control group, all IGK dogs survived. Mean arterial blood pressure, heart rate, cardiac output, mixed venous oxygen saturation, and end tidal CO(2) recovered toward baseline levels in the IGK group. In conclusion, severe bupivacaine-induced cardiovascular collapse in dogs was effectively reversed with the insulin treatment.

ACUTE CARDIOPULMONARY EFFECTS OF A DUAL–ENDOTHELIN RECEPTOR ANTAGONIST ON OLEIC ACID–INDUCED PULMONARY ARTERIAL HYPERTENSION IN DOGS

The objective of this study was to evaluate the cardiopulmonary effects of a dual–endothelin (ET) receptor antagonist, Tezosentan, on oleic acid (OA)-induced acute lung injury with pulmonary arterial hypertension in dogs. Twelve pentobarbital-anesthetized dogs with intravenous OA-induced acute lung injury (ALI) were divided into 2 groups. The control group (n = 6) received saline treatment, whereas the treatment group (n = 6) received the ET receptor antagonist, Tezosentan (1 mg/kg intravenous [IV] + 1 mg/kg/h IV infusion). Cardiopulmonary parameters were monitored continuously for 1 hour. OA administration resulted in a significant increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) and a decrease in mean systemic arterial pressure (MSAP), systemic vascular resistance (SVR), and cardiac output (CO) in all dogs. Tezosentan treatment markedly attenuated the pulmonary hypertension, with a 32% decrease in MPAP (from 23±2 mm Hg to 15±2 mm Hg; P < .01) and a 22% decrease in PVR (from 860±105 dyn · s · cm−5to 670±96 dyn · s · cm−5; P < .01) at the end of study. MSAP and SVR were unchanged after Tezosentan treatment, and there was an increase in cardiac output and a decline in peak inspiratory pressure (PIP) in the Tezosentan group compared with the control group. These results indicate that the dual–ET receptor antagonist, Tezosentan, can attenuate the pulmonary hypertension induced by OA. Thus, dual–ET receptor antagonists such as Tezosentan may be useful in the management of acute pulmonary arterial hypertension, complicating the course of OA-induced lung injury.