Awake Dogs Research Articles

Diastolic right ventricular filling vortex in normal and volume overload states.

Functional imaging computational fluid dynamics simulations of right ventricular (RV) inflow fields were obtained by comprehensive software using individual animal-specific dynamic imaging data input from three-dimensional (3-D) real-time echocardiography (RT3D) on a CRAY T-90 supercomputer. Chronically instrumented, lightly sedated awake dogs (n = 7) with normal wall motion (NWM) at control and normal or diastolic paradoxical septal motion (PSM) during RV volume overload were investigated. Up to the E-wave peak, instantaneous inflow streamlines extended from the tricuspid orifice to the RV endocardial surface in an expanding fanlike pattern. During the descending limb of the E-wave, large-scale (macroscopic or global) vortical motions ensued within the filling RV chamber. Both at control and during RV volume overload (with or without PSM), blood streams rolled up from regions near the walls toward the base. The extent and strength of the ring vortex surrounding the main stream were reduced with chamber dilatation. A hypothesis is proposed for a facilitatory role of the diastolic vortex for ventricular filling. The filling vortex supports filling by shunting inflow kinetic energy, which would otherwise contribute to an inflow-impeding convective pressure rise between inflow orifice and the large endocardial surface of the expanding chamber, into the rotational kinetic energy of the vortical motion that is destined to be dissipated as heat. The basic information presented should improve application and interpretation of noninvasive (Doppler color flow mapping, velocity-encoded cine magnetic resonance imaging, etc.) diastolic diagnostic studies and lead to improved understanding and recognition of subtle, flow-associated abnormalities in ventricular dilatation and remodeling.

Short-term administration of ethanol does not affect functional recovery from myocardial stunning in awake dogs.

Chronic ingestion of small doses of ethanol protects the myocardium from ischemic damage. It was demonstrated that short-term administration of ethanol (SAE) enhances the recovery of stunned myocardium in acutely instrumented, anesthetized dogs. It is unclear whether this beneficial effect of SAE also occurs in awake dogs. Therefore, we investigated the effects of SAE on regional myocardial stunning in awake dogs. Thirty-six dogs were chronically instrumented for measurement of heart rate, left atrial, aortic, and left ventricular pressure, left systolic ventricular contactility (dP/dt(max)) and diastolic ventricular function (dP/dt(min)), and regional myocardial wall-thickening fraction (WTF). Occluders around the left anterior descending (LAD) artery allowed the induction of reversible ischemia in the LAD-perfused myocardium. The dogs were assigned to one of three groups that differed in the dose of ethanol administered in the ethanol experiment (I, 0.125 g/kg [n = 12]; II, 0.25 g/kg [n = 12]; III, 0.5 g/kg [n = 12]). In each group, the dogs underwent two ischemic episodes (randomized crossover fashion; separate days): 10 min of LAD occlusion after the application of ethanol IV over 30 min (ethanol group) and without ethanol (control). WTF and hemodynamic variables were measured at baseline and at predetermined time points until complete recovery of myocardial stunning occurred. LAD-ischemia led to a significant decrease of LAD-WTF in all groups. There was no difference in WTF and hemodynamic variables with or without SAE during reperfusion. We conclude that SAE (0.125 g/kg, 0.25 g/kg, and 0.5 g/kg) does not significantly affect myocardial stunning in conscious dogs. In contrast to previous experiments in anesthetized dogs, short-term administration of ethanol does not alter myocardial stunning in conscious dogs.

Comparison of vasodilation by CVT-3146, a novel A2Areceptor agonist, and adenosine in different vascular beds in awake dogs

Comparison of vasodilation by CVT-3146, a novel A2Areceptor agonist, and adenosine in different vascular beds in awake dogs

Impact of autologous skeletal myoblast transplantation on hemodynamics and left ventricular function in repeated coronary microembolization-induced heart failure in awake dogs

Impact of autologous skeletal myoblast transplantation on hemodynamics and left ventricular function in repeated coronary microembolization-induced heart failure in awake dogs

Long-Term Measurement of Bronchial Vascular Resistance in Awake Sheep and Dogs

Long-Term Measurement of Bronchial Vascular Resistance in Awake Sheep and Dogs

Selective A2A adenosine receptor agonist as a coronary vasodilator in conscious dogs: potential for use in myocardial perfusion imaging.

The authors sought to demonstrate the advantages of a selective, potent, short-acting A adenosine receptor agonist, CVT-3146 (2-(N-pyrazolyl)Ado derivative), for potential clinical use as a coronary vasodilator during myocardial perfusion imaging. The use of adenosine in a pharmacological stress test during myocardial imaging is limited by side effects mediated by A1 and A2B adenosine receptors and by its ultrashort duration of action. CVT-3146 (0.1-5 microg/kg) and adenosine (13-267 microg/kg) were given as peripheral intravenous injections in 10 awake dogs instrumented for measurement of coronary blood flow (CBF). CVT-3146 caused a dose-dependent increase of CBF (ED50 = 0.34 +/- 0.08 microg/kg, maximal increase = 221 +/- 18%, n = 6). Adenosine was less potent (ED = 51 +/- 15 microg/kg, p < 0.05) but equieffective (maximal increase in CBF = 227 +/- 11%). The increase in CBF caused by 2.5 microg/kg CVT-3146 reached 84 +/- 5% of the maximal reactive hyperemia following 20 s of coronary occlusion (n = 4). After a 10-s injection of CVT-3146 (2.5 microg/kg), the increase in CBF remained at least twofold above baseline for 97 +/- 14 s, whereas for adenosine (267 microg/kg), the twofold increase in CBF lasted only 24 +/- 2 s (p < 0.01, n = 6). A 30-s injection of 2.5 microg/kg CVT-3146 prolonged the twofold increase in CBF up to 221 +/- 20 s. No atrioventricular block was noted. At 2.5 microg/kg, the peak effect of CVT-3146 on CBF was associated with a short-lasting (20 +/- 6 s) increase in heart rate (78 +/- 9 bpm) and decrease in mean arterial blood pressure (13 +/- 6 mm Hg, p < 0.05, n = 6). CVT-3146 is a potent coronary vasodilator. Its short duration of action, minimal and transient systemic hemodynamic effects, and ease of administration may make this agonist suitable for pharmacological coronary vasodilation during myocardial perfusion imaging for noninvasive detection of subcritical arterial stenosis.

Naloxone prevents increased atrial natriuretic peptide release during regional myocardial ischaemia and stunning in awake dogs

Atrial natriuretic peptide (ANP) release is increased in patients with ischaemic left ventricular dysfunction. A beneficial effect of naloxone on recovery from myocardial stunning was shown previously. The aim of this study was to investigate the effects of naloxone on ANP release during regional myocardial ischaemia and stunning in awake dogs. Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic, and left ventricular pressure (LVP), LV dP x dtmax/min(-1), and myocardial wall-thickening fraction. An occluder around the left anterior descending artery (LAD) allowed induction of reversible ischaemia in the LAD-perfused myocardium. Each dog underwent two ischaemic episodes (randomized crossover fashion; separate days): 10 min of LAD occlusion (1) after application of naloxone (63 microg kg(-1)), and (2) without naloxone. ANP levels were measured at baseline (BL) and at predetermined time points until complete recovery of myocardial stunning occurred. LAD ischaemia-induced release of ANP (peak level: 182 (30) vs 27 (7) pg ml(-1) BL) only in the control group without naloxone. Between 1 and 180 min of reperfusion, ANP levels were significantly higher only in the control group (P<0.05). Pre-ischaemic application of naloxone prevents this ischaemia-induced ANP-release in conscious dogs.

Endogenous endothelin and vasopressin support blood pressure during epidural anesthesia in conscious dogs.

We studied whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during high epidural anesthesia when efferent sympathetic drive is diminished. On different days, six awake dogs underwent each of the following five interventions: blockade of vasopressin V(1a) receptors using [d(CH(2))(5)Tyr(Me(2))]AVP, (40 microg/kg) or endothelin receptors using tezosentan (3 mg/kg followed by 3 mg. kg(-1). h(-1)) with or without epidural anesthesia (1% lidocaine, intraindividual dose did not differ between experiments), and epidural saline (n = 5). The effects of endothelin- or vasopressin-receptor blockade were analyzed (means +/- SEM) and compared by an analysis of variance for repeated measures (paired Student's t-test, alpha-adjusted, P < 0.05). Vasopressin-receptor blockade decreased blood pressure (10 +/- 2 mm Hg) only in the presence of epidural anesthesia, whereas endothelin-receptor blockade reduced blood pressure both in the presence and absence of epidural anesthesia (12 +/- 3 versus 10 +/- 1 mm Hg). During baseline and each intervention, plasma concentrations of vasopressin and big-endothelin were measured and compared by a Wilcoxon's rank sum test; P < 0.05. Vasopressin concentrations increased during epidural anesthesia and after additional endothelin receptor blockade, but big-endothelin concentrations remained unchanged during each intervention. We conclude that vasopressin acts as a reserve system, as it stabilizes blood pressure specifically during epidural anesthesia, whereas the unchanged concentrations of big-endothelin indicate that the endothelin system is not specifically activated to support blood pressure during epidural anesthesia. We studied in awake dogs whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during resting conditions and epidural anesthesia. Only vasopressin was specifically activated to support blood pressure during epidural anesthesia, whereas endothelin supported blood pressure to the same extent during epidural anesthesia and during resting conditions.

Effects of antagonism of NMDA receptors on transient lower esophageal sphincter relaxations in the dog

Transient lower esophageal sphincter relaxation is the major cause of gastroesophageal reflux. Mechanisms underlying transient lower esophageal sphincter relaxation are poorly understood although gastric mechanosensitive vagal afferent pathways play a central role. Glutamate is a key transmitter of vagal afferents acting partly on NMDA receptors. The aim of this work was to study the effects on transient lower esophageal sphincter relaxation in awake dogs ( n=5) of the competitive NMDA receptor antagonist cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755; 0.3 and 3 mg/kg i.v., the high dose was given at two separate occasions to each dog). Transient lower esophageal sphincter relaxations were evoked by intragastric infusion of a liquid meal followed by air insufflation and were scored during a 45-min period. Neither dose produced any significant effect on the group average number of transient lower esophageal sphincter relaxations. Synchronous contractions of the esophagus were commonly seen during transient lower esophageal sphincter relaxation and CGS 19755 at both doses greatly reduced their occurrence. The findings indicate that NMDA receptor antagonism selectively inhibits the esophageal component of transient lower esophageal sphincter relaxation although the rate of transient lower esophageal sphincter relaxations is not consistently affected.

Nitric oxide synthases in vagal neurons are crucial for the regulation of heart rate in awake dogs.

Nitric oxide synthase (NOS) inhibitors elicit bradycardias independent of the endothelium (e-NOS) or increases in blood pressure. Therefore, this bradycardia could be mediated by other NOS isoforms, most likely that of the nervous system (n-NOS). If so, heart rate variability (HRV) as a measure of vagal activity should be an indicator of the activity of n-NOS in vagal neurons. To test this, we studied the dose-effect relations of L-NAME (0.3 - 50 mg x kg(-1)) on heart rate (HR), HRV and systemic vascular resistance (SVR) in seven awake dogs. HRV was analyzed in the time domain as standard deviation of the RR-intervals (SDNN) and in the frequency domain as power in the high (0.15 - 0.5 Hz) and low (0.04 - 0.15 Hz) frequency range. The effects of HR and SDNN reached their maxima at a dose of 3 mg x kg(-1) and had their ED50 at 0.27 +/- 0.03 mg x kg(-1) and 0.43 +/- 0.1 mg x kg(-1), respectively, whereas SVR had its maximum at 10 mg x kg(-1) and ED50 at 0.86 +/- 0.11 mg x kg(-1) (p < 0.05). HF-power (vagal activity) predominated compared to LF-power (mainly sympathetic activity) during baseline as well as after L-NAME. The effects on HR and HRV were absent after ganglionic blockade (hexamethonium), whereas the effects on SVR remained unchanged. Thus, NO exerts a powerful restraining activity on vagal neurons and plays a key role in the adjustment of heart rate in awake resting animals with prevailing vagal activity.

Effects of thoracic epidural anesthesia with and without autonomic nervous system blockade on cardiac monophasic action potentials and effective refractoriness in awake dogs.

The effects of thoracic epidural anesthesia (TEA) on myocardial repolarization and arrhythmogenicity are only incompletely understood. This is primarily because of the lack of appropriate experimental models. In most of the studies performed thus far, TEA was used in anesthetized animals. Baseline anesthesia itself may have modified the effects of TEA. This study investigates right atrial and ventricular repolarization by recording monophasic action potentials after TEA in awake dogs. The authors hypothesized that an antiarrhythmic role of TEA exists, which may be related to a direct effect of TEA on myocardial repolarization. The hypothesis was tested in an in vivo canine model, in which atrial and ventricular myocardial action potential duration and refractoriness are recorded by means of monophasic action potential catheters. Thoracic epidural anesthesia significantly increased ventricular monophasic action potential duration for cycle lengths shorter than 350 ms. Changes in monophasic action potential duration were paralleled by a concomitant prolongation of effective refractory period (ERP) at higher rates so that the ratio of ERP to action potential duration was unaffected. This model helps to study the role of TEA on ventricular repolarization and arrhythmogenicity. Because lengthening of repolarization and prolongation of refractoriness may, in some circumstances, be antiarrhythmic, TEA may be protective against generation of ventricular arrhythmias mediated, e.g., by increased sympathetic tone. The results also imply that the beneficial role of TEA might be stronger at the ventricular site as compared with the atrium. At atrial sites there was only a trend toward prolongation of repolarization even at short cycle lengths.

In vivo recording of monophasic action potentials in awake dogs--new applications for experimental electrophysiology.

Despite enormous developments in the field of clinical and experimental electrophysiology there is still a gap in evaluating repolarization in the awake animal. Numerous previous studies have used monophasic action potentials (MAP) to assess repolarization in vitro and in vivo in anesthetized animal models. However, an approach for recording MAP in awake dogs without interference of anesthesia has not yet been developed. We developed an experimental technique to record MAP in conscious dogs by means of conventional rubber introducers which were implanted into the internal jugular vein. In seven awake dogs, atrial as well as ventricular MAP were simultaneously measured without complications. Pacing thresholds were low and stable over time ranging from 0.2 to 4.0 mA. The MAP amplitudes ranged from 10 to 30 mV for ventricular and from 5 to 15 mV for atrial MAP. Continuous MAP recordings of stable amplitude could be made from the same endocardial site for periods of up to one hour. Antegrade and retrograde AV-nodal conduction properties could be assessed. Programmed stimulation was performed to simultaneously determine local refractory periods and MAP duration at cycle lengths from 500 to 200 ms. In awake, unsedated dogs the measurement of MAP via rubber introducers permits safe, long-term recording of MAP. Such recordings may be useful for safety pharmacological studies in evaluating cardiovascular and non-cardiovascular drugs with regard to their effects on repolarization. In various canine in vivo models including in vivo models of long QT syndrome, heart failure or sudden cardiac death, the present technique permits electrophysiological measurements without interference of anesthesia.

A method for visualizing the dorsal acetabular rim and the coverage of the femoral head

SummaryThe authors describe a new technique to visualize the dorsal acetabular rim and the coverage of the femoral head in the nonsedated dog. The technique involves using an overhead beam, directed at an angle tangential to the dorsal rim of the acetabulum, with a film positioned caudal to the standing dog. Anatomical landmarks that can routinely be identified include: the ilial crest, ilial shaft, ischial tuberosity, acetabulum, acetabular rim (particularly the dorsocaudal component), femoral head, greater trochanter, femoral neck, femoral shaft, rectum and the tail. Because the animal is standing and is not sedated, the technique may have additional value as a means of evaluating subluxation of the hip joint. It maintains a posture as close as possible to that experienced by the animal in normal activity. If the technique has prognostic value in that regard, more investigation is needed, but it is useful in itself as a technique to visualize the area of the acetabulum.A new radiographic technique to evaluate the canine hip joint is described. The view involves tangential projection of the acetabulum in the standing, awake dog. Nineteen dogs have been radiographed to develop the technique and the method has been found to be technically simple and consistent. It allows examination of the dorsal acetabular rim and may help examine the amount of subluxation of the hip as well as the presence of any degenerative joint disease. The authors advocate additional study to determine the technique’s prognostic value in predicting degenerative change associated with hip dysplasia.

Left stellate ganglion block has only small effects on left ventricular function in awake dogs before and after induction of heart failure. (Institut für Klinische Anaesthesiologie, Heinrich‐Heine‐Universität, Düsseldorf, Germany) Anesth Analg 2000;91:787–792.

This study investigated the effects of left stellate ganglion block (LSGB) in chronically instrumented awake dogs before and after the induction of pacing‐induced congestive heart failure. Twelve dogs were instrumented for measurement of global hemodynamics (LV pressure [LVP]), its first derivative, cardiac output (CO), and regional myocardial function (systolic posterobasal, segment length shortening, mean velocity [SLmv]). Before the induction of heart failure, LSGB did not affect CO and SLmv, but slightly reduced LVP. Conclude that even during heart failure the hemodynamic changes after LSGB are small, confirming a broad margin of safety.Comment by James E. Heavner, D.V.M., Ph.D. The outcomes of this very nice animal study should provide some comfort to clinicians that perform stellate ganglion blocks on patients with a history of heart failure. In chronically instrumented animals, left stellate ganglion block had minimal affect on cardiac function either before or after heart failure had been induced. However, caution should always be exercised in extrapolating animal data to humans. In this regard, the investigators point out that in healthy humans, an impairment of left ventricular relaxation can be seen after left stellate ganglion block. They further caution that patients with acute heart failure in whom the response to changes in sympathetic tone is maintained, may be more susceptible to the adverse effects of left stellate ganglion block on cardiac dynamics.

Relation between oxygen consumption and cardiac output during inhalation anesthesia under the influence of catecholamines. A study in dogs

The metabolic regulation of tissue blood flow manifests itself in a linear relation between blood flow and oxygen consumption (VO2). It is unknown, however, if this fundamental physiological principle operates also during inhalation anaesthesia and catecholamine therapy, both known to be associated with changes of cardiac output (Q) and VO2 in opposite directions. On different days, 17 trained, healthy dogs (26-33 kg) with chronically implanted flow probes around the pulmonary artery were either anaesthetized with halothane, enflurane, isoflurane, sevoflurane, and desflurane at increasing minimum alveolar concentrations (1-3 MAC) or treated with one of the endogenous catecholamines epinephrine and norepinephrine or the synthetic ones dobutamine and dopexamine (a total of 186 experiments). Cardiac Output (ultrasound transit-time flowmeter) and VO2 (indirect calorimetry) were measured continuously and the relations between both variables (Q/VO2 relations) analyzed. In awake dogs under basal metabolic conditions, VO2 was 4.6 +/- 0.1 ml x kg-1 x min-1 and Q 105 +/- 3 ml x kg-1 x min-1 (mean +/- SEM). During inhalation anaesthesia, VO2 and Q decreased in parallel, yielding a uniform Q/VO2 relation, which was nearly linear. Above 2 MAC, O2 extraction increased by 50%, indicating compromised oxygen delivery (DO2). Imposed increases in Q and thus DO2 during anaesthesia to rates comparable to that in the awake state did not restore VO2 to baseline. Catecholamines increased both VO2 and Q in a dose-dependent manner, albeit to a different extent. The resulting Q/VO2 relations were linear up to the maximum effects, but their slopes increased about threefold in the order norepinephrine (34), epinephrine (54), dobutamine (86), and dopexamine (105). Despite these differences, VO2 and Q correlated linearly over the whole range studied, which covered a doubling of VO2 and an up to fourfold increase in Q. The metabolic regulation of blood flow apparently also operates during inhalation anaesthesia, regardless of the anaesthetic. Catecholamines (except norepinephrine) preferentially stimulated Q rather than VO2 (excess perfusion), so that agents like dopexamine might be preferred in the treatment of low cardiac output states because of its low metabolic costs. Our observations imply that cardiac output alone provides little information on the function of the circulation during inhalation anaesthesia and catecholamine therapy unless related to metabolic demands, i.e. to VO2.

Effect of fentanyl on baroreflex control of circumflex coronary conductance.

1. Fentanyl, a synthetic mciro-opioid receptor agonist, is the preferred induction and maintenance anaesthetic agent in cardiac surgery. 2. Its actions on myocardial blood flow are poorly understood. There are reports of intra-operative myocardial ischaemia. Its reported actions on cardiorespiratory control vary widely, but do involve hypertension, bradycardia and peripheral vasoconstriction. 3. Accordingly, the postulate that fentanyl would cause coronary vasoconstriction and myocardial disadvantage was examined in awake dogs with a continuous wave Doppler flow probe mounted on the circumflex coronary artery. 4. Continuous intravenous infusion of fentanyl citrate (550 ng/kg per min) raised plasma concentrations of fentanyl to 3.37 ng/mL in a linear fashion at 20 min. There was a fall in core temperature of 0.7 degrees C and, although no apparent depression of ventilation or fall in arterial or coronary sinus PO2, there was a rise in PCO2 and H+ concentration. Some dogs salivated and panted transiently. Thus, fentanyl may reset temperature regulation in low doses but, at higher doses, is associated with metabolic acidosis. 5. In sinus rhythm, the arterial pressure of the dogs fell slightly, then rose to 115% of resting control. Circumflex flow and conductance rose early, then conductance steadily declined to 83%. Heart rate fell, then rose before returning to pre-infusion levels. The early circumflex coronary vasodilator effects, but not the later vasoconstrictor effects, were reduced in dogs with paced hearts. 6. In dogs with paced hearts, a dose-effect study using 138, 275, 550 and 1100 ng/kg per min fentanyl suggested that, at low plasma concentrations of 1-2 ng/mL, vasodilatation does occur in both coronary and systemic circulations; however, at higher doses, intense coronary and systemic vasoconstriction supervenes. 7. The dose-response effect of fentanyl on arterial baroreflex control of circumflex conductance was examined during the immediate 8 s circumflex vasodilator response to a step rise in aortic pressure caused by inflation of an intra-aortic balloon. At low plasma concentrations of fentanyl, baroreflex control of circumflex conductance appears to be enhanced but, with increasing plasma concentrations of fentanyl, appears to be depressed. 8. Therefore, the effects of fentanyl are dose dependent. At low plasma concentrations, left ventricular blood flow and its baroreflex control is enhanced but, at higher concentrations, it is depressed.

Left stellate ganglion block has only small effects on left ventricular function in awake dogs before and after induction of heart failure.

Left stellate ganglion block (LSGB) results in acute sympathetic denervation of the left ventricular (LV) posterobasal wall. We investigated the effects of LSGB in chronically instrumented awake dogs before and after the induction of pacing-induced congestive heart failure. Twelve dogs were instrumented for measurement of global hemodynamics [LV pressure (LVP)], its first derivative (dP/dt), cardiac output (CO), and regional myocardial function (systolic posterobasal segment length shortening, mean velocity [SLmv]). Before the induction of heart failure (n = 12), LSGB did not affect CO [3.2+/-1.4 (control, mean +/- SD) vs. 3.3+/-1.6 L/min (LSGB, P = 0.45)] and SLmv (11.1+/-4.0 vs. 10.8+/-4.0 mm/s, P = 0.16), but slightly reduced LVP (130+/-12 vs. 125+/-14 mm Hg, P = 0.04), dP/dt(max) (3614+/-755 vs. 3259+/-644 mm Hg/s, P = 0.003) and dP/dt(min) (-3153+/-663 vs. -2970+/-725 mm Hg/s, P = 0.03). During heart failure (n = 8), global hemodynamics [CO (2.8+/-1.2 vs. 2.7+/-1.2 L/min, P = 0.04), LVP (119+/-6 vs. 112+/-9 mm Hg, P = 0.01), dP/dt(max) (1945+/-520 vs. 1824+/-554 mm Hg/s, P = 0.03) and dP/dt(min) (-2402+/-678 vs. -2243+/-683 mm Hg/s, P = 0.04)], as well as regional myocardial function, were significantly different after LSGB [SLmv] (8.0+/-3.8 vs. 6.9+/-3.4 mm/s, P = 0.02)]. In conclusion, even during heart failure, the hemodynamic changes after LSGB are small, confirming its broad margin of safety.

Chronic exercise training preserves prostaglandin-induced dilation of epicardial coronary artery during development of heart failure in awake dogs☆

Although it has been shown that long-term exercise training preserves endothelium-mediated nitric oxide vasodilator function in chronic heart failure (CHF), whether exercise training exerts similar beneficial effects on endothelial/prostaglandin-mediated vasodilator capacity in coronary circulation during the development of CHF has not been determined. Fifteen mongrel dogs were surgically instrumented for measurement of left ventricular pressure, aortic pressure, coronary blood flow and left circumflex coronary artery diameter. Dogs ( n = 5) who underwent 4 weeks of cardiac pacing (210 b/min for 3 weeks and 240 b/min for the 4th week) developed CHF as characterized by significant reduction in left ventricular systolic pressure, mean arterial pressure and left ventricular dP/dt, increases in left ventricular end-diastolic pressure and heart rate, as well as clinical signs of CHF. Endothelial prostaglandin-mediated vasodilation of the epicardial coronary artery was impaired, as manifested by an attenuated arachidonic acid (AA)-induced dilation of the artery (epicardial artery diameter increased by: 0.78 ± 0.84% in CHF versus 4.6 ± 0.89% in normal, P < 0.05); however, prostacyclin (PGI 2)-induced and nitroglycerin-induced vasodilation of the coronary circulation were not altered. In contrast, dogs ( n = 6) with cardiac pacing plus daily exercise training (4.4 ± 0.3 km/h, 2 h/day) only developed mild cardiac dysfunction, and the response of the epicardial coronary artery diameter to AA was preserved (epicardial artery diameter increased by 4.2 ± 0.98% from baseline, P > 0.05 compared to its respective control). Thus, long-term exercise training preserves endothelial/prostaglandin-mediated dilation of epicardial coronary artery during development of CHF.

Role of Na+-glucose cotransport in jejunal meal-induced absorption.

In awake dogs, meal ingestion stimulates the absorption of water and electrolytes from neurovascularly intact jejunal Thiry-Vella loops, even though these loops are isolated from the remainder of the gut. This study was designed to investigate the role of Na+-glucose cotransport in mediating this event. Meal ingestion enhanced absorption when the jejunal lumen was perfused with an isotonic solution containing D-glucose, D-galactose, or 3-O-methylglucose. This response was absent when the perfusate contained mannitol or when phlorizin was added to the D-glucose solution. Mucosa from the jejunal loops was serially biopsied and assayed for brush-border Na+-glucose cotransporter (SGLT1) mRNA and protein expression. Although no changes in SGLT1 mRNA levels were observed, protein levels significantly increased within 30 min following meal ingestion. The time course of SGLT1 protein expression corresponded with that of increased Na+ and water absorption. These results suggest that meal-stimulated jejunal absorption may be mediated through an induction of mucosal SGLT1.

Clinical effects and plasma concentration determination after 2,4-dichlorophenoxyacetic acid 200 mg/kg administration in the dog.

To investigate the clinical effects and to determine the 2,4-dichlorophenoxyacetic acid plasma concentrations after a dose of twice the reported LD50 (100 mg/kg) was administered orally to dogs. Investigation included electromyographic evaluations and biochemical parameter determinations, as well as observable clinical signs. Six beagle dogs were administered 2,4-dichlorophenoxyacetic acid 200 mg/kg orally. Dogs were monitored for the development of clinical signs and were anesthetized at 24 hours for needle electromyography. Blood was collected pre- and 24-hours postadministration. Plasma was analyzed for total and unbound 2,4-dichlorophenoxyacetic acid by high-performance liquid chromatography with fluorescence detection. Serum was submitted for clinical chemistry parameter analysis. Statistical analyses of the chemistry parameters were performed using paired t-tests. All 6 dogs survived after oral administration of twice the reported LD50. Clinical signs observed were vomiting in 33% and diarrhea in 100% of the dogs. No gait abnormalities were seen in awake dogs. Electromyographic findings revealed predominantly insertional myotonia with 1 dog having spontaneous fibrillations. Decreases from baseline measurements were seen in serum calcium, potassium, and total bilirubin. The mean total and unbound plasma 2,4-dichlorophenoxyacetic acid concentrations were 511 mg/L and 129 mg/L, respectively. This study demonstrates that the beagle dog is less sensitive to the acute effects of 2,4-dichlorophenoxyacetic acid than previously reported. The main clinical effects seen after oral administration of twice the reported LD50 were vomiting and diarrhea. Total and unbound plasma 2,4-dichlorophenoxyacetic acid concentrations may be a useful indicator of toxicity.