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  • Author or Editor: Tomohiro Nakayama x
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Abstract

Objective—To determine acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs.

Animals—14 mature healthy Beagles.

Procedure—12 dogs were anesthetized with morphine and α-chloralose. Catheters were placed in the aorta, left ventricle, and right atrium to record systemic and pulmonary pressures and determine vascular resistance and cardiac output. Electrocardiograms (leads I, aVF, and V3) were recorded to determine electrocardiographic changes. Variables were measured before and after IV injection of incremental doses of carvedilol (cumulative doses, 10, 30, 70, 150, 310, and 630 μg/kg of body weight; n = 6) or vehicle alone (6). Pharmacokinetic analysis was performed, using 2 conscious dogs given 160 mg of carvedilol/kg as a single IV injection.

Results—Heart rate and velocity of fiber shortening at zero load (Vmax) increased slightly but significantly from baseline values at doses of carvedilol ≥ 310 μg/kg and 10 μg/kg, respectively. Carvedilol did not affect systemic and pulmonary pressures or vascular resistances. Intravenous administration of approximately 150 μg of carvedilol/kg resulted in a plasma carvedilol concentration of approximately 100 ng/ml. Mean elimination halflife was 54 minutes, half-life of distribution was 3.5 minutes, and volume of distribution was 2,038 ml/kg.

Conclusions and Clinical Relevance—The therapeutic plasma concentration of carvedilol in humans is 100 ng/ml. At that plasma concentration in dogs, the reduction in afterload and positive inotropic effect that we observed would be beneficial for treating heart failure and minimizing the cardiotoxic effects of doxorubicin. (Am J Vet Res 2000;61:57–60)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast.

Animals—28 Beagles.

Procedure—Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV).

Results—Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in their T waves.

Conclusion and Clinical Relevance—Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dosedependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval. (Am J Vet Res 2000;61:1364–1368)

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in American Journal of Veterinary Research

Abstract

Objective

To determine the effects of various doses of sotalol on myocardial relaxation in healthy dogs.

Animals

12 healthy adult mixed-breed dogs anesthetized with thiopental and α-chloralose.

Procedures

Left ventricular pressure (LVP), aortic pressure, and aortic flow velocity were measured. The time constant of isovolumic relaxation (τ) was determined by means of linear regression of the natural logarithm of LVP and by means of direct measurement from the LVP-versus-time curve. Sotalol was administered IV at cumulative doses of 1, 2, 4, and 8 mg/kg to 6 dogs; the other 6 were used as controls. Mean systolic aortic pressure was used to assess afterload, and maximal rate of increase in LVP versus time (dP/dt) was used as an index of contractility.

Results

After administration of the first dose of sotalol, τ was increased significantly, and maximum dP/dt was decreased significantly, compared with baseline values. Administration of additional doses of sotalol did not result in any additional change in τ, but maximum dP/dt increased, and maximum dP/dt after administration of the final dose of sotalol was significantly higher than maximum dP/dt after administration of the first dose. There were no significant changes in mean systolic aortic pressure.

Conclusions and Clinical Relevance

In healthy dogs, sotalol did not have any negative effect on myocardial relaxation beyond those attributable to its β-blocking properties, despite an increase in intracellular ionized calcium concentration, as suggested by an increase in maximum dP/dt after an initial decrease. (Am J Vet Res 1999;60:717-721)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine the feasibility for use of a 6- minute walk test (6-MWT) in dogs with congestive heart failure (CHF) and document that the distance walked in 6 minutes decreases when a dog has CHF.

Animals—16 young mature male hound-crossbred dogs weighing between 25 and 37 kg.

Procedure—An unobstructed path (22.73 m) was measured in a hallway. Each dog was walked on a leash for 6 minutes; each dog was allowed to set its own pace. At the end of 6 minutes (as measured by use of a stopwatch), the total distance walked was measured. Heart rate (HR) obtained by auscultation and mean systemic arterial pressure (MAP) obtained by oscillometry were recorded before and after the 6- MWT. Heart failure was induced by use of rapid ventricular pacing. Mean of the distance walked, HR, and MAP before and after the 6-MWT were compared between the control period and after dogs developed induced CHF.

Results—Dogs with CHF had a significant increase in resting HR, significant decrease in MAP, and a significant decrease in the distance walked in 6 minutes. The MAP increased slightly after exercise during the control period but decreased slightly after exercise during the CHF period. Fractional shortening decreased significantly when dogs had CHF.

Conclusions and Clinical Relevance—Analysis of these results indicated that the distance walked in 6 minutes decreased significantly when a dog had CHF. The 6-MWT requires little time, space, or equipment and may replace the treadmill exercise test. ( Am J Vet Res 2004;65:311–313)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To investigate the in vitro differentiation of canine bone marrow stromal cells (BMSCs) into functional, mature neurons.

Sample—Bone marrow from 6 adult dogs.

Procedures—BMSCs were isolated from bone marrow and chemically induced to develop into neurons. The morphology of the BMSCs during neuronal induction was monitored, and immunocytochemical analyses for neuron markers were performed after the induction. Real-time PCR methods were used to evaluate the mRNA expression levels of markers for neural stem or progenitor cells, neurons, and ion channels, and western blotting was used to assess the expression of neuronal proteins before and after neuronal induction. The electrophysiological properties of the neuron-like cells induced from canine BMSCs were evaluated with fluorescent dye to monitor Ca2+ influx.

Results—Canine BMSCs developed a neuron-like morphology after neuronal induction. Immunocytochemical analysis revealed that these neuron-like cells were positive for neuron markers. After induction, the cells’ mRNA expression levels of almost all neuron and ion channel markers increased, and the protein expression levels of nestin and neurofilament-L increased significantly. However, the neuron-like cells derived from canine BMSCs did not have the Ca2+ influx characteristic of spiking neurons.

Conclusions and Clinical Relevance—Although canine BMSCs had neuron-like morphological and biochemical properties after induction, they did not develop the electrophysiological characteristics of neurons. Thus, these results have suggested that canine BMSCs could have the capacity to differentiate into a neuronal lineage, but the differentiation protocol used may have been insufficient to induce development into functional neurons.

Full access
in American Journal of Veterinary Research

Abstract

Objective

To examine our hypothesis that changes of the mitral valve in dogs with mitral regurgitation lead to various degrees of protrusion of the cusp in individual dogs in systole.

Design

Assessing the mitral protrusion, using B-mode echocardiography in dogs with mitral regurgitation.

Animals

33 dogs with chronic mitral regurgitation and 40 clinically normal dogs.

Procedure

The mitral valve was imaged in the right parasternal left ventricular long-axis view, and we measured the height (H) from the coaptation point or tip of the protruded cusp to the mitral annular plane. When the tip of the protruded cusp was located beyond the mitral annular plane extending into the left atrium, H was expressed as negative values.

Results

The H in clinically normal dogs was 3.7 ± 0.8 mm. In dogs with mitral regurgitation, the mitral cusp protruded toward the left atrium to various degrees, and H was −0.7 ± 1.9 mm (range, 2.9 to −5.0 mm). The 2 dogs in the latter group with the lowest H (−5.0 and −4.5 mm, respectively) presented typical mitral flail on B-mode images. The indices of left atrial and ventricular dimension (left atrial dimension/aortic dimension and left ventricular end-diastolic dimension/body weight, respectively) were significantly higher than those in the clinically normal dogs and were negatively correlated with H.

Conclusion

The mitral valve in individual dogs with mitral regurgitation has different degrees of protrusion. The degree of protrusion might be related to the hemodynamic condition in mitral regurgitation. (Am J Vet Res 1996;57:791–797)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To describe neuroendocrine responses that develop in dogs subjected to prolonged periods of ventricular pacing.

Animals—14 adult male hound-type dogs.

Procedure—Samples were obtained and neuroendocrine responses measured before (baseline) and after 3 periods of ventricular pacing. A pacemaker was used to induce heart rates of 180, 200, and 220 beats/min (BPM). Each heart rate was maintained for 3 weeks before increasing to the next rate. Atrial natriuretic peptide, antidiuretic hormone, aldosterone, norepinephrine, epinephrine, and dopamine concentrations and plasma renin activity were measured. Severity of left ventricular compromise was estimated.

Results—Shortening fraction decreased significantly with increasing heart rates (mean ± SE, 35.5 ± 1.4, 25.0 ± 1.4, 19.5 ± 1.9, and 12.2 ± 2.3 for baseline, 180 BPM, 200 BPM, and 220 BPM, respectively). Atrial natriuretic peptide concentrations increased significantly at 180 BPM (44.1 ± 3.0 pg/mL) and 200 BPM (54.8 ± 5.5 pg/mL), compared with baseline concentration (36.8 ± 2.6 pg/mL). Dopamine concentration increased significantly at 200 BPM (70.4 ± 10.4 pg/mL), compared with baseline concentration (44.2 ± 7.3 pg/mL). Norepinephrine concentrations increased significantly from baseline concentration (451 ± 46.2 pg/mL) to 678 ± 69.8, 856 ± 99.6, and 1,003 ± 267.6 pg/mL at 180, 200, and 220 BPM, respectively.

Conclusions and Clinical Relevance—Dogs subjected to ventricular pacing for 9 weeks developed neuroendocrine responses similar to those that develop in humans with more chronic heart failure and, except for epinephrine concentrations, similar to those for dogs subjected to ventricular pacing for < 6 weeks. (Am J Vet Res 2002;63:1413–1417)

Full access
in American Journal of Veterinary Research