Anonlethal, Anesthetized Canine Model for Efficacy Evaluation of Anticyanide Therapy

Efficacy evaluations of anticyanide therapeutic compounds historically have used lethality in unanesthetized animals as the toxic endpoint, and a nonlethal, repeated-testing, anesthetized canine model has been reported. Time to respiratory arrest (TRA) induced by a continuous, slow intravenous (IV) infusion of sodium cyanide (Na CN) was shown to be a consistent, well-defined endpoint in anesthetized canines. Thirty seconds after respiratory arrest (RA), an IV bolus of a methemoglobin-forming compound reversed the respiratory effects. This study was designed to determine the variability in TRA, survivability of anesthetized dogs repeatedly infused with Na CN and treated with hydroxylamine, replicability of the procedure within an animal and between animals, and development of trends in data. Four animals were anesthetized, intubated, catheterized, and instrumented to record respiratory rate and heart rate. Immediately following baseline data collection, a 4-mgl m L. Na CN solution w as infused at a rate of 2 m Llmin. Following a 10-s period without functional respiration, infusion was stopped and this moment was designated as RA. Hydroxylamine therapy was administered 30 s after RA. There were 4 replicate experiments per animal with a 1-week washout period between replicates. Interanimal variability in TRA was significant (p = <.04). The average variability in TRA within an animal was less than 10%. Baseline heart and respiratory rates were not altered significantly. Data confirm, by replicate testing, the utility of this model.

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Expiratory muscle contribution to tidal volume in head-up dogs

Journal of Applied Physiology ◽

10.1152/jappl.1989.67.4.1438 ◽

1989 ◽

Vol 67 (4) ◽

pp. 1438-1442 ◽

Cited By ~ 12

Author(s):

G. A. Farkas ◽

M. Estenne ◽

A. De Troyer

Keyword(s):

Tidal Volume ◽

Lung Volume ◽

Muscle Relaxation ◽

Rib Cage ◽

Expiratory Muscle ◽

Residual Capacity ◽

Anesthetized Dogs ◽

Expiratory Muscles ◽

S Period ◽

Average Contribution

A change from the supine to the head-up posture in anesthetized dogs elicits increased phasic expiratory activation of the rib cage and abdominal expiratory muscles. However, when this postural change is produced over a 4- to 5-s period, there is an initial apnea during which all the muscles are silent. In the present studies, we have taken advantage of this initial silence to determine functional residual capacity (FRC) and measure the subsequent change in end-expiratory lung volume. Eight animals were studied, and in all of them end-expiratory lung volume in the head-up posture decreased relative to FRC [329 +/- 70 (SE) ml]. Because this decrease also represents the increase in lung volume as a result of expiratory muscle relaxation at the end of the expiratory pause, it can be used to determine the expiratory muscle contribution to tidal volume (VT). The average contribution was 62 +/- 6% VT. After denervation of the rib cage expiratory muscles, the reduction in end-expiratory lung volume still amounted to 273 +/- 84 ml (49 +/- 10% VT). Thus, in head-up dogs, about two-thirds of VT result from the action of the expiratory muscles, and most of it (83%) is due to the action of the abdominal rather than the rib cage expiratory muscles.

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Pressor Response to Adrenalin Shown by Spinal Dogs

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1956.186.1.85 ◽

1956 ◽

Vol 186 (1) ◽

pp. 85-88

Author(s):

Paul K. Mooring ◽

John Rathe ◽

Walter S. Root

Keyword(s):

Mean Arterial Pressure ◽

Arterial Pressure ◽

Intravenous Injection ◽

Blood Pressure Response ◽

Pressor Response ◽

Percentage Increase ◽

Average Percentage ◽

Anesthetized Dogs ◽

Unanesthetized Animals ◽

Acute Changes

Intravenous injection of Adrenalin (1 ml of 1:300,000–1:25,000) into 10 normal, anesthetized (Nembutal) dogs produced an average increase in mean arterial pressure which amounted to about 25 at the lower and 100 mm Hg at the higher doses. Essentially the same responses were shown by seven anesthetized, vagotomized dogs and five anesthetized, vagotomized animals in which the carotid regions were denervated. Eight anesthetized dogs with spinal cords cut between C8 and T1 showed after Adrenalin injection an average percentage increase in mean arterial pressure which was some threefold greater than that found in normal, anesthetized animals. This difference was increased still further by bilateral section of the vagi in eight spinal dogs. Section of the spinal cord one or two segments below C8 to T1 (4 dogs) decreased the response to Adrenalin. The increase in mean arterial pressure induced by the intravenous injection of Adrenalin was greater in six spinal dogs (C8 to T1) anesthetized with Nembutal than in two similar unanesthetized animals. Acute changes in plasma volume did not influence the magnitude of the blood pressure response to Adrenalin shown by four high spinal animals.

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Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro- or chemoreceptor reflex responses

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00263.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. R1011-R1022 ◽

Cited By ~ 19

Author(s):

Kamon Iigaya ◽

Jouji Horiuchi ◽

Lachlan M. McDowall ◽

Alex C. B. Lam ◽

Yusuf Sediqi ◽

...

Keyword(s):

Sodium Cyanide ◽

Central Administration ◽

Respiratory Effects ◽

Cardiorespiratory Responses ◽

Cardiorespiratory Response ◽

Orexin Receptors ◽

Orexin Neuron ◽

Restricted Group ◽

Before And After ◽

Neuron Group

Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.

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Reflex cardiovascular and respiratory effects of serotonin in conscious and anesthetized dogs.

Circulation Research ◽

10.1161/01.res.47.4.509 ◽

1980 ◽

Vol 47 (4) ◽

pp. 509-515 ◽

Cited By ~ 18

Author(s):

I H Zucker ◽

K G Cornish

Keyword(s):

Respiratory Effects ◽

Anesthetized Dogs

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Correction to: Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa by Dufour VL, et al. Hum Gene Ther 2020;31:253–267. DOI: 10.1089/hum.2019.297

Human Gene Therapy ◽

10.1089/hum.2019.297.correx ◽

2020 ◽

Vol 31 (19-20) ◽

pp. 1140-1140

Keyword(s):

Retinitis Pigmentosa ◽

Canine Model ◽

Virus Vector ◽

Efficacy Evaluation ◽

Adeno Associated Virus ◽

Subretinal Injection

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Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, in anesthetized dogs.

Folia Pharmacologica Japonica ◽

10.1254/fpj.91.151 ◽

1988 ◽

Vol 91 (3) ◽

pp. 151-161

Author(s):

Takahito KIMURA ◽

Hiroko MURAKAMI ◽

Hisashi SAKAI ◽

Isami WAKI

Keyword(s):

Analgesic Agent ◽

Respiratory Effects ◽

Anesthetized Dogs

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Comparative Efficacy of three Methemoglobin Formers in Delaying Effects of Infused Sodium Cyanide

International Journal of Toxicology ◽

10.1080/109158197227242 ◽

1997 ◽

Vol 16 (2) ◽

pp. 151-164

Author(s):

R. G. Menton ◽

F. M. Reid ◽

C. T. Olson ◽

N. A. Niemuth ◽

K. K. Audet ◽

...

Keyword(s):

Sodium Thiosulfate ◽

Respiratory Arrest ◽

Vehicle Control ◽

Primary Response ◽

Sodium Cyanide ◽

Current Therapy ◽

Comparative Efficacy ◽

Total Blood ◽

Period 2 ◽

Scheduled Time

A prophylactic treatment is needed to circumvent constraints of the current therapy for cyanide (CN-) intoxication: intravenous administration of sodium nitrite and sodium thiosulfate. Experiments were conducted to compare the anticyanide effects of three candidate pretreatment methemoglobin (MHb)-forming compounds in an anesthetized animal model. The experiment was conducted in 5 periods, with each of 9 animals receiving the vehicle control in period 1, 0.2 mg/kg p-aminopropiophenone (PA PP) in period 2, and 2.5 mg/kg WR242511 in period 3. Four of the animals received the vehicle control in period 4 followed by 7 mg/kg p-aminoheptanophenone (PA HP) in period 5, and 5 animals received 7 mg/kg PA HP in period 4 followed by the vehicle control in period 5. Sodium cyanide (Na CN) infusions for PAPP, PAHP, and WR242511 experiments were initiated when the predicted MHb level was approximately 5%. Infusions were stopped 10 s after no functional breaths (respiratory arrest) were observed. Blood samples were collected for hemoglobin (Hb), MHb, and total blood CN levels at scheduled time points. Time to respiratory arrest, percent MHb, and Na CN dose were the primary response parameters. A 11 pretreatment regimens effectively mitigated the effects of Na CN poisoning compared to the vehicle control (p <.05). No discernable differences in protection were provided by the three compounds. The results indicated that the protective effect is related to the MHb level rather than the specific pretreatment drug.

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Cardiorespiratory reflexes from muscles during dynamic and static exercise in the dog

Journal of Applied Physiology ◽

10.1152/jappl.1985.58.3.844 ◽

1985 ◽

Vol 58 (3) ◽

pp. 844-852 ◽

Cited By ~ 18

Author(s):

G. Tallarida ◽

F. Baldoni ◽

G. Peruzzi ◽

G. Raimondi ◽

P. Di Nardo ◽

...

Keyword(s):

Pulmonary Ventilation ◽

Abrupt Increase ◽

Hindlimb Muscles ◽

Static Contraction ◽

Muscle Receptors ◽

Anesthetized Dogs ◽

Rhythmic Contractions ◽

S Period ◽

End Tidal ◽

End Tidal Co2

Cardiorespiratory reflex responses during the initial phase of dynamic and static contraction of hindlimb muscles were studied in anesthetized dogs. Muscle contractions were elicited by stimulating the femoral and gastrocnemius nerves at 3 and 100 Hz with the intensity of 2.0–2.5 times the motor threshold for a 20-s period. Rhythmic contractions caused a decrease in arterial pressure (Pa) and heart rate (HR) and increased pulmonary ventilation (VE) by increasing frequency (f) without significantly changing VT. Tetanic contractions provoked an increase in Pa and HR and a hyperpnea resulting from a rise in both f and VT. Similar responses were also obtained in anesthetized dogs with carotid sinuses denervated and cervical vagi cut. The abrupt increase in VE at the start of both types of exercise was not associated with immediate significant decreases in end-tidal CO2 values. These two patterns of cardiocirculatory and respiratory responses were closely similar to those reported in anesthetized rabbits in previous studies. Both patterns of responses were reflexes initiated by activation of muscle receptors verified by interrupting the afferents from the contracting muscles. It is concluded that, during dynamic and static work, two distinct muscular reflex mechanisms might exert their drives, related to the muscular metabolic rate, on the circulatory and respiratory function.

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High Density Intramural Mapping of Post-Infarct Premature Ventricular Contractions.

10.22541/au.161091219.97680079/v1 ◽

2021 ◽

Author(s):

Eugene Downar ◽

Michiel Janse ◽

Abhishek Bhaskaran ◽

Ahmed Niri ◽

Arulalan Velluppillai ◽

...

Keyword(s):

Canine Model ◽

High Density ◽

Ischemic Myocardium ◽

Acute Ischemia ◽

Ectopic Activity ◽

Premature Ventricular Contractions ◽

Diagonal Branch ◽

Graded Responses ◽

Anesthetized Dogs ◽

Unipolar Electrograms

Background: Spontaneous ventricular premature contractions (PVCs) in the post infarct milieu is assumed to be due to automaticity. However, the mechanism has not been studied with appropriate mapping tools. Objective: To study the mechanism of spontaneous PVCs with high density intramural mapping in a canine model, to test the hypothesis that post-infarct PVCs are due to re-entry rather than automaticity. Methods: In 15 anesthetized dogs, using 768 intramural unipolar electrograms, simultaneous recordings were made. After 30 mins of stabilization, recordings were made during the first 10 minutes of ischemia, and activation maps were constructed of individual beats. Acute ischemia was produced by clamping the left anterior descending coronary artery proximal to the first diagonal branch. The analysis was limited to the activation pattern of spontaneous ventricular beats. Results: In all experiments ST-T alternans occurred. In 8 of 15 dogs spontaneous ventricular beats occurred. In all 8 of these experiment earliest, ectopic activity occurred in the endocardium, well within the ischemic zone. From there, activity spread rapidly along the subendocardium, with endo-to epicardial spread along the non ischemic myocardium. Epicardial breakthrough always occurred at the border of the ischemic myocardium. In 3 dogs, delayed potentials were observed, which were earliest at the ischemic epicardium and extended transmurally with increasing delay towards the endocardium, where they culminated in a premature beat. Conclusion: Graded responses that occur with each sinus beat intramurally, when able to propagate from epicardium to endocardium is the mechanism by which PVCs are generated in post-infarct myocardium.

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