Optimising conditions for studying the acute effects of drugs on indices of cardiac contractility and on haemodynamics in anaesthetized guinea pigs.
ABSTRACT Detecting adverse effects of drugs on cardiac contractility is becoming a priority in pre-clinical safety pharmacology. The aim of this work was to optimise conditions and explore the potential of using the anaesthetized guinea pig as an in vivo model.
Guinea pigs were anaesthetized with Hypnorm/Hypnovel, isoflurane, pentobarbital or fentanyl/pentobarbital. The electrocardiogram (ECG), heart rate, arterial blood pressure and indices of cardiac contractility were recorded. In further experiments in fentanyl/pentobarbital anaesthetized guinea pigs the influence of bilateral versus unilateral carotid artery occlusion on haemodynamic responses was investigated and the effects of inotropic drugs on left ventricular (LV) dP/dt(max) and the QA interval were determined.
Pentobarbital, given alone or after fentanyl, provided suitable anaesthesia for these experiments. Bilateral carotid artery occlusion did not alter heart rate or arterial blood pressure responses to isoprenaline or angiotensin II. Isoprenaline and ouabain increased LVdP/dt(max) and decreased the QA interval whereas verapamil had opposite effects and strong inverse correlations between LVdP/dt(max) and the QA interval were found.
Conditions can be optimised to allow the pentobarbital-anaesthetized guinea pig to be used for simultaneous measurement of the effects of drugs on the ECG, haemodynamics and indices of cardiac contractility. The use of this small animal model in early pre-clinical safety pharmacology should contribute to improvements in detecting unwanted actions on the heart during the drug development process.
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ABSTRACT: A facile system for obtaining electrocardiograms from conscious animals was used to conduct studies on 12 animals studied both conscious and anesthetized, on 4 conscious animals given vehicle (0.5% methylcellulose) and QT-lengthening test articles, and on 6 animals given test articles thought to not lengthen QTc. In 12 animals whose ECGs were monitored via a bipolar transthoracic ECG, heart rates were slowed with 1.0 mg/kg zatebradine, while they were conscious in their slings, and after being anesthetized with ketamine/xylazine. The following regression equations were obtained relating QT to RR: QT = 44.7 ln RR - 132.9, r2 = 0.7, for conscious animals; QT = 79.4 ln RR - 287.4, r2 = 0.8 for anesthetized animals, with RR intervals varying between 150 and 550 ms. The anesthetic increases QT at all RR intervals (p < 0.001), but does not change the slope of the relationship between QT and RR when compared with the conscious guinea pig. The Fridericia method was best for correcting QT for RR interval in conscious guinea pigs, but the Bazett method was best for correcting in anesthetized animals. QTc lengthened significantly in all conscious guinea pigs given, orally, cisapride, ketoconazole, and sotalol (positive test articles) and did not change with methylcellulose (the vehicle) or with propranolol, verapamil, or enalapril (negative controls). These techniques and relationships demonstrate that this methodology may be useful in exploring torsadogenic effects of novel pharmacological entities.Toxicological Sciences 12/2003; 76(2):437-42. · 4.33 Impact Factor
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ABSTRACT: Urethane (ethyl carbamate) is used alone or in combination with other drugs to produce anaesthesia in laboratory animals. Although originally studied as a potential phytocide, urethane demonstrated antineoplastic properties when administered to rats with the Walker rat carcinoma 256. Subsequent trials in humans led to its use as a chemotherapeutic agent for various leukaemias. Mice develop pulmonary adenomas earlier in life and at a higher incidence following urethane administration. Urethane's carcinogenic influence is greater in neonatal mice; it also has a transplacental influence in mice. In rats, urethane increases the incidence of pulmonary adenomas, Zymbal Gland tumours, and a variety of other neoplasms. Urethane is absorbed sufficiently from the skin of laboratory animals to produce a transient narcosis. The carcinogenic effect appears to be due to an undefined oncogenic intermediate formed in the blood. Considering the properties urethane demonstrates in animals, the safety of its use by laboratory personnel is in question. However, if appropriate guidelines are followed, urethane should continue to be a useful anaesthetic agent for laboratory animals.Laboratory Animals 08/1988; 22(3):255-62. · 1.26 Impact Factor
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ABSTRACT: Anesthetizing guinea pigs is difficult with varying outcomes. The primary purpose of the study reported here was to evaluate six injectable anesthetic regimens for use in guinea pigs and assess the depth of anesthesia and, thus, their effectiveness in terms of their use for major surgical procedures. Other variables that were measured and evaluated included time from injection until onset of anesthesia, duration of anesthesia, depth of anesthesia, and vital signs (i. e., respiratory rate, heart rate, and body temperature). Female Dunkin Hartley guinea pigs that were 9 to 12 weeks old were randomly assigned to receive one of the following anesthetic regimens: ketamine/xylazine (KX), ketamine/detomidine (KD), ketamine/medetomidine (KM), 4) tiletaminezolazepam/ xylazine (TX), tiletamine-zolazepam/detomidine (TD), or tiletamine-zolazepam/medetomidine (TM). All anesthetics were administered intramuscularly. Anesthesia was assessed by attempting to perform an ovariohysterectomy. Surgery could not be performed on any guinea pigs in the groups given ketamine or TD. There was a high rate of adverse effects in guinea pigs receiving detomidine. Four of six guinea pigs in the TD group died during or after the anesthetic episode. Fourteen of 30 (46.7%) guinea pigs given TX underwent successful surgery, and 23 of 29 (79.3%) given TM underwent successful surgery. A combination of tiletamine-zolazepam and xylazine or medetomidine was effective for inducing anesthesia and providing sufficient analgesia to perform a major surgical procedure on guinea pigs. However, TM was the most reliable regimen.Contemporary topics in laboratory animal science / American Association for Laboratory Animal Science 08/1998; 37(4):58-63. · 0.82 Impact Factor