Drug-induced effects on cardiovascular function in pentobarbital anesthetized guinea-pigs: invasive LVP measurements versus the QA interval.
J Pharmacol Toxicol Methods
; 66(2): 152-9, 2012 Sep.
Article
in En
| MEDLINE
| ID: mdl-22813982
ABSTRACT
INTRODUCTION:
Evaluation of drug-related effects on cardiovascular function is part of the core battery described in the ICH S7A guideline. Anesthetized guinea-pigs are excellent models for the evaluation of drug-induced prolongation of ventricular repolarization; however less information is available regarding other cardio-hemodynamic parameters in this model. The current study aimed to document cardio-hemodynamic responses in anesthetized guinea-pigs after administration of a number of reference drugs with known pharmacological actions.METHODS:
Experiments were carried out in closed chest pentobarbital anesthetized female guinea-pigs. Compounds were administered intravenously while arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were measured continuously. The rate of LVP contraction (LV dP/dt(max)) was used to evaluate cardiac performance; and was compared to the QA interval; which has previously been proposed as an indirect measurement of cardiac function.RESULTS:
Baseline values for heart rate and blood pressure were lower in anesthetized animals compared to literature data of conscious guinea-pigs. Heart rate increased after administration of adrenaline, isoprenaline and salbutamol, but not after L-phenylephrine. Verapamil and amiodarone decreased heart rate and blood pressure. Zatebradine infusion led to a decrease in heart rate with minimal effects on blood pressure. Sodium nitroprusside (SNP) caused a reduction in mean blood pressure at higher doses followed by reflex tachycardia. Both adrenaline and L-phenylephrine increased arterial blood pressure. Furthermore, adrenaline, isoprenaline and salbutamol increased LV dP/dt(max) and decreased the QA interval. L-phenylephrine increased LV dP/dt(max), but transiently prolonged the QA interval. Both verapamil and amiodarone decreased LV dP/dt(max) and prolonged the QA interval, whereas zatebradine did not affect this parameter.DISCUSSION:
In addition to its utility for the assessment of test compounds on ventricular repolarization the pentobarbital anesthetized guinea-pig model shows promise for early stage cardio-hemodynamic screening. Furthermore, the QA interval shows potential for prediction of adverse effects on cardiac contractility.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cardiovascular System
/
Cardiovascular Physiological Phenomena
/
Toxicity Tests
/
Drug Evaluation, Preclinical
/
Drug-Related Side Effects and Adverse Reactions
Type of study:
Guideline
/
Prognostic_studies
/
Qualitative_research
Limits:
Animals
Language:
En
Journal:
J Pharmacol Toxicol Methods
Journal subject:
FARMACOLOGIA
/
TOXICOLOGIA
Year:
2012
Document type:
Article
Affiliation country:
Belgium