Drug-induced effects on cardiovascular function in pentobarbital anesthetized guinea-pigs: invasive LVP measurements versus the QA interval.
BACKGROUND
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.


CONCLUSIONS
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.
Bio-Plus Safety Pharmacology, Vlasmeer 5/0003, B-2400 Mol, Belgium. dj@bio-plus.org
D M
DM
Johnson
R
R
Geys
J
J
Lissens
P J
PJ
Guns
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D017408:Guidelines as Topic; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D018675:Toxicity Tests / Q000379:methods*; D016277:Ventricular Function, Left / Q000187:drug effects