Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium.
BACKGROUND
Ketamine exerts both an indirect, positive inotropic effect and a direct, negative inotropic effect in isolated ferret ventricular myocardium. This negative inotropic effect becomes apparent after inactivation of the sympathetic neuroeffector junction. The aim of this study was to investigate the mechanisms of ketamine's intrinsic negative inotropic effect.


METHODS
The authors analyzed the effects of ketamine after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca(++)-regulated photoprotein aequorin. Ketamine's effects were also evaluated in a preparation in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular myocardium in which the SR is poorly developed.


RESULTS
Ketamine at concentrations > or = 3.3 x 10(-5) M decreased contractility and the amplitude of the intracellular Ca++ transient. After inactivation of sarcoplasmic reticulum Ca++ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, ketamine caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and ketamine's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Furthermore, > or = 10(-4) M ketamine decreased contractility in frog ventricular myocardium, a species that is almost entirely dependent on transsarcolemmal Ca++ influx for its myofibrillar activation.


CONCLUSIONS
These findings indicate that the direct negative inotropic effect of ketamine results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of ketamine's action is caused by inhibition of transsarcolemmal Ca++ influx.
Kongsayreepong
S
S
Department of Anesthesiology, Mayo Foundation, Rochester, Minnesota 55905.
Cook
D J
DJ
Housmans
P R
PR
D000331:Aequorin / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004347:Drug Interactions; D005289:Ferrets; D006321:Heart / Q000187:drug effects*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D011894:Rana pipiens; D012433:Ryanodine / Q000494:pharmacology; D013045:Species Specificity
D012433:Ryanodine; D000331:Aequorin; D007649:Ketamine; D002118:Calcium