Platelet-activating factor and WEB-2086 directly modulate rat cardiomyocyte contractility.
In various isolated cardiac tissue preparations the phospholipid mediator platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine) may elicit a positive, negative or no inotropic response. In the multicellular preparation it is difficult to differentiate and characterize the direct actions of PAF on the myocardium from the effects due to the release of secondary mediators from non-myocyte cell types. Thus in the present study the inotropic effects of PAF (10(-11), 10(-9), 10(-7) M) and a specific PAF receptor antagonist, WEB-2086, PAF receptor antagonist. WEB-2086, on the contractility of enzymatically isolated adult rat cardiomyocytes have been investigated. PAF (10(-7) M) reduced maximum cell shortening by 23% compared to the initial level, delayed excitation contraction coupling, abbreviated the contraction cycle and reduced the maximum rate of cell lengthening during relaxation. Lower concentrations of PAF elicited smaller negative inotropic responses. There was no evidence of a positive inotropic effect of PAF at any concentration tested or at any time after the onset of treatment. Co-treatment with WEB-2086 (10(-5) M) prevented the negative inotropic response to PAF. WEB-2086 alone increased maximum shortening by 16% compared to initial performance, extended the contraction cycle and increased the maximum rates of shortening and lengthening. WEB-2086 had no effect on excitation contraction coupling latency. The selective alteration of contraction parameters induced by PAF and WEB-2086 indicates that, in addition to antagonizing the negative inotropic action of exogenous PAF, WEB-2086 alone enhances contractility. These results demonstrate that PAF has a direct, receptor-mediated negative inotropic effect on adult contractility. These results demonstrate that PAF has a direct, receptor-mediated negative inotropic effect on adult cardiomyocytes.
Delbridge
L M
LM
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Stewart
A G
AG
Goulter
C M
CM
Morgan
T O
TO
Harris
P J
PJ
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086