Mechanisms of platelet-activating factor-induced cardiac depression in the isolated perfused rat heart.
A potent phospholipid (platelet-activating factor, PAF) has been implicated in a variety of inflammatory and ischemic responses (eg, myocardial ischemia and anaphylactic shock). In isolated rat hearts perfused at constant flow, PAF produced a dose-dependent increase in coronary perfusion pressure (CPP) and a decrease in contractile force (CF). At 20 nM, PAF increased CCP by 21 +/- 1 mm Hg and decreased CF by 31 +/- 3% in nine hearts. At the peak of the PAF response, coronary effluent contained LTC4, LTD4, and LTE4 (0.22 +/- 0.05 pmol/ml) and TxB2 (0.97 +/- 0.16 pmol/ml). Addition of specific PAF receptor antagonists (eg, BN-52021 and CV-3988) inhibited peptide leukotriene and TxB2 production and blocked the coronary vasoconstriction and decrease in contractile force. Cyclooxygenase inhibitors (eg, naproxen) or specific TxA2 receptor antagonists (eg, BM-13,505) failed to prevent the increase in CPP or the decrease in CF. Furthermore, a lipoxygenase inhibitor (ie, propyl gallate) or a specific LTD4 receptor antagonist (ie, LY-171,883) prevented the increase in CPP but did not antagonize the negative inotropic response. These data indicate that the coronary constriction in the isolated perfused rat heart is a result of the PAF-induced release of endogenous peptide leukotrienes but not TxA2 production. However, the negative inotropic response appears to be partly due to a direct negative inotropic action of PAF on cardiac muscle. Thus, PAF produces a variety of direct actions and indirect effects via release of eicosanoid mediators contributing to cardiac impairment in the rat heart.
Stahl
G L
GL
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Lefer
A M
AM
D000818:Animals; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D017999:Leukotriene E4; D008297:Male; D009200:Myocardial Contraction; D010477:Perfusion; D010972:Platelet Activating Factor / Q000502:physiology*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D014655:Vascular Resistance
D010972:Platelet Activating Factor; D013189:SRS-A; D013929:Thromboxane B2; D017999:Leukotriene E4