Comparison of cardiac and hemodynamic effects of plateletactivating factor-acether and leukotriene D4 in anesthetized dogs

Abstract

In anesthetized dogs, platelet-activating factor-acether (PAF; 0.2-1.6 micrograms/kg) and leukotriene (LT) D4 (0.5, 1, and 3 micrograms/kg) were injected into the left circumflex (LCX) coronary artery. Cardiac and systemic hemodynamics, and the ECG were continuously recorded. PAF reduced cardiac performance and affected hemodynamics in a dose-dependent manner: At 7 +/- 3s, LCX flow initially increased by 40%-172% followed by a reduction of 43%-100%, and coronary diameter (measured with ultrasonic techniques) decreased by 4%-10%. Total and late coronary resistance increased. Left ventricular (LV) systolic pressure fell by 22%-48% and LV filling pressure decreased by 5 mm Hg after 0.8 microgram/kg PAF. The LVdP/dtmax diminished by 38%-47%. Peak blood pressure reduction (35%) occurred 60 s after PAF application and lasted for 1.4 min. Heart rate decreased by 10%-17% at peak PAF actions. LTD4 reduced LCX flow by 38%-87%, and coronary diameter by 5%-12%, returning to control value within 3.4 min. Blood pressure, LV pressure, and LVdP/dtmax decreased while heart rate and LV filling pressure increased. ST segments and R-wave voltage of the ECG in lead II elevated after either compound although the effects were more pronounced after LTD4. Indomethacin (5 mg/kg i.v.) pretreatment did not affect LTD4 actions on cardiohemodynamics, but the putative leukotriene antagonist FPL 55712 (1 mg/kg i.v.) blocked LTD4 actions on the heart and circulation. PAF influences on LCX flow were modified by indomethacin: initial flow rose by 250%, and coronary diameter fell by 12%, followed by sustained flow and diameter reduction during the second phase on PAF action. FPL 55712 did not affect the early flow increase after PAF but attenuated the later flow reduction, which was blocked by indomethacin. Thus, PAF and LTD4 may have effects on canine conduit arteries besides their effects on the coronary resistance vessels. The circulatory derangement after PAF may be aggravated by additional eicosanoid release. PAF and LTD4 may be involved in coronary blood flow variations and negative inotropy accompanying anaphylactic disease state.

Mechanisms of the coronary vascular effects of platelet‐activating factor in the rat perfused heart

“…In previous studies, the leukotriene antagonist FPL-55712, was shown to attenuate the vasocons-C4 and LTD4 trictor response following injections of PAF (Feuerstein et al., CM FR-900452. 1984;Piper & Stewart, 1986;Fiedler et al, 1987). However, not affect the the vasodilator effect, when observed, was not altered by FPL-)Opmol LTC4 55712 (Feuerstein et al, 1984;Fiedler et al, 1987 (Piper & Stewart, 1986; us to examine Man et al, 1990) ts, Specific binding of radiolabelled PAF was first demonn the coronary strated in platelets (Valone et al, 1982;Hwang et al, 1983) and subsequently demonstrated in a number of tissues (see review of Braquet et al, 1987).…”

“…Other studies showed a biphasic effect, i.e. an increase in flow followed by a decrease in flow, after intracoronary injection of PAF (Feuerstein et al, 1984;Mehta et al, 1986;Erza et al, 1987;Fiedler et al, 1987). In a previous study, we demonstrated that depending on the dose, bolus injections of PAF could produce vasodilator (10fmol-1 pmol PAF), vasoconstrictor (1 nmol PAF) or a biphasic response (10 and 100pmol PAF) in rat perfused hearts (Man et al, 1990).…”

Involvement of nitric oxide and eicosanoids in platelet‐activating factor‐induced haemodynamic and haematological effects in dogs

“…Inhibitors Control (n = 12) IM, (n = 6) (2 mg kg-) VAP, (n = 7) (100 Mg kg') AA-861, (n=7) (5 mg kg-') L-NAME, (n = 6) (5 mg kg-l) TCV-309, (n = 5) (300 pg kg') (Fiedler et al, 1987). Also, PAF itself had direct negative inotropic effects (Tamargo et al, 1985;Robertson et al, 1988 (Toyofuku et al, 1988;Yamanaka et al, 1992), and leukotrienes (Piper & Stewart, 1986) in response to exogenous PAF have been observed.…”

Interaction of vasoactive substances released by platelet‐activating factor in the rat perfused heart

“…PAF has been detected in the effluent blood from the coronary sinus in patients with coronary artery disease undergoing atrial pacing (Montrucchio et al, 1986) and release of PAF from ischaemic-reperfused rabbit heart has been demonstrated (Montrucchio et al, 1989). The effects of PAF in the coronary circulation have been shown in a number of in vivo (Levi et al, 1984;Piper & Stewart, 1986;Man et al, 1990) and in vitro studies (Feuerstein et al, 1984;Jackson et al, 1986;Mehta et al, 1986;Ezra et al, 1987;Fiedler et al, 1987).…”