The pattern of cardiovascular alterations induced by infusion of platelet-activating factor in rabbit is modified by pretreatment with H1-H2 receptor antagonists but not by cyclooxygenase inhibition

Abstract

The intravenous infusion of platelet activating factor (PAF) (0.8 micrograms/kg b.w.) induced ECG and hemodynamic alterations characterized by the following sequential three phases. Phase I (15 sec) consisted of a transient bradycardia with reduction in left ventricular pressure (LVPs), mean arterial pressure (MAP) and cardiac output (CO). Phase II developed within 30 sec and consisted of a rise in cardiac frequency, increase in LVPs, MAP and total peripheral resistances (TPR), which were associated with a decrease in CO. Finally, phase III, that occurred about 90 sec after PAF infusion, was characterized by marked ECG changes (ST segment depression and conduction arrhythmias), a decrease in LVPs and MAP, as well as a rise in TPR and in right atrial pressure (RAP). All these alterations were reversible within 30-60 min. Pretreatment with promethazine and cimetidine, as H1 and H2 histamine receptor antagonists, markedly prevented the development of phase II, namely the rise in cardiac frequency, LVPs, MAP and TPR, but did not significantly modify phase I and III. In contrast, pretreatment with indomethacin, an inhibitor of cyclooxygenase, moderatively attenuated, but did not abolish, the three phases of cardiovascular changes induced by PAF infusion.

Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

“…Moreover, the generation of thromboxane A 2 from platelets may contribute to the development of hemodynamic alterations in rabbit. Indomethacin indeed determined an overall reduction in the extent of PAF-induced hemodynamic changes (290). These results suggest that the release of histamine and thromboxane A 2 from platelets may in part account for hemodynamic alterations induced by PAF.…”

“…The hemodynamic alterations developed in three sequential phases: 1) a transient bradycardia (15 s) with reduction in left ventricular systolic pressure (LVSP), MAP, and cardiac output occurred; 2) a rise in cardiac frequency, which developed within 30 s, an increase in LVSP, MAP, total peripheral resistances (TPR), and cardiac output was observed; and 3) ϳ90 s after PAF infusion, LVSP and MAP were decreased, whereas TPR and right arterial systolic pressure persisted elevated. These alterations were reversed in 30 -60 min (290). When low doses of PAF (0.2 g/kg) were used the hemodynamic response was similar, but the intensity was attenuated (unpublished observations).…”

“…onists markedly prevented the development of the second phase, namely, the rise in cardiac frequency, LVSP, MAP, and TPR, but did not significantly modify the first and third phases (290). Moreover, the generation of thromboxane A 2 from platelets may contribute to the development of hemodynamic alterations in rabbit.…”

“…This line of research was initiated by the observation that one of the two antihypertensive lipids isolated from renal medulla and from renal venous effluent after unclipping one-kidney, oneclip hypertensive rats, the polar renomedullary lipid, has the same chemical structure of PAF (303,304,338). Early hemodynamic studies emphasized that antihypertensive polar renal lipid as well as synthetic PAF, in microgram doses, lowered arterial pressure in guinea pigs (135), rats (44,67,148,233,273,344,347,360,406,430), and rabbits (12,160,161,245,290,303) in the normal and hypertensive states after intravenous or oral administrations. The potential role of PAF in the modulation of blood pressure was inferred from the observation of decreased levels of PAF (275) and increased activity of plasma acetyl hydrolase (42) in hypertensive rats.…”

“…Pharmacological studies demonstrated that the early increase in CBF is independent from the generation of cyclo-and lipoxygenase-derived metabolites, while the subsequent vasoconstriction is primarily due to the production of thromboxane A 2 (133). PAF induces coronary vasoconstriction and S-T depression also in rabbits (290). Conflicting effects were observed in dogs (199,282,405).…”