The effects of a PAF antagonist on ischemic myocardial damage and arrhythmia in the dog

Leong, Lillian L. L.; Sturm, M.; Papadimitriou, John; Stephens, Charlene J.; Taylor, Roger R.

doi:10.1016/0022-2828(92)91048-a

“…It was reported that specific PAF receptor antagonists reduced the myocardial damage and cardiac arrhythmias produced by myocardial ischaemia and reperfusion in experimental animals [14,20], although our own studies did not support that contention [21,22]. Several years ago, some considered PAF to play an important role in the pathophysiology of myocardial ischaemia.…”

Section: Discussioncontrasting

confidence: 63%

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Taylor

¹

,

Fatovich

²

,

Hitchcock

³

et al. 2001

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Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n=35), or matching placebo (n=36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5x10(6) units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43+/-28 mmHg (mean+/-S.D.) and 40+/-26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to <90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3+/-17.5 and 40.2+/-13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

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“…Several years ago, some considered PAF to play an important role in the pathophysiology of myocardial ischaemia. It was reported that specific PAF receptor antagonists reduced the myocardial damage and cardiac arrhythmias produced by myocardial ischaemia and reperfusion in experimental animals [14,20], although our own studies did not support that contention [21,22]. The present study was not designed to examine these questions, and we do not know of clinical studies that have done so.…”

Section: Discussioncontrasting

confidence: 63%

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Taylor¹,

Fatovich²,

HITCHCOCK³

et al. 2001

View full text Add to dashboard Cite

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n=35), or matching placebo (n=36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5x10(6) units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43+/-28 mmHg (mean+/-S.D.) and 40+/-26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to <90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3+/-17.5 and 40.2+/-13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

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“…In dogs, conflicting results were obtained with different PAF receptor antagonists. With the use of BN 52021, SRI 63441, and TCV-309, a protective effect was observed (156, 267-270, 408), whereas WEB 2086 was uneffective (248,249). Moreover, it was found that CV 6209 prevented pulmonary edema following coronary ligation in dogs (409).…”

Section: B Role Of Paf In Ischemia-reperfusion Injury Of the Heartmentioning

confidence: 99%

Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

Montrucchio

¹

,

Alloatti

²

,

Camussi

³

2000

Physiological Reviews

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Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

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The effects of a PAF antagonist on ischemic myocardial damage and arrhythmia in the dog

Cited by 12 publications

References 18 publications

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

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