Ferenc Hermán

Increased levels of platelet-activating factor in blood following intestinal ischemia in the dog

The possible role of platelet-activating factor (PAF) in superior mesenteric artery occlusion induced circulatory collapse was studied in anesthetized dogs. PAF was measured by platelet aggregation assay. Identity of PAF-like product in blood was ascertained by thin layer chromatography, high pressure liquid chromatography and alkaline treatment. Low amount of PAF was detected in the mesenteric blood under normal conditions, during reperfusion PAF levels were significantly higher. Pretreatment of the animals with BN 52021, a specific PAF receptor antagonist abolished the fall in mean arterial pressure and the rise in hematocrit due to ischemia/reperfusion. These findings suggest that PAF may play an important role in mesenteric ischemia-induced circulatory collapse.

Prostacyclin mediates antiaggregatory and hypotensive actions of endothelin in anaesthetized beagle dogs.

The effects of endothelin on blood pressure and in vivo aggregation of platelets were studied in anaesthetized beagle dogs. Intravenous administration of endothelin (0.03‐0.3 nmol kg−1) resulted in a dose‐dependent transient hypotension followed by a long‐lasting hypertension and inhibition of platelet aggregation. These changes were accompanied by dose‐dependent elevation of plasma 6‐keto prostaglandin F1α levels. Pretreatment of the animals with acetylsalicylic acid significantly attenuated both the vascular and antiaggregatory responses to endothelin. These data provide evidence for in vivo release of prostacyclin by endothelin in anaesthetized dogs.

Platelet Aggregation of Migraineurs during and between Attacks

Platelet aggregation induced by ADP, collagen and platelet-activating factor was studied in common (migraine without aura) and classical migraine (migraine with aura) patients during and between attacks. The EC 50 * values for ADP and platelet-activating factor were significantly higher, whilst that for collagen was significantly lower in classical migraine patients during headache-free intervals compared to healthy volunteers. The EC50 values obtained for common migraine sufferers during symptom-free periods were similar to those of controls. During attacks, the EC 50 value for ADP, but not for collagen and platelet-activating factor, was significantly higher than that of the controls. In healthy subjects a positive correlation was found between ADP and collagen-induced aggregation. In contrast, there was a U-shaped correlation matrix in classical migraine patients. The present observations show that platelet aggregation is altered in migraine patients and this raises the possibility that platelet-activating factor may be involved in the pathogenesis of migraine.

Antiaggregatory and hypotensive effects of endothelin-1 in beagle dogs: role for prostacyclin.

The effects of endothelin-1 (ET-1) on blood pressure and platelet aggregation were studied in anesthetized beagle dogs. Platelet aggregation was monitored in vivo by a filter-loop technique and in vitro by using platelet-rich plasma and whole blood. ET-1 (0.03-0.3 nmol/kg) induced a transient dose-dependent hypotension and inhibited platelet aggregation in vivo. These changes were accompanied by dose-dependent elevation of plasma 6-keto-PGF1 alpha levels. Pretreatment of animals with indomethacin (2 mg/kg plus 3 mg/kg/h) completely abolished the antiaggregatory action of ET-1 and significantly attenuated the hypotensive response to ET-1. Intra-arterial infusion of prostacyclin at concentrations similar to those observed following ET-1 injections mimicked the antiaggregatory and hypotensive actions of ET-1. ET-1 (0.1-100 nM) did not modify platelet aggregation induced by ADP, collagen, and platelet-activating factor in vitro, suggesting that dog platelets do not possess ET-1 receptors. These findings indicate that the antiaggregatory and hypotensive actions of ET-1 in beagle dogs are mediated through release of prostacyclin.

C-reactive protein inhibits binding of platelet-activating factor to human platelets

Serum concentration of C-reactive protein (CRP), a prototypical acute-phase protein rises dramatically in response to tissue injury or inflammation. We report here that CRP (1-20 micrograms/ml) inhibited platelet-activating factor (PAF)-induced aggregation of human platelets in time-, and dose-dependent manner. This inhibitory action of CRP was nearly completely removed by treatment with anti CRP antiserum. At higher concentrations (20-100 micrograms/ml), CRP stabilized platelet membrane against the detergent-like effect of beta-deoxy-lysolecithin. Furthermore, CRP (10 micrograms/ml) diminished specific [3H]PAF binding to platelets and displaced previously bound labeled PAF from platelets. These results suggest that by depressing the bioavailability of PAF, CRP may be an important modulator of platelet activation during acute inflammatory reactions.

Dexamethasone-induced gastric mucosal damage in the rat: possible role of platelet-activating factor

1 The aim of the present experiments was to study the possible role of platelet‐activating factor (PAF) in mediating gastric mucosal damage induced by dexamethasone in the rat by measuring gastric tissue levels of PAF during dexamethasone‐treatment and by investigating the effects of specific PAF receptor antagonists on dexamethasone‐induced gastric lesions. PAF‐like bioactivity extracted from the rat glandular stomach was determined by a platelet aggregation assay. 2 Dexamethasone treatment (0.4– 4 mg kg−1, daily for 1– 6 days) produced time‐ and dose‐dependent damage to the glandular mucosa of the stomach as characterized by extensive, uniform hyperaemia with multiple, focal petechiae and erosions. 3 These changes were accompanied by a time‐, and dose‐dependent increase in PAF content of the glandular stomach. Control rat stomach contained small amounts of PAF (0.14 ± 0.04 ng per g wet weight), which increased over 40 fold in response to dexamethasone treatment (4 mg kg−1, daily for 6 consecutive days). The presence of PAF‐like material in the stomach extract was ascertained by thin‐layer chromatography, high performance liquid chromatography and by alkaline hydrolysis. 4 Pretreatment of the animals with one or other of the structurally unrelated PAF receptor antagonists, BN 52021 (10 mg kg−1, i.p.) or BN 50727 (1 mg kg−1, i.p.) significantly reduced dexamethasone‐induced gastric damage. In these animals neither petechiae nor erosions were observed. 5 These observations suggest that PAF is a likely endogenous mediator of glucocorticoid‐induced gastric mucosal damage in the rat.

The in vivo antiaggregatory action of endothelin-1 is not mediated through the endothelin ETA receptor

Intravenous bolus injection of endothelin-1 (0.1 and 0.25 nmol/kg) resulted in a dose-dependent inhibition of in vivo platelet aggregation in anesthetized Beagle dogs. Pretreatment of the animals with the selective ETA receptor antagonist, BQ-123 (1 mg/kg), completely abolished the pressor response to endothelin-1 without affecting the magnitude of the depressor response. BQ-123 neither modified the antiaggregatory action of endothelin-1 nor affected the increase in plasma 6-keto prostaglandin F1 alpha level elicited by endothelin-1. These findings indicate that the in vivo antiaggregatory and prostacyclin releasing actions of endothelin-1 are not mediated by activation of the ETA receptor.

Platelet-activating factor may mediate dexamethasone-induced gastric damage in the rat

The possible role of platelet-activating factor (PAF) in dexamethasone-induced gastric mucosal damage was studied in rats. PAF was measured by a platelet aggregation assay. The identity of the PAF-like product recovered from gastric tissues was ascertained by thin-layer chromatography and high-pressure liquid chromatography. Low levels of PAF were detected in the normal rat stomach, while in dexamethasone-treated animals PAF levels were significantly higher. Pretreatment of the animals with BN 52021, a specific PAF receptor antagonist, significantly attenuated dexamethasone-induced mucosal injury. These findings suggest that PAF may be a mediator of mucosal damage induced by glucocorticoids.

In vivo measurement of the disaggregatory action of prostacyclin. A methological study

The disaggregating effect of PGI2 was measured in a modified in vivo model described by Hornstra. The arterial blood of mongrel dogs was directed through an extracorporeal filter by a roller pump, and the pressure proximal to the filter was measured. The filter became spontaneously occluded mostly by aggregates of platelets within a few minutes, and as a result the pressure before the filter increased continuously. PGI2, administered either before the filter or intravenously, produced dose-related reduction in filtration pressure. Results obtained in control experiments revealed that the rate of platelet aggregation was reproducible; neither the count of platelets in the circulating blood nor the in vitro sensitivity of platelets to ADP and PGI2 changes significantly in the course of an experiment. The technique described seems to be useful to determine the disaggregatory potency of prostacyclin and other substances.