Ejw Bowie

Hirudin, heparin, and placebo during deep arterial injury in the pig : the in vivo role of thrombin in platelet-mediated thrombosis

Three dosages (0.3, 0.7, and 1.0 mg/kg) of recombinant hirudin, a specific inhibitor of thrombin, were compared with heparin (50 units/kg) and placebo for reducing thrombus formation in the carotid arteries of 50 pigs after deep injury by balloon dilatation. Each drug was administered as a bolus followed immediately by a continuous infusion of the same dose per hour. Major end points were quantitative indium-111-labeled platelet and iodine-125-labeled fibrinogen deposition and the incidence of mural thrombosis. This study showed that heparin, at a dose that prolonged the activated partial thromboplastin time (APTT) to twice the control time, did not prevent mural thrombosis or significantly reduce platelet deposition compared with placebo but did reduce fibrinogen deposition. Recombinant hirudin markedly reduced platelet and fibrinogen deposition in a dose-related manner and totally eliminated mural thrombosis at an APTT of two to three times that of control. Platelet deposition (x 10(6)/cm2, mean +/- SEM) in areas of deep arterial injury for the placebo, heparin, and 0.3, 0.7, and 1.0 mg/kg hirudin groups was 54 +/- 21, 33 +/- 9, 22 +/- 6, 8 +/- 1, and 7 +/- 1, respectively; electron microscopy showed a single layer (or less) of platelets at the two highest hirudin dosages. The incidence of macroscopic mural thrombosis was 76% with placebo, 57% with heparin, 46% with 0.3 mg/kg hirudin; there were no thrombi with 0.7 or 1.0 mg/kg hirudin (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dietary supplementation with cod-liver oil on endothelium-dependent responses in porcine coronary arteries.

To study the effect of dietary supplementation with fish oil on endothelium-dependent responses, Yorkshire pigs were maintained on a normal diet or on a low (0.6 ml/kg/day) or a high (1.0 ml/kg/day) dose of cod-liver oil for 4 weeks. Endothelium-dependent responses were examined in vitro in rings of proximal left anterior descending coronary arteries taken from control and treated animals studied in parallel. Endothelium-dependent relaxations in response to bradykinin, serotonin, adenosine diphosphate, and thrombin were facilitated in arteries from treated but not in those from control animals, whereas the relaxations in response to A23187 were unaltered. The facilitated relaxations were not altered by indomethacin but significantly inhibited by methylene blue. Aggregating platelets from control and treated pigs induced comparable, facilitated endothelium-dependent relaxations in rings taken from treated pigs. The platelet-induced contractions were significantly reduced in rings with endothelium taken from treated pigs, and they were comparable in rings without endothelium in both groups. Aggregating platelets from control and treated pigs released comparable amounts of serotonin and thromboxane A2. Endothelium-dependent relaxations induced by arachidonic acid and eicosapentaenoic acid were unaltered, whereas transient endothelium-dependent contractions induced by arachidonic acid were significantly reduced by the treatment with cod-liver oil. Relaxations to sodium nitroprusside or isoproterenol,and contractions to potassium chloride or serotonin were not different in rings without endothelium from control or treated pigs. These results indicate that dietary supplementation with cod-liver oil facilitates endothelium-dependent relaxations and inhibits endothelium-dependent contractions in porcine coronary arteries.

Arteriosclerosis in normal and von Willebrand pigs: long-term prospective study and aortic transplantation study.

In a long-term prospective study, five normal control pigs and five pigs with homozygous von Willebrands disease received a nonfatty diet from age 3 months to 4 years; then the aortas were analyzed. The fibrous arteriosclerotic plaques in the distal abdominal aortic region involved an average of 28% of the surface area in control pigs and only 7% of the surface area in pigs with von Willebrands disease (F < 0.01). In a subsequent study of 3-month-old pigs, the distal abdominal aortic segments from nine normal pigs were cross-transplanted with segments from nine other normal pigs (control study), and aortic segments from four normal pigs were transplanted into four host pigs with von Willebrands disease (exchange study). All pigs received a 2% cholesterol diet for up to 6 months; then the transplanted aortic segments were analyzed. The donor normal aortic segments in the host normal pigs developed arteriosclerosis that involved an average of 20% of the surface; the endothelial fluorescent pattern of von Willebrand factor was identified. In contrast, the donor normal aortic segments in the host pigs with von Willebrands disease had arteriosclerosis that involved an average of only 4% of the surface (P < 0.01); the endothelial cell von Willebrand factor was not identified. The long-term prospective study indicates that pigs with von Willebrands disease are resistant to the development of spontaneous arteriosclerosis. The aortic transplantation data are compatible with the hypothesis that the absence of von Willebrand factor in pigs with von Willebrands disease may cause impairment of platelet-arterial wall interaction and resistance to arteriosclerosis.

Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease.

We have observed that pigs with Impaired platelet function in the form of severe von Wlllebrands disease (vWd) are resistant to spontaneous and to diet-Induced aortic atherosclerosis. However, it has been reported that vWd pigs are susceptible to coronary atherosclerosis produced by balloon-Induced injury of coronary arteries combined with an atherogenlc diet. We have evaluated the development of coronary atherosclerosis in normal control (NC) and homozygous vWd pigs In two prospective studies: 1) as a spontaneous process In five NC and vWd pigs receiving a regular diet from the age of 3 months to 4 years; and 2) in nine NC and five vWd receiving a high-fat and high-cholesterol (2%) diet from the age of 3 to 9 months. All of the coronary arteries were analyzed postmortem In 5-mm sections. None of the NC nor the vWd pigs in the spontaneous study showed coronary atherosclerosis or myocardial lesions. In the study of diet-induced atherosclerosis, only one NC and one vWd pig had discrete stenoses; the stenoses affected the three coronary arteries and were significant (50% to 80%) In the NC and mild (>25%) In the vWd pigs; no pigs showed myocardial lesions. Pigs with vWd are resistant to atherosclerosis of the aorta. To assess the resistance or susceptibility to coronary disease In these pigs, a longer follow-up study would be necessary.

Aortic atherosclerosis in pigs with heterozygous von Willebrand disease. Comparison with homozygous von Willebrand and normal pigs.

We have reported that pigs with severe homozygous von Willebrand disease (vWd) are resistant to spontaneous and high fat, high cholesterol, diet-induced atherosclerosis. In this study we report the quantitation of aortic atherosclerotic plaques in three groups of pigs fed with a high fat, high cholesterol (2%) diet from age 3 to 9 months. Nine normal pigs (normal factor VIM antigen, VIII R:AG, and ristocetin co-factor, VIII:RWF) had a mean of 21% atherosclerotic involvement of the distal aortic surface and a 4.5% mean involvement of the entire aorta. Five homozygous vWd pigs (undetected VIII R:AG and VllhRWF) had a mean of 4.2% atherosclerotic involvement of the distal aortic surface and 1.2% involvement of the entire aorta (p < 0.01, rank sum test). Five heterozygous vWd pigs (approximately 35% VIM R:AG and VllhRWF) had a mean of 25% atherosclerotic involvement of the distal aortic surface and 6% involvement of the entire aorta; the results were not significantly different from those in the normal pigs. We concluded that resistance to atherosclerosis is not found in animals with moderate reduction of VIII R:AG and VllhRWF. This may have implications for humans, since in human vWd both factors are almost always present.