Shimokawa, Hiroaki

This study examined the effects of dietary supplementation with cod-liver oil on impaired endothelium-dependent relaxations in hypercholesterolemia and in atherosclerosis in porcine coronary arteries. Sixteen male Yorkshire pigs underwent balloon endothelium removal of the left coronary arteries and were fed a 2% high-cholesterol diet for 10 weeks, with or without dietary supplementation of cod-liver oil (30 ml/day) (oil-fed and cholesterol-fed groups, respectively). This model allowed the simultaneous examination of the effects of dietary cod-liver oil on vascular reactivity in hypercholesterolemia alone (right coronary artery) and in atherosclerosis (left coronary artery). After 10 weeks of feeding, the dietary treatment with cod-liver oil caused an increase in plasma levels of eicosapentaenoic acid and a decrease in the plasma levels of arachidonic acid, whereas the treatment had no significant effect on the increases in plasma lipid levels induced by the high-cholesterol feeding. Morphometric analysis showed significant inhibition of coronary atherosclerosis by the treatment. Endothelium-dependent responses were examined in vitro in ring preparations and in bioassay experiments. Endothelium-dependent relaxations to bradykinin, serotonin, and adenosine 5'-diphosphate were larger in both right and left coronary arteries from oil-fed than from cholesterol-fed animals. Aggregating platelets from cholesterol-fed and oil-fed pigs induced comparable, larger endothelium-dependent relaxations in rings from oil-fed than from cholesterol-fed pigs. The contractions induced by serotonin or aggregating platelets were significantly inhibited in rings with endothelium from oil-fed pigs, whereas they were comparable in rings without endothelium in both groups. Relaxations to sodium nitroprusside and contractions to potassium chloride or serotonin were comparable in rings without endothelium in both groups. The bioassay experiments revealed that the release of endothelium-derived relaxing factor in response to bradykinin and the relaxations of vascular smooth muscle to the endothelial factor were greater after the fish-oil diet. These results indicate that dietary supplementation of cod-liver oil delays the impairment of endothelium-dependent relaxations in hypercholesterolemia and in atherosclerosis, partly because of an improved release of endothelium-derived relaxing factor and partly because of an improved relaxation of coronary smooth muscle to the factor.

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.

We sought to determine the effect of dietary omega-3 polyunsaturated fatty acids on cerebrovascular endothelium-dependent responses in studies performed on isolated porcine basilar arteries. Male Yorkshire pigs (6-8 weeks old) were kept for 4 weeks on a standard diet (control group, n = 12) or on chow supplemented with polyunsaturated fatty acids (eicosapentaenoic acid, 3.5 g/day, or docosahexaenoic acid, 1.5 g/day; treated group, n = 12). Isometric tension recording of the basilar artery was carried out and responses were compared between the two groups. The regimen resulted in a decrease in the plasma arachidonic acid level and an increase in eicosapentaenoic acid. Endothelium-dependent relaxations induced by bradykinin and adenosine diphosphate were augmented in the basilar arteries of the treated group. Incubation with indomethacin (10(-5) M) prevented the augmentation of the relaxations induced by bradykinin, but not those caused by adenosine diphosphate. The indomethacin-sensitive, endothelium-dependent contractions to arachidonic acid remained comparable in the two groups, indicating that the activity of cyclooxygenase was not affected by the diet. Dietary supplementation with omega-3 polyunsaturated fatty acids enhances endothelium-dependent relaxations in the basilar artery by two mechanisms: 1) replacement of endogenous arachidonic acid and suppression of the concomitant release of vasoconstrictor prostaglandins from the endothelium, and 2) enhancement of the release of endothelium-derived relaxing factor.