Effects of methylmercury and trimethyltin on cardiac, platelet, and aorta eicosanoid biosynthesis and platelet serotonin release.
The effects of two organometals on heart, platelet, and aorta prostaglandin biosynthesis were examined in vitro. Methylmercuric chloride (MMC, 39-796 nM) increased the biosynthesis of thromboxane A2 (TxA2) and prostacyclin (PGI2) in the heart and stimulated the biosynthesis of PGI2 in incubates of aorta rings. The aorta biosynthesis of PGI2 was monitored by its inhibition of platelet aggregation and serotonin [5-hydroxytryptamine (5-HT)] secretion, while the metabolites 6-keto-PGF1a and TxB2 were quantified by radioimmunoassay. In platelet experiments, low concentrations of MMC (5 microM) enhanced aggregation to adenosine diphosphate (ADP) and at high concentrations MMC (50-100 microM) directly stimulated aggregation and 5-HT secretion. These effects of MMC were inhibited by nonsteroidal antiinflammatory drug, thromboxane synthetase, and phospholipase A2 inhibitors. Trimethyltin (TMT), another highly toxic organometal, had no effect on prostaglandin biosynthesis in either heart or aorta incubates. TMT did not increase platelet aggregation responses to ADP, nor did it directly trigger aggregation. At moderate concentrations, TMT (20-45 microM) slightly depressed ADP aggregation; however, this was paradoxically associated with increased 5-HT secretion. In platelets pretreated with either NDGA or ASA, TMT in the absence of aggregation enhanced 5-HT secretion in response to ADP. TMT, unlike MMC, did not stimulate platelet TxB2 biosynthesis from exogenous [3H]arachidonic acid, whereas MMC stimulates heart, vascular, and platelet eicosanoid biosynthesis. TMT, unlike MMC, does not directly activate the arachidonic acid cascade.
Ally
A
A
Biomedical NMR, National Research Council of Canada, Ottawa, Ontario.
Buist
R
R
Mills
P
P
Reuhl
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid; D015777:Eicosanoids / Q000096:biosynthesis*; D011464:Epoprostenol / Q000097:blood; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008767:Methylmercury Compounds / Q000494:pharmacology*; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood*; D013928:Thromboxane A2 / Q000097:blood; D014298:Trimethyltin Compounds / Q000494:pharmacology*
D015777:Eicosanoids; D008767:Methylmercury Compounds; D014298:Trimethyltin Compounds; D012701:Serotonin; D008315:Malondialdehyde; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol