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Preeclampsia usually occurs after week 20 of gestation and features hypertension and an increased peripheral vascular resistance. The mechanisms are unknown (1). Several lines of evidence implicate angiotensin II (Ang II) and its binding site, the AT 1 receptor. Preeclamptic patients manifest exaggerated pressor responses to Ang II. Gant et al. (2) infused Ang II into pregnant patients from week 10 of pregnancy onward and observed that those who later developed sustained hypertension required diminishing amounts of Ang II to obtain a similar pressor response. One possible explanation for this phenomenon might be increased expression of the AT 1 receptor. Baker et al. (3) also performed Ang II infusion experiments in pregnant patients and identified five patients who subsequently developed hypertension after week 20. These women were compared with seven who did not develop hypertension. The platelets of the preeclamptic women exhibited increased calcium signaling and increased binding sites for Ang II. The authors suggested increased stimulus-effect coupling in terms of Ang II responses in preeclamptic patients. We also observed increased cytosolic calcium responses in the platelets of preeclamptic patients in response to Ang II (4). However, circulating levels of Ang II are not increased in preeclampsia (5-7). In an earlier study of patients with essential hypertension, we observed a remarkably high incidence of circulating antibodies that cross-reacted with the α1-adrenoceptor and stimulated its signaling mechanism (8). In the present study, we tested the hypothesis that circulating antibodies to a vascular receptor might be responsible for the hypertension observed in preeclampsia. We employed a bioassay of beating neonatal rat cardiomyocytes, as well as Western blotting and confocal microscopy. We found that immunoglobulin from preeclamptic women contains a factor that binds to, and stimulates, the AT 1 receptor. MethodsCell culture. Isolation and cultivation of neonatal heart cells were performed as described previously (9). Briefly, single cells were dissociated from the minced ventricles of Wistar rats (1-2 days old) with a 0.25% solution of crude trypsin and were cultured as monolayers with a density of 800 cells/mm 2 in Halle SM 20-I medium equilibrated with humidified air. The medium contained 10% heat-inactivated FCS and 2 µmol/l fluorodeoxyuridine (Serva, Heidelberg, Germany) the latter to prevent proliferation of nonmuscle cells. On the third or fourth days, the cells were incubated for 2 h in 2 ml fresh serum-containing medium. Seven to 10 selected cells or synchronously contracting cell clusters per flask were counted for 15 s. This procedure was Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT 1 receptor-mediated stimulation of cultured neonatal rat cardio...

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) protect against cardiovascular disease by largely unknown mechanisms. We tested the hypothesis that EPA and DHA may compete with arachidonic acid (AA) for the conversion by cytochrome P450 (CYP) enzymes, resulting in the formation of alternative, physiologically active, metabolites. Renal and hepatic microsomes, as well as various CYP isoforms, displayed equal or elevated activities when metabolizing EPA or DHA instead of AA. CYP2C/2J isoforms converting AA to epoxyeicosatrienoic acids (EETs) preferentially epoxidized the -3 double bond and thereby produced 17,18-epoxyeicosatetraenoic (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) from EPA and DHA. We found that these -3 epoxides are highly active as antiarrhythmic agents, suppressing the Ca 2؉ -induced increased rate of spontaneous beating of neonatal rat cardiomyocytes, at low nanomolar concentrations. CYP4A/4F isoforms -hydroxylating AA were less regioselective toward EPA and DHA, catalyzing predominantly -and minus 1 hydroxylation. Rats given dietary EPA/DHA supplementation exhibited substantial replacement of AA by EPA and DHA in membrane phospholipids in plasma, heart, kidney, liver, lung, and pancreas, with less pronounced changes in the brain. The changes in fatty acids were accompanied by concomitant changes in endogenous CYP metabolite profiles (e.g. altering the EET/EEQ/EDP ratio from 87:0:13 to 27:18:55 in the heart). These results demonstrate that CYP enzymes efficiently convert EPA and DHA to novel epoxy and hydroxy metabolites that could mediate some of the beneficial cardiovascular effects of dietary -3 fatty acids.

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Cardiac function can be normalized in selected patients with end-stage IDC by MCSS. The degree of preoperative myocardial fibrosis may be an indicator for outcome; A-beta1-AABs can be used to monitor myocyte recovery. Weaning from MCSS offers an alternative to cardiac transplantation in certain patients.