Ca2+ release mechanism of primate drug-induced coronary vasospasm.
Cellular mechanisms of protection against drug-stimulated coronary vasospasm were studied by multiweek estrogen plus progesterone (P) vs. medroxy-progesterone acetate (MPA) treatments by measuring intracellular Ca2+ and protein kinase C (PKC) signals. Ovariectomized monkeys (OVX) were treated by slow-release implants with either P or MPA for 4 wk added to estradiol-17 beta (E2) begun 2 wk earlier. A third group received E2 for 2 wk and withdrawal of E2 (W; no steroid treatment) during the last 4 wk. OVX coronary artery vascular muscle cells (VMC) in primary culture conditions were labeled by the fluorescent indicators, fluo 3 and hypericin, respectively, to study intracellular Ca2+ and PKC mechanisms of coronary artery hyperre-activity, using digital analysis of single VMC by photon-counting camera. Stimulation by 10 microM serotonin and 100 nM U-46619 (thromboxane A2 mimetic) caused Ca2+ increases (2-5 min) and no PKC activation in VMC from five P-treated monkeys but prolonged (> or = 30 min) increases in both Ca2+ and PKC signals in VMC from six MPA-treated monkeys or seven W-treated monkeys; these P vs. MPA (or W) differences were maintained > or = 14 days. We hypothesize that hyperreactivity in VMC from MPA- or W-treated monkeys results from accelerated prolonged Ca2+ release, with concomitant PKC activation, and that MPA (but not P) negates the coronary vasospasm protective effect of E2.
Miyagawa
K
K
Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton 97006, USA.
Vidgoff
J
J
Hermsmeyer
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004338:Drug Combinations; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014018:Tissue Distribution; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004338:Drug Combinations; D004967:Estrogens; D045167:Progesterone Congeners; D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; D012701:Serotonin; D011374:Progesterone; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017258:Medroxyprogesterone Acetate; D011493:Protein Kinase C; D002118:Calcium