ryanodine and 2-(4-amylcinnamoyl)amino-4-chlorobenzoic-acid

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin is able to produce endothelium-dependent relaxation in addition to its lipid-lowering properties. The underlying mechanisms were investigated in bovine aortic endothelial cells (BAEC). Simvastatin induced an increase in cytosolic calcium ([Ca(2+)](i)) in BAEC, by releasing Ca(2+) from intracellular stores sensitive to thapsigargin and ryanodine, and increasing Ca(2+) entry. Simvastatin response was not altered by the phospholipase A(2) inhibitor ONO-RS-082, or the combination of superoxide dismutase plus catalase. However, the response to simvastatin was reduced by the product of HMG-CoA reductase, mevalonate or by the inhibitor of small G proteins of the Rho family, Clostridium botulinum C3 toxin. Thus, increase in [Ca(2+)](i) involving the activation of Rho protein through mevalonate-dependent pathway is essential for the action of simvastatin and might contribute to its beneficial effects against vascular diseases. This study helps elucidate the mechanisms of endothelial factor generation by simvastatin in BAEC.

Topics: Aminobenzoates; Animals; Aorta; Botulinum Toxins; Bradykinin; Calcium; Calcium Signaling; Catalase; Cattle; Cells, Cultured; Chlorobenzoates; Cinnamates; Endothelium, Vascular; Free Radical Scavengers; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; ortho-Aminobenzoates; Phospholipases A; rho GTP-Binding Proteins; Ryanodine; Simvastatin; Superoxide Dismutase; Superoxides; Thapsigargin

In pancreatic acini, administration of the phospholipase C inhibitor, U-73122, abolished Ca2+ oscillations and amylase secretion induced by CCK but had much less effect on the action of CCK analog JMV-180. In contrast, the phospholipase A2 inhibitor, ONO-RS-082, inhibited both Ca2+ spikes and amylase secretion induced by JMV-180, but it had little effect on the action of CCK-8. Both arachidonic acid (AA) and a cytochrome P-450 inhibitor, SKF-96365, generated Ca2+ spikes from the agonist-sensitive pool. AA was capable of releasing Ca2+ from the endoplasmic reticulum (ER), suggesting the direct Ca2+ releasing pathway. There is no evidence of Ca(2+)-induced Ca2+ release (CICR) since neither caffeine, a CICR potentiator, nor ryanodine, a CICR inhibitor, modulated agonist-induced Ca2+ oscillations and Ca2+ release from the ER. On the contrary, increasing concentrations of caffeine abolished agonist-induced Ca2+ spikes. Therefore we have demonstrated that depending on the agonists used, CCK receptor activation may result in the differential involvement of the phosphoinositol and arachidonic acid pathways to mediate calcium oscillation and amylase secretion.

Topics: Aminobenzoates; Amylases; Animals; Arachidonic Acid; Calcium; Chlorobenzoates; Cinnamates; Estrenes; Imidazoles; Inositol 1,4,5-Trisphosphate; Male; ortho-Aminobenzoates; Pancreas; Periodicity; Phospholipases A; Phospholipases A2; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Ryanodine; Signal Transduction; Sincalide; Type C Phospholipases