dihydropyridines and Necrosis

Topics: Actin Cytoskeleton; Animals; Anti-Infective Agents; Bacterial Toxins; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Clostridioides difficile; Cytokines; Dihydropyridines; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glucosyltransferases; Humans; Kinetics; Mice; NADPH Oxidases; Necrosis; Reactive Oxygen Species; Virulence Factors

Nifedipine is a calcium channel blocker dihydropyridine that has been used in the treatment of hypertension. The production of reactive species and calcium overload are the main contributors to myocardial ischemia-reperfusion (I / R) injury. We investigated the ability of novel dihydropyridines (DHPs) to improve the effect of protecting against the injury induced by ischemia and reperfusion in cardioblasts when compared to nifedipine. Forty three DHPs were created varying the fatty chains derived from palmitic acid, stearic acid and oleic acids and aromatic moiety in addition to the addition of chemical elements such as chlorine, nitrogen dioxide, furfural, hydroxyl and methoxy. Cytotoxicity and inhibition of linoleic oxidation were evaluated for all new DHPs and also for nifedipine. The alpha-tocopherol and butylated hydroxytoluene (BHT) were used as antioxidants controls. The compounds with the best antioxidant potential were used in the ischemia and reperfusion (I / R) induction test in cardioblasts (H9c2). Cardioblasts were treated 24 h after assembly of plates and submitted to the ischemia simulation (30 min), after which, normoxia and cellular nutrition conditions were reestablished, simulating reperfusion (additional 30 min). Right after, cell viability, apoptosis, necrosis, and the generation of reactive oxygen species (ROS) were evaluated. Cell viability during I / R was not altered in cells treated with nifedipine, BHT and the new DHP composed of palmitic acid with hydroxyl group in the aromatic substituent. The other new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the I / R group, demonstrating the antioxidant capacity of the new DHPs. Therefore, DHPS with palmitic and oleic acids in the C3 and C5 position with NO2 or Cl in aromatic moiety, presented the highest antioxidant potential (linoleic oxidant test). The new DHPs increased cell viability during I / R simulation and reduced levels of reactive species compared to the ischemia and reperfusion group, demonstrating the antioxidant capacity of the new DHPs. Taken together, these results indicate that those new DHPs have a greater cardioprotective antioxidant capacity to face the damages of ischemia and reperfusion.

Topics: Animals; Antioxidants; Cardiotonic Agents; Cell Line; Cell Survival; Dihydropyridines; Myoblasts; Myocardial Reperfusion Injury; Necrosis; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury

Nitric oxide (NO) and the partial pressure of oxygen (pO(2)) in the liver were simultaneously quantified in rats with partial hepatic ischemia/reperfusion injury (PHIRI). Real-time NO/pO(2) monitoring and immunohistochemical analysis for superoxide dismutase and inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) were performed to evaluate the protective effects of a dihydropyridine-type calcium-channel blocker--CV159--on PHIRI. Serum high-mobility-group box-1 (HMGB-1) was measured to assess cellular necrosis. Moreover, we used in vitro/ex vivo electron paramagnetic resonance spin trapping to assess the hydroxyl radical (*OH)-scavenging activity (OHSA) of CV159 and the liver tissue. The NO levels were significantly higher in CV159-treated rats than in control rats throughout the ischemic phase. Immediately after reperfusion, the levels temporarily increased in waves and then gradually decreased in the treated rats but remained constant in the control rats. pO(2) was continually higher in the treated rats. In these rats, hepatic eNOS expression increased, whereas iNOS expression decreased. The treated rats exhibited significantly higher cytosolic and mitochondrial concentrations NOx (NO(2)+NO(3)). The serum HMGB-1 levels significantly decreased in the treated rats. Moreover, CV159 directly scavenged *OH and both mitochondrial and cytosolic OHSA were preserved in the treated rats. Thus, CV159-mediated inhibition of intracellular Ca(2+) overloading may effectively minimize organ damage and also have *OH-scavenging activity and the cytoprotective effects of eNOS-derived NO.

Topics: Animals; Calcium Channel Blockers; Cytosol; Dihydropyridines; Electrodes; Electron Spin Resonance Spectroscopy; Endothelium; Free Radical Scavengers; HMGB1 Protein; Hydroxyl Radical; Liver; Male; Mitochondria; Necrosis; Nitric Oxide; Nitric Oxide Synthase; Nitrogen Oxides; Oxygen; Rats; Rats, Sprague-Dawley; Reperfusion Injury