Consequences of uncontrolled calcium entry and its prevention with calcium antagonists

Abstract

Heart muscle fibres always undergo severe functional and structural alterations, finally resulting in necrotization, if free extracellular Ca2+ ions penetrate abundantly through the sarcolemma membrane into the myoplasm, so that the capacities of the Ca2+ binding or extrusion processes become overpowered. The crucial reaction consists of high-energy phosphate exhaustion which is brought about (a) by excessive activation of Ca2+-dependent intracellular ATPases, and (b) by Ca2+-induced impairment of the mitochondria. Intracellular Ca2+ overload proved to the common denominator in the pathogenesis of severe myocardial fibre injury and death produced under the following circumstances: Overdoses of beta-adrenergic catecholamines, dihydrotachysterol or vitamin D3, alimentary K+ or Mg2+ deficiency, hereditary cardiomyopathy of Syrian hamsters. Moreover, intracellular Ca2+ overload develops in the course of myocardial hypoxia or ischaemia thus causing additional precipitous damage of the mitochrondria. Following our first observations made in 1968, it has turned out that in all these cases, Ca2+ antagonists are capable of protecting myocardial cell integrity in that they prevent excessive transmembrane Ca2+ uptake. This is also true of the Ca2+ paradox: Ca2+ antagonists possibly inhibit the development of sarcolemmal leaks in the Ca2+-deprived myocardium. However, it is more likely that Ca2+ antagonists restrict the exaggerated influx of Ca2+ through these leaks, when the Ca+-deprived myocardial fibres return to a normal Ca2+-containing medium.

CD8+T-cell-derived soluble factor(s), but not β-chemokines RANTES, MIP-1α, and MIP-1β, suppress HIV-1 replication in monocyte/macrophages

“…CD8 ϩ T cells were positively selected as described above from PBMCs derived from an HIV-1-infected, asymptomatic individual. Approximately 5 ϫ 10 6 cells were infected with approximately 10 6 plaque-forming units of herpesvirus saimiri (HVS) strain 488-779 (kindly provided by R. C. Desrosiers, New England Regional Primate Center, Harvard Medical School, Southborough, MA), as described (25). HVStransformed CD8 ϩ T cells (HVS͞HIV ϩ ͞CD8 ϩ T cells) were maintained in long-term culture (more than 6 months) in RPMI 1640 medium supplemented with 10% heat-inactivated FBS and recombinant human IL-2 (2.5 units͞ml; Boehringer Mannheim).…”

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…63 In rats receiving 1 and 4 weeks ALDOST, we monitored intracellular Ca 2+ levels in several tissues that included the heart and PBMC. We found increased Ca 2+ levels in the myocardium and PBMC during pre-clinical, clinical and pathological stages, accompanied by biomarker evidence of oxidative stress that included increased levels of malondialdehyde and 8-isoprostane in the heart and increased H 2 O 2 production by PBMC.…”

Mechanism of action of cysteinyl leukotrienes on glucose and lactate balance and on flow in perfused rat liver

“…Nevertheless, attempts were made to obtain more direct evidence for this conclusion. The calcium antagonist, nifedipine [25], was found to prevent flow changes caused by nerve stimulation, noradrenaline infusion or prostaglandinFZa infusion nearly completely, without reducing the metabolic effects significantly (Athari and Jungermann, preliminary findings) [21]. However, 50 pM nifedipine did not alter the extent and the kinetics of the reduction of flow and of the increase of glucose output caused by 5 nM LTD4 (Fig.…”

“…This increase might be brought about by calcium release from intracellular stores in the endoplasmic or sarcoplasmic reticulum, or by uptake of calcium from the extracellular space. Since the calcium antagonist nifedipine [25] did not affect the metabolic or hemodynamic actions of LTC4 and LTD4, nifedipine-inhibitable slow calcium channels [25] do not appear to be involved in the mechanism of leukotriene action.…”

“…The solutions used for infusion had a concentration about 60-fold higher than the final concentrations indicated in the figures. The calcium antagonist nifedipine [25], the phospholipase-A2 inhibitor bromophenacyl bromide [26] and the cyclooxygenase inhibitor indomethacin [27] were first dissolved in dimethylsulfoxide to a concentration of 50 mM or 20 mM and then added to the perfusion medium to a final concentration of 50 pM or 20 pM, respectively.…”