Interaction of monoclonal antiparathyroid antibody with Ca2+ agonistic actions of Mn2+ in normal human parathyroid cells.

Effects of the monoclonal antiparathyroid antibodies G11 and E11 on Mn2+ interaction with individual normal human parathyroid cells were studied. At 0.5mM Ca2+, 3mM Mn2+ induced a rapid transient increase in cytoplasmic Ca2+ [Ca2+i] followed by quenching of the fluorescence from the Ca2+ indicator fura-2 as Mn2+ entered into the cells. Whereas the antibody E11 had no effects, treatment with G11 abolished the Ca2+i transient and considerably delayed the entry of Mn2+. The results support the presence of a cation-sensitive receptor mechanism on parathyroid cells and indicate that the antibody G11 not only blocks the interaction between Ca2+ and this receptor mechanism but also that of Mn2+.

Control of voltage-dependent Ca2+ channels by G protein-coupled receptors.

G proteins act as transducers between membrane receptors activated by extracellular signals and enzymatic effectors controlling the concentration of cytosolic signal molecules such as cAMP, cGMP, inositol phosphates and Ca2+. In some instances, the receptor/G protein-induced changes in the concentration of cytosolic signal molecules correlate with activity changes of voltage-dependent Ca2+ channels. Ca2+ channel modulation, in these cases, requires the participation of protein kinases whose activity is stimulated by cytosolic signal molecules. The respective protein kinases phosphorylate Ca2+ channel-forming proteins or unknown regulatory components. More recent findings suggest another membrane-confined mechanism that does not involve cytosolic signal molecules but rather a more direct control of voltage-dependent Ca2+ channels by G proteins. Modulation of Ca2+ channel activity that follows this apparently membrane-confined mechanism has been described to occur in neuronal, cardiac, and endocrine cells. The G protein involved in the hormonal stimulation of Ca2+ channels in endocrine cells may belong to the family of Gi-type G proteins, which are functionally uncoupled from activating receptors by pertussis toxin. The G protein Gs, which is activated by cholera toxin, may stimulate cardiac Ca2+ channels without the involvement of a cAMP-dependent intermediate step. Hormonal inhibition of Ca2+ channels in neuronal and endocrine cells is mediated by a pertussis toxin-sensitive G protein, possibly Go. Whether G proteins act by binding directly to Ca2+ channels or through interaction with as yet undetermined regulatory components of the plasma membrane remains to be clarified.

The mechanism of ischemia-induced brain cell injury. The membrane theory.

Temporal ischemia of the brain injures only the selectively vulnerable brain cells. The dying process evolves along with glutamate-mediated intracellular signal-transduction system, together with a loss of Ca2+ homeostasis. Such post-ischemic changes eventually disrupt functional and structural integrity of the cell membrane and kill the neuron. Molecular basis in pharmacoprotective agents is discussed.

Calcium channel agonists and antagonists regulate protein phosphorylation in intact synaptosomes.

Protein phosphorylation in intact synaptosomes is highly sensitive to alterations in calcium fluxes and was used to probe the possible mechanism of action of the calcium channel agonist BAY K 8644 and antagonists verapamil and nifedipine. These agents (at 1 microM) all increased the basal phosphorylation of a specific set of 4 synaptosomal phosphoproteins termed P139, P124, P96 and P60, but did not alter depolarization-dependent protein phosphorylation. The increases could not be explained by a direct stimulation of protein kinases and appears unrelated to the known effects of these drugs on K+-stimulated neurotransmitter release. This finding may reveal a possible new mechanism of action for drugs which interact with calcium channels.

Los antagonistas del calcio en la trombosis coronaria / Calcium antagonists in coronary thrombosis

El beneficio de los antagonistas del calcio en la cardiopatía isquémica se atribuye al aumento del flujo coronario por vasodilatación y a factores que reducen el consumo de oxígeno como son la disminución de la precarga, postcarga e inotropismo. Sorprende que el papel de estas sustancia en la trombosis coronaria haya recibido escasa atención, aun cuanto hay evidencias experimentales y clínicas que ponen de relieve su acción antiagregante plaquetaria. Se ha demostrado, por otra parte, que un grupo diferente de sustanccias anticálcidas cuyo prototipo está bien representado por la cinnarizina, flunarizina y bublomedil, tienen la propiedad de reducir la viscosidad sanguínea y mejorar el flujo de la microcirculación en condiciones de isquemia. Estas drogas participan en la defensa de la integridad del endotelio y en el aumento de la capacidad de deformación de los eritrocitos que está estrechamente ligado a los flujos de calcio. La acción de ambos grupos de inhibidores del calcio sobre el endotelio vascular y los elementos figurados de la sangre que están involucrados en el proceso de la coagulación, constituyen hallazgos auspiciosos que podrían influir en un mejor conocimiento de la trombosis arterial

Clinical and laboratory effects of nifedipine in Raynaud's phenomenon.

The calcium channel blocking drug nifedipine was shown to be more effective than placebo as a treatment for Raynaud's phenomenon. Given in a dose of 10 mg four times a day it was well tolerated and reduced both the frequency and the severity of vasospastic attacks. There was, however, a large individual variation in response and while approximately half the patients showed marked improvement others showed no improvement at all. Patients with idiopathic Raynaud's phenomenon responded more favourably than those with systemic sclerosis. Nifedipine was shown to inhibit mitogen-induced lymphocyte proliferation but only in patients who responded to the drug clinically. Calcium channel blocking drugs may therefore have potential as immunoregulatory agents.

Cardiac calcium channels and their control by neurotransmitters and drugs.

Calcium channels, which play a primary role in the control of the calcium influx into cardiac cells, were initially studied by recording macroscopic currents in multicellular preparations. More recently, channel research has combined studies of whole cell calcium currents and elementary currents through single calcium channels, both measured in isolated cardiac cells. These studies provide insight into the mechanism of opening and closing of single calcium channels and enable inferences to be made about the whole cell calcium current from the average gating behavior of single channels. In addition, they promise a more complete understanding of the relation between the biophysical properties and molecular structure of the calcium channel. New information has also been obtained on the modulation of calcium channel gating by neurotransmitters and drugs.

Symposium on the management of ventricular dysrhythmias. Antifibrillatory versus antiectopic therapy.

The concept of antifibrillatory action distinct from antiarrhythmic effect has recently been recognized. An antiarrhythmic (antiectopic) action leads to a decrease in the frequency of ventricular ectopic beats. In contrast, an antifibrillatory drug action increases myocardial electric stability, decreasing the propensity for ventricular fibrillation. Agents with predominant antiarrhythmic action (designated class I) include lidocaine, quinidine, procainamide and disopyramide. Bretylium is an agent with predominant antifibrillatory action (class III). Amiodarone and sotalol are experimental class III drugs. The beta-blockers (class II) also possess antifibrillatory action, particularly in ischemic heart disease. The rationale for the use of agents with antiarrhythmic (antiectopic) effects is the reduction of triggering events for more complex ventricular tachyarrhythmias. These agents act by slowing conduction, decreasing abnormal automaticity and affecting phase IV depolarization. In contrast, agents with antifibrillatory action may exert little effect on cardiac conduction and automaticity. However, they raise the energy threshold required for premature electrical discharge to initiate ventricular fibrillation (ventricular fibrillation threshold). The inhomogeneity of electrophysiologic properties and adrenergic tone in different portions of the heart may be reduced or eliminated. Direct electrophysiologic effects of agents such as bretylium include a general lengthening of the refractory period and the action potential duration in the heart and a diminution in the disparity of their durations between normal and abnormal myocardium. Clinical studies are incomplete, but they support the concept of antifibrillatory therapy. In postmyocardial infarction patients at intermediate risk of sudden death, the broad use of oral antiarrhythmic agents has not decreased the incidence of sudden death, whereas high-dose beta-blocker therapy, which exerts experimental antifibrillatory effects, may reduce sudden death by 30 to 70%.(ABSTRACT TRUNCATED AT 250 WORDS)