Perfused rat hearts release or accumulate approximately 10% of total Mg2+ content when stimulated with norepinephrine (NE) or carbachol, respectively. Collagenase-dispersed rat ventricular myocytes increase or decrease total cell Mg2+ by 1 mM within 5 minutes when stimulated with these same transmitters. Measurements of Mg2+ transport using 28Mg or atomic absorbance spectrophotometry indicate that the rate and the extent of both stimulated Mg2+ efflux and influx are independent of the concentration of extracellular Mg2+ (0 to 1.2 mM). Mg2+ release induced by NE is rapidly reversed by the addition of carbachol, and Mg2+ uptake induced by carbachol is reversed by NE. Decreasing extracellular Na+ or Ca2+ decreases or abolishes Mg2+ efflux from myocytes. Cd2+ or other Ca2+ channel blockers also inhibit Mg2+ efflux in the presence of a physiological concentration of extracellular Ca2+. Replacement of extracellular Ca2+ with Sr2+ or with Mn2+ decreases or abolishes both stimulated efflux and influx of Mg2+. Redistribution of 85Sr in myocytes and in the supernatant indicates that under those conditions Sr2+ is released or accumulated by NE or carbachol in a manner similar to that of Mg2+. Hence, at least in the case of Sr2+, the inhibition of Mg2+ fluxes can be explained by the transport of Sr2+ rather than Mg2+ through the transport(s) systems. By contrast, replacement of extracellular Ca2+ with Ba2+ inhibits stimulated Mg2+ uptake but not Mg2+ release. These results indicate that cardiac myocytes have a major pool of Mg2+ that can be rapidly mobilized upon hormonal stimulation. The net uptake and release of Mg2+ are quantitatively similar and appear to be independent of the extracellular Mg2+ concentrations but are affected, to various degrees, by the presence of other cellular or extracellular cations.

A large Mg:* cell uptake against concentration gradients is stimulated in collagenase-disper~ed ra: myocytes by carbachol and in hepato~t~ by carbachol or vasoprcssin. The signalling pathway(s) responsible for this stimulation o1" Mg ~-+ uptake was inv.+stigated by using various activators or inhibitors of protein kinase C (PKC) and by correlatin/~ Mg :+ uptake with cell PKC activity and cAMP content. In both cell preparations, the dir~.,ct stimulation of PKC by diaeylglycerol analogs or phorbol esters reproduce the same pattern of MS -+" uptake as that induced by carbachol or vasopressin. These data indicate that the activation of PKC is responsible for a stimulation of Mg:" uptake by myocytes or hepatocytes, whereas increase in cAMP in these cells stimulates Mg a' release.

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SUMMARYWe hypothesized that the altered immunoglobulin synthesis and/or lymphocyte ("unciion apparent in patients with IgA nephropathy (IgAN) is due to a primary defeet in lymphokine regulation. In addition, we reasoned that such changes in lymphokine production might be, at least partially, genetically determined. To assess the extent ot'lymphocyte abnormalities, we investigated lhe profile of cytokine production from peripheral blood mononuclear cells (PBMC) in .14 IgAN piilicmsand44 of their first degree relatives, 10 of whom had persistent mierohaematuria. Compared wilh healthy volunteers (o = 34), PBMC from patients showed increased IL-2 production both spontaneously or after phytohaemagglutinin (PHA) (20 /ig/ml) stimulation, whereas lL-4 and interferon-gamma (IFN-y) production were significantly higher only after stimulation. Mierohaemaluric relatives liad a similar pattern of eytokine production, whereas non-microhaematuric relatives showed no significant diflerence versus normals. The altered pattern of cytokine production appeared to be quite specific to IgAN patients and their microhaematuric relatives, because patients with other forms of primary glomerulonephritis (n= 17) did not differ from normal individuals. Patients and relatives that hyperproduced IL-4 were also hyperproducers of IL-2. No such congruence was seen in any other group or with any other pairing of eytokines. We propose that a subpopulation of IgAN patients bear lymphocytes intrinsically hyper responsive. Among those individuals such hyperresponsiveness may be causally related to the pathogenesis and/or character of IgAN.

The in vitro addition of thyroid hormone to isolated rat heart or liver mitochondria induces the extrusion of approximately 2-4 nmol Mg2+/mg protein from both mitochondria preparations. The mobilization of Mg2+ is not accompanied by extrusion of matrix ATP or K+, or by mitochondria swelling, thus excluding that the phenomenon occurs through the nonspecific opening of the mitochondrial permeability transition pore. Moreover, the Mg2+ extrusion is completely prevented by bongkrekic acid, a membrane-permeant inhibitor of the adenine nucleotide translocase (AdNT), and by cyclosporine, which has also been reported to inhibit AdNT in a bongkrekate-like manner, operating at the matrix site of the translocase. By contrast, atractyloside, another specific inhibitor of AdNT that operates at the cytosolic site of the AdNT, only partially affects the Mg2+ mobilization (< 30% inhibition). These findings and the binding of 125I-labeled thyroid hormone to both the dimeric and monomeric moiety of AdNT support the hypothesis that AdNT can operate as a specific receptor for thyroid hormone in the mitochondria, and suggest that thyroid hormone operates at the matrix site of the translocase. In addition, these observations may imply that some of the so called "nongenomic effects" exerted by thyroid hormone on mitochondrial metabolism could occur through changes in the matrix content of Mg2+.