Distribution of intravenously administered acidic and basic fibroblast growth factors in the mouse

Summary Iodinated acidic or basic fibroblast growth factor (aFGF or bFGF) were separately injected into adult mice to follow their distribution in the main organs of the animals. Iodinated FGFs intravenously injected into mice cleared from blood with aT _1/2 of 30 s. They mainly bound to kidney, liver and spleen. The binding of FGFs to these organs was maintained when the latter were washed with a physiological buffer containing 0.15 M NaCl, but it was eliminated when the buffer contained 2 M NaCl. Simultaneous injections of the FGFs together with increasing doses of heparin weakened the binding of FGF to vessels in a dose-dependent manner.     

Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels

Transmembrane influx of extracellular calcium through specific calcium channels is now accepted to have an important role in the excitation-contraction coupling of cardiac and smooth muscle. The importance of such slow calcium channels has been underlined by the development of specific calcium channel blocking agents, the 'calcium antagonists', typified by verapamil, nifedipine and diltiazem. These drugs have been used to investigate the properties of slow calcium channels in a variety of tissues. We have found that small modifications to the nifedipine molecule produce other dihydropyridine derivatives (see Fig. 1) with effects diametrically opposite to those of the calcium antagonists: cardiac contractility is stimulated and smooth muscle is contracted. These effects are competitively antagonized by nifedipine. Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel. In contrast to nifedipine, however, the new compounds promote--instead of inhibiting--the influx of Ca2+ ions. We report here the properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate), one of the most potent of these novel compounds.     

Direct access to serum macromolecules by intraerythrocytic malaria parasites.

Trafficking pathways in malaria-infected erythrocytes are complex because the internal parasite is separated from the serum by the erythrocyte and parasitophorous vacuolar membranes. Intraerythrocytic Plasmodium falciparum parasites can endocytose dextrans, protein A and an IgG2a antibody. Here we show that these macromolecules do not cross the erythrocyte or parasitophorous vacuolar membranes, but rather gain direct access to the aqueous space surrounding the parasite through a parasitophorous duct. Evidence for this structure includes visualization of membranes that are continuous between the parasitophorous vacuolar and erythrocyte membranes, and surface labelling of the parasite with fluorescent macromolecules under conditions that block endocytosis. The parasite can internalize by fluid-phase endocytosis macromolecules from the aqueous compartment surrounding it. Thus, surface antigens on trophozoites and schizonts should be considered as targets for antibody-directed parasiticidal agents.     

Orientation of spin labels attached to cross-bridges in contracting muscle fibres

Electron micrographs showing different cross-bridge orientations in different states of muscle fibres, and X-ray diffraction patterns indicating axial cross-bridge disorder in contracting muscle first suggested that force generation in the contracting muscle involved a change in orientation of the myosin heads that form cross-bridges between thick and thin filaments. This has been supported by subsequent work; the myosin molecule has the required flexibility for changes in orientation. The orientation of muscle tryptophans and of probes attached to the myosin heads of permeable muscle fibres depends on the state of the muscle. Recently, fluorescence polarization fluctuations and time-resolved X-ray diffraction patterns have suggested that cross-bridges of a contracting muscle can rotate. We have used electron paramagnetic resonance (EPR) spectroscopy to monitor the orientation of spin labels attached specifically to a reactive sulphydryl on the myosin heads in glycerinated rabbit psoas skeletal muscle. Previously, it has been shown that the paramagnetic probes are highly ordered in rigor muscle, with a nearly random angular distribution in relaxed muscle. We show here that during the generation of isometric tension, approximately 80% of the probes display a random angular distribution as in relaxed muscle while the remaining 20% are highly oriented at the same angle as found in rigor muscle. These findings indicate that a domain of the myosin head does not change orientation during the power stroke of the contractile interaction.