Endocrine and exocrine pancreatic function after camostate-induced growth of the organ

It is well known that oral administration of camostate induces hyperplasia and hypertrophy of the rat pancreas. It is not clear, however, whether pancreatic hormone and enzyme secretion are affected by camostate treatment.In rats, daily administration of 200 mg camostate/kg b. wt for 14 days significantly increased pancreatic weight and pancreatic content of DNA, protein, amylase, lipase, trypsin and chymotrypsin, as well as the amount of insulin, glucagon and somatostatin. In the intact animal, blood glucose levels and serum concentrations of insulin and glucagon in response to an oral glucose load were not impaired after camostate treatment. In the isolated perfused pancreas, however, insulin and glucagon secretions were reduced, whereas somatostatin release was not affected. The volume of pancreatic juice produced by the unstimulated isolated perfused organ, as well as protein and enzyme secretion, were increased after camostate treatment. Likewise, the isolated perfused pancreas from camostate-treated rats secreted a larger volume of pancreatic juice and more protein in response to cholecystokinin (CCK), while enzyme secretion was affected in a non-parallel manner: amylase release was markedly reduced, lipase release was unchanged, and release of trypsin and chymotrypsin was increased.     

Dual role of cAMP duringDictyostelium development

cAMP plays an essential role duringDictyostelium development both outside and inside the cell. Membrane-bound receptors and adenylyl cyclase are responsible for sensing and producing extracellular cAMP, whereas a phosphodiesterase is responsible for maintaining a low basal level. The molecular events underlying this type of hormone like signalling, which are now beginning to be deciphered, will be presented, in the light of cAMP analogue studies. The importance of intracellular cAMP for cell differentiation has been demonstrated by the central role of the cAMP dependent protein kinase. Mutants as well as strains obtained by reverse genetics will be reviewed which lead to our current understanding of the role of intracellular cAMP in the differentiation of both stalk and spore cells.     

The influence of prostacyclin (PGI2) on contractile properties of isolated right ventricle of rat heart

The mechanism of the positive inotropic effect of prostacyclin (PGI₂) (2.6×10^?6 mol/l) on the isolated right ventricle of rat heart was studied. Our results show that the positive inotropic effect of prostacyclin is produced indirectly through beta adrenoceptors and slow Ca²⁺ channels, because blockade of slow Ca²⁺ channels with verapamil (10^?6 mol/l) and beta adrenoceptors with propranolol (10^?6 mol/l) abolishes this effect. Alpha adrenoceptors do not mediate the action of PGI₂.     

Alpha 1-adrenoceptor subtypes linked to different mechanisms for increasing intracellular Ca2+ in smooth muscle

Receptor-mediated increases in intracellular Ca2+ levels can be caused by release from intracellular organelles and/or influx from the extracellular fluid. Noradrenaline (NA) released from sympathetic nerves acts on alpha 1-adrenoceptors to increase cytosolic Ca2+ and promote smooth muscle contraction. In many cells activation of alpha 1-adrenoceptors causes formation of inositol 1,4,5-trisphosphate which promotes Ca2+ release from intracellular stores. The mechanism by which receptor activation opens cell surface Ca2+ channels is not known, although in some cases it may be secondary to formation of inositol phosphates or release of stored intracellular Ca2+ (ref. 3). However, alpha 1-adrenoceptors have recently been shown to have different pharmacological properties in different tissues, and it has been proposed that different alpha 1-adrenoceptor subtypes may control mobilization of intracellular Ca2+ and gating of extracellular Ca2+ influx. We here report evidence for two subtypes of alpha 1-adrenoceptors which cause contractile responses through different molecular mechanisms. One subtype stimulates inositol phosphate (InsP) formation and causes contractions which are independent of extracellular Ca2+, and the other does not stimulate inositol phosphate formation and causes contractions which require the influx of extracellular Ca2+ through dihydropyridine-sensitive channels. These results suggest that neurotransmitters and hormones may control Ca2+ release from intracellular stores and influx through voltage-gated membrane channels through distinct receptor subtypes.     

Suppression of in vitro haematopoiesis following human immunodeficiency virus infection

Viral infections are frequently associated with haematological disorders. Abnormalities including leukopenia, anaemia and thrombocytopenia are commonly observed in patients with the acquired immune deficiency syndrome (AIDS) or the AIDS-related complex (ARC). The underlying cause of these haematological abnormalities is poorly understood. We report here that bone marrow progenitors isolated from AIDS or ARC patients are responsive to recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF) and recombinant erythropoietin. Antibodies present in the serum of patients infected with the human immunodeficiency virus (HIV), however, could suppress the growth of these progenitors, but not the growth of progenitors from HIV seronegative controls. A component of this immune-mediated suppression appears to be antibodies directed towards the envelope glycoprotein (gp120) of HIV.     

Activation of a G protein promotes agonist responses to calcium channel ligands

The activation of a guanine nucleotide binding (G) protein is an essential step in coupling certain receptors to the inhibition of voltage-activated calcium channels. We have previously observed that analogues of GTP potentiate the effect of receptor agonists and inhibit calcium currents in cultured dorsal root ganglion (DRG) neurones. A residual sustained 'L-type' component of the calcium channel current is resistant to inhibition by internal guanosine 5'-O-3-thiotriphosphate (GTP-gamma-S). Because calcium channel antagonists such as D600, nifedipine and diltiazem inhibit L currents, we examined their effect on GTP-gamma-S-modified currents. These compounds all produced a rapid and very marked potentiation of calcium channel currents in the presence of internal GTP-gamma-S and this effect was prevented by pertussis toxin which ADP ribosylates the G proteins Gi/Go (for review see ref. 10). We suggest that this potentiation indicates that activated G protein can interact with the calcium channel, and that this enhances the action of calcium channel ligands at their agonist sites on the channel in its resting state. These results represent the first electrophysiological evidence that guanine nucleotides are able to influence cellular responses to calcium channel ligands.     

An AIDS-related cytotoxic autoantibody reacts with a specific antigen on stimulated CD4+ T cells

Patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related conditions are known to have abnormalities of T cell subpopulations, including a decreased helper/inducer (bearing the CD4 antigen) to suppressor/cytotoxic (bearing the CD8 antigen) T cell ratio and decreased absolute numbers of T cells with the CD4+ phenotype. Infection of T cells with a retrovirus, termed human immunodeficiency virus (HIV), is thought to be important in these abnormalities. HIV infection alone does not adequately explain the CD4+ T-cell abnormalities seen in AIDS, however, and the nature of T-cell destruction in this disease remains poorly characterized. Here we describe an AIDS-related serum autoantibody that reacts with an antigen of relative molecular mass 18,000 (Mr 18K) restricted to lectin-stimulated or HIV-infected CD4+ T cells. The antibody also suppresses proliferation of CD4+ T cells in vitro and induces cytotoxicity of these cells in the presence of complement. Its role in the development of AIDS merits attention.     

The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro

Cell-free extracts prepared from human 293 cells, supplemented with purified SV40 large-T antigen, support replication of plasmids containing the SV40 origin of DNA replication. A cellular protein (Mr approximately 36,000) that is required for efficient SV40 DNA synthesis in vitro has been purified from these extracts. This protein is recognized by human autoantibodies and is identified as the cell-cycle regulated protein known as proliferating cell nuclear antigen (PCNA) or cyclin.     

Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage

Multiple endocrine neoplasis type 2A (MEN2A) is one of several kinds of cancers that appear to be inherited in an autosomally dominant fashion. We have assigned the MEN2A locus to chromosome 10 by linkage with a new DNA marker (D10S5). The linkage led us to investigate other chromosome 10 markers and demonstrate linkage between the disease locus and the interstitial retinol-binding protein (IRBP) gene. The D10S5 locus was sublocalized to 10q21.1 by hybridization in situ and the IRBP gene to p11.2----q11.2 with a secondary site at q24----q25. The linkages were established using 292 members of five families, three different restriction fragment length polymorphisms (RFLPs) at D10S5 and two RFLPs recognized by the IRBP probe. The recombination frequencies from pairwise linkage analysis between the disease and two marker loci D10S5 and IRBP were 0.19 and 0.11, with maximum lod scores of 3.6 and 8.0 respectively. Ordering of the three loci by multipoint analysis placed the IRBP gene approximately midway between the disease and D10S5 loci.     

No requirements of cyclic conformation of antagonists in binding to vasopressin receptors

Early reports that acyclic analogues of oxytocin and vasopressin (AVP) have drastically reduced agonistic activities established as dogma that an intact hexapeptide ring structure is essential for the pharmacological activities of analogues of neurohypophysial hormones. Thus, virtually all the many hundreds of agonistic and antagonistic analogues of the neurohypophysial peptides that have been reported contain an intact ring. Here we report that an intact ring is not essential for binding of antagonistic AVP analogues to vasopressor (V1) or antidiuretic (V2) AVP receptors. In fact, one acyclic AVP analogue seems to be about as potent as any previously reported cyclic V2 antagonist. This finding suggests new possibilities for the design of AVP analogues as pharmacological probes and for therapeutic use. Similar modifications might be useful in the design of analogues of other cyclic peptides, such as calcitonin, somatostatin and the atrial natriuretic factors.