Action of histamine on the rapidly adapting airway receptors in the dog

The effects of histamine on the activity of rapidly adapting receptors (RAR) of the airways were investigated in anesthetized dogs. With bolus injections given into the right atrium, the threshold dose of histamine required for the excitation of RAR (n = 7) was 0.82 microgram/kg (+1.33/-0.51, geometric mean). With increasing doses of histamine, a dose-response relationship was seen in the activity of RAR. Obstruction of the lymphatic drainage from the lungs reduced the threshold dose to histamine (i.e., shifted the dose-response curve to the left significantly). This change in the dose-response relationship was not accompanied by a corresponding change in the relationship of histamine dose to airway pressures recorded before and after lymphatic obstruction. Against a background of pulmonary venous congestion produced by partial obstruction of the mitral valve, subthreshold doses of histamine stimulated the RAR (n = 4). The excitatory effect of histamine on RAR was found to be abolished by the administration of the H1 receptor antagonist diphenhydramine but not by the H2 receptor antagonist cimetidine. Intravenous infusion of histamine (0.4 microgram.kg-1.min-1) for a period of 10 min increased the RAR activity (n = 6) significantly without producing detectable changes in airway mechanics. The results indicate that contraction of the smooth muscle of the airways may not be a prerequisite for the excitation of RAR, especially at low doses. It is suggested that some of the effects of histamine on RAR are mediated by a local expansion of the extravascular fluid caused by an increase in the permeability of the bronchial vasculature.     

A review of the in vitro and in vivo neurochemical characterization of the NMDA/PCP/Glycine/Ion channel receptor macrocomplex

Conclusions Current neurochemical studies of the NMDA receptor macromolecular complex are yielding new insights into the interactions of the subunits of this complex and the associated potential clinical benefits of selective modulation of these subnits. Such studies offer the great potential for a new generation of pharmacotherapies for a wide range of CNS disorders, including stroke, a condition for which there is currently no effective pharmacological treatment. However, it is essential to understand that the first generation products in this area may not be optimal pharmacotherapies, such that haracterization of possible receptor subtypes and understanding the molecular biology of the component proteins of the receptor complex will be crucial in the design of the optimal pharmacological modulators of the NMDA receptor complex.Special issue dedicated to Dr. Erminio Costa     

Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate

Previous studies have shown that murine macrophages immunostimulated with interferon gamma and Escherichia coli lipopolysaccharide synthesize NO2-, NO3-, and citrulline from L-arginine by oxidation of one of the two chemically equivalent guanido nitrogens. The enzymatic activity for this very unusual reaction was found in the 100,000g supernatant isolated from activated RAW 264.7 cells and was totally absent in unstimulated cells. This activity requires NADPH and L-arginine and is enhanced by Mg2+. When the subcellular fraction containing the enzyme activity was incubated with L-arginine, NADPH, and Mg2+, the formation of nitric oxide was observed. Nitric oxide formation was dependent on the presence of L-arginine and NADPH and was inhibited by the NO2-/NO3- synthesis inhibitor NG-monomethyl-L-arginine. Furthermore, when incubated with L-[guanido-15N2]arginine, the nitric oxide was 15N-labeled. The results show that nitric oxide is an intermediate in the L-arginine to NO2-, NO3-, and citrulline pathway. L-Arginine is required for the activation of macrophages to the bactericidal/tumoricidal state and suggests that nitric oxide is serving as an intracellular signal for this activation process in a manner similar to that very recently observed in endothelial cells, where nitric oxide leads to vascular smooth muscle relaxation [Palmer, R. M. J., Ashton, D. S., & Moncada, S. (1988) Nature (London) 333, 664-666].     

Opiate actions on mesocortical dopamine metabolism in the rat

The actions of parenteral morphine were examined with regard to dopamine metabolism in the mesocortical dopaminergic pathways of the rat. The effects of morphine on dopamine metabolism in the prefrontal, cingulate, pyriform and entorhinal cortices were compared with the actions of morphine on the metabolism of dopamine in the striatum and olfactory tubercle. In all tissues, except the entorhinal cortex, morphine significantly elevated the dopamine metabolites dihydroxphenylacetic acid and homovanillic acid. These data, along with previous studies of various pharmacological agents, clearly indicate that the mesocortical dopaminergic projections possess unique opioid and non-opioid regulatory inputs.     

Expression of the cytochrome b-URF6-URF5 region of the mouse mitochondrial genome

The nature of RNA coded by the only light-strand (L-strand) open-reading frame unidentified reading frame 6 (URF6) was studied by using a variety of single- and double-strand DNA subclones derived from the 3.6-kilobase (kb) cytochrome b (cyt b)-URF5 coding region of the mouse mitochondrial genome. Northern blot experiments using single-strand-specific M13 clones indicate that both the heavy (H) and L strands of this genomic region are symmetrically transcribed and processed into poly(adenylic acid) [poly(A)] RNAs of comparable size. The 1.2- and 2.4-kb RNAs coded by the H strand, putative mRNAs for cyt b and URF5 reading frames, respectively, are derived from a common precursor of 3.6-kb RNA. The L-strand-coded 1.15-kb RNA, on the other hand, is derived from a short-lived precursor of 3.6-kb RNA by a multiple-step processing involving a 2.4-kb intermediate RNA. The S1 nuclease protection experiments using both the 3'- or 5'-end-labeled DNA probes and also affinity-purified 32P-labeled RNA probes indicate that the 1.15-kb RNA maps between the start of the URF6 reading frame (3' end) and a region 590-600 nucleotides to the 5' end of this reading frame. The 1.15-kb RNA thus contains the entire URF6 coding sequence and an about 590-nucleotide-long 3' untranslated region. The molar abundance of the three mRNAs in the steady-state mitochondrial RNA varies markedly. The 1.15-kb URF6 mRNA is only one-tenth the level of 1.2-kb cyt b mRNA, although it is nearly as abundant as the 2.4-kb URF5 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)