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 comparison of the predicted and X-ray structures of angiogenin. Implications for further studies of model building of homologous proteins

The three-dimensional structure of human angiogenin has been determined by X-ray crystallography and is compared here with an earlier model which predicted its structure, based on the homology of angiogenin with bovine pancreatic ribonuclease A. Comparison of the predicted model and crystal structure shows that the active-site histidine residues and the core of the angiogenin molecule, including most of the-strands and-helices, were predicted reasonably well. However, the structure of the surface loop regions and residues near the truncated C-terminus differs significantly. The C-terminal segment includes the active-site residues Asp-116, Gln-117, and Ser-118; Gln-117 in particular has been shown to be important in affecting the ribonucleolytic activity of angiogenin. Also, the orientation of one helix in the model differed from the orientation observed experimentally by about 20°, resulting in a large displacement of this chain segment. The difficulty encountered in predicting the surface loop regions has led to a new algorithm [Palmer and Scheraga (1991),J. Comput. Chem.,12, 505–526; (1992),J. Comput. Chem.,13, 329–350] for predicting the conformations of surface loops.     

Sterol and bile acid metabolism during development: 2. Identification of 3β-hydroxy-5-cholenoic acid (an intermediate in alternate pathway of bile acid synthesis) in newborn and fetal guinea pig

3β-hydroxy-5-cholenoic acid was found in the bile and feces of new-born and fetal guinea pigs. The identity of this compound was confirmed by gas chromatography and mass spectrometry. This finding suggests that the formation of chenodeoxycholic acid through 3β-hydroxy-5-cholenoic acid is intermediate in the early life of guinea pigs. Thus, it provides a useful model for studying the details of regulatory factors and significance of this pathway. This study also revealed that, unlike the adult guinea pig, the newborn guinea pig has significant amounts of glycine conjugates of bile acid.     

Responses of pulmonary C-fibre and rapidly adapting receptor afferents to pulmonary congestion and edema in dogs.

The effects of cardiogenic and noncardiogenic pulmonary edema on the activities of rapidly adapting receptors (RARs) and pulmonary C-fibre receptors were investigated in dogs anaesthetized with chloralose. Cardiogenic pulmonary edema was produced by elevating the mean left atrial pressure by 25 mmHg (1 mmHg = 133.32 Pa) above the control value for a period of 45 min, by partial obstruction of the mitral valve. Noncardiogenic pulmonary edema was produced by injecting alloxan (100 mg/kg) intravenously. The effect of the latter was examined on RARs alone. Cardiogenic edema activated RARs (n = 8) and the activity was greatest during the first few minutes after elevation of mean left atrial pressure. The pulmonary C-fibre receptors (n = 6) were also activated by cardiogenic edema, but these responses were variable. Noncardiogenic pulmonary edema also activated RAR (n = 6), and this response was maintained during the entire recording period (20 min). The extravascular lung water (%), measured 15 min (n = 5) and 45 min (n = 5) after the elevation of the mean left atrial pressure, was significantly elevated above control values. However, these two values were not significantly different from each other. The extravascular lung water increased significantly after the injection of alloxan also (n = 5). These results show that during pulmonary edema, there is significant stimulation of the RARs and the pulmonary C-fibre receptors. It is suggested that the reflex respiratory responses observed in pulmonary edema may be due to the activation of both the RARs and the pulmonary C-fibre receptors.     

Exogenous glycosaminoglycans (GAG) differentially modulate GAG synthesis by anchorage-independent cultures of the outer cells from neonatal rat calvaria in the absence and presence of TGF-β

In anchorage-dependent (AD) cultures of the outer cell population (OCP) from neonatal rat calvaria, transforming growth factor-₁ (TGF-) specifically upregulated the synthesis of chondroitin sulfate (CS) proteoglycan (PG) and uncoupled the inhibitory effect of increasing cell density on CS PG synthesis (reference #30). Utilizing the same cell population, we have further examined the possibility that glycosaminoglycans (GAG) known to be synthesized and secreted by bone cells might exert feedback effects on GAG synthesis and/or its stimulation by TGF-. Although addition of TGF- alone stimulated net synthesis of HA and CS in both AD and anchorage-independent (AI) cultures, significant alterations of basal and TGF--stimulated GAG synthesis by exogenous GAGs were observed only in AI cultures. In AI cultures exogenously added hyaluronic acid (HA) markedly enhanced the basal synthesis of HA and CS while heparin (H) suppressed the basal synthesis of HA, CS as well as dermatan sulfate (DS). Also, the addition of HA markedly potentiated the stimulation by TGF- of HA and CS synthesis as did heparan sulfate (HS) for CS and DS synthesis. H suppressed the stimulation of the synthesis of HA, CS and DS by TGF-. Overall, our results indicate specific effects of individual GAGs on basal and TGF--stimulated GAG synthesis in OCP cultures. We suggest that some of the GAGs in the OCP microenvironment (which with the exception of HA are covalently linked to protein cores of secreted PGs), acting in concert with TGF-, may serve as an amplification system for upregulating GAG synthesis in the rapidly growing neonatal calvarium.