Cone dysfunction and supernormal scotopic electroretinogram with a high-intensity stimulus

An unusual form of scotopic electroretinogram with a bright white stimulus, which consisted of a rectangular a-wave of normal amplitude and a b-wave of supernormal amplitude, was recorded in three patients with cone dysfunction. In addition to poor visual acuity, abnormal color vision and reduced amplitude of the photopic electroretinogram, these patients showed a 2-log unit elevation of the dark-adaptation threshold. Funduscopic examination and fluorescein angiography revealed fine granular pigment disturbances at the mascula. The relationship between the response of the dark-adapted electroretinogram versus stimulus intensity was unique to these patients. The b-wave thresholds were elevated by 1 log unit. The b-waves were reduced in amplitude and markedly delayed in implicit time to dim stimuli, but supernormal in amplitude and normal in implicit time to bright stimuli.Abbreviations GMP guanosine monophosphate     

G proteins (Gi,Go) in the medial temporal lobe in schizophrenia: preliminary report of a neurochemical correlate of structural change

Summary We have measured the amount of Gi (the inhibitory G-protein) or Go (a similar G-protein of unknown function) in 5 areas of the medial temporal lobe of control and schizophrenic brains utilizing pertussis toxin-catalyzed ADP ribosylation. The material used has previously been shown to have asymmetrical structural abnormalities of the ventricular system. The amount of Gi or Go was reduced on the left side in the hippocampus, amygdala and parahippocampal gyrus, the difference reaching significance in the hippocampus. This data is the first report of a neurochemical correlate of the structural change in the brains of patients with schizophrenia. Decreased Gi or Go in hippocampus may relate to other reported neurochemical deficits or other transmembrane signalling abnormalities. Further investigations of these indices of secondary messenger function in relation to structural changes are indicated.     

Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans

Summary The involvement of nitric oxide as an intracellular messenger in the control of insulin secretion from pancreatic Beta cells was studied in rat islets of Langerhans by measuring: (i) nitric oxide generation in response to physiological insulin secretagogues; (ii) the effects of inhibitors of nitric oxide synthesis on insulin secretory responses to physiological secretagogues, and on insulin synthesis; (iii) changes in islet cyclic guanosine monophosphate in response to secretagogues; (iv) the effects of exogenous cyclic guanosine monophosphate and dibutyryl cyclic guanosine monophosphate on insulin secretion from electrically permeabilised islets and from intact islets, respectively. These studies produced no evidence that nitric oxide generation is required for the initiation of insulin secretion by common secretagogues. However, the results of our experiments suggest that the generation of nitric oxide may be involved in long-term, glucose-dependent increases in cyclic guanosine monophosphate content of islet cells, although the physiological relevance of these changes requires further investigation.     

Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

Effect of nitric oxide on mitogenesis and proliferation of cerebellar glial cells

In the brain, nitric oxide (NO) has been identified as a messenger molecule and a mediator of excitatory amino acid-induced neurotoxicity. In this study, the effects of NO on serum-induced mitogenesis and cell proliferation of the cerebellar glial cells were assessed. NO-generating agent, S-nitroso-N-acetylpenicillamine (SNAP) increased intracellular cyclic guanosine monophosphate (cGMP) levels. Furthermore, 2 chemically dissimilar NO-generating agents, SNAP and sodium nitroprusside (SNP) inhibited serum-induced thymidine incorporation and cell proliferation. The antimitogenic effect of NO was mimicked by 8-bromo-cGMP and blocked by hemoglobin, a known inhibitor of NO. The effect of NO was not cytotoxic, since the cells were not stained with Trypan blue and did not show increased release of lactate dehydrogenase in the culture supernatants. However, NO-treated cells showed decreased conversion of tetrazolium to blue formazan suggesting that NO inhibited mitochondrial activity in the glial cells. These results demonstrate that NO inhibits serum-induced mitogenesis and cell proliferation of cultured rat cerebellar glial cells.     

慢性低O2高CO2时NO-sGC-cGMP细胞信号转导通路变化及与肺动脉高压的关系

目的 :探讨慢性低O2 高CO2 性肺动脉高压发生与发展中NO sGC cGMP细胞信号转导通路的变化和作用。方法 :雄性Sprague Dawley大鼠随机分为对照组与低O2 高CO2 肺动脉高压 1w、2w及 4w组。用比色法测定血浆NO含量 ,酶动力学法测定肺组织sGC活性 ,12 5 I 放射免疫法检测肺组织cGMP含量。结果 :低O2 高CO2 1w、2w、4w组mPAP较对照组均明显升高 (P均 <0 .0 1)。而血浆NO含量、肺组织sGC活性和肺组织cGMP含量均显著降低 (分别P <0 .0 5,P <0 .0 1或P <0 .0 0 1)。mPAP与血浆NO含量 (r =-0 .80 7,P <0 .0 1)、与肺组织sGC活性 (r=-0 .754,P <0 .0 1)、与肺组织cGMP含量 (r=-0 .62 1,P <0 .0 1)之间均存在显著负相关。结论 :低O2 高CO2 引起的NO sGC cGMP转导通路的遏制性变化导致肺动脉舒张性降低是形成肺动脉高压的重要机制     

Atrial natriuretic factor (ANF) does not affect ion transport in human intestine but does in porcine intestine

The aim of this study was to test whether atrial natriuretic factor (ANF) exerts any effect on human intestinal ion transport, and the porcine intestine was used as a positive control of ANF's effects. Tissues from human proximal (n = 6) and distal (n = 6) colons, and from distal ileum (n = 6) were mounted in Ussing chambers, and short circuit current (I_sc) was measured subsequent to serosal application of ANF (10^--⁶ m), 8–Br-cyclic guanosine monophosphate (8–Br-cGMP) (10^--⁴ m), and theophylline (10^--² m). ANF did not affect I_sc whereas 8–Br-cGMP increased I_sc by 28 (8–53), 16 (3–36), and 16 (5–41) μA cm^-2 in the distal colon (DC), proximal colon (PC) and distal ileum (DI), respectively. Likewise, transepithelial potential difference (PD) became more negative by 5.0 (0.6–8.9), 2.5 (0.4–4.0) and 0.9 (0.3–2.3) mV in DC, PC, and DI, respectively, subsequent to addition of 8–Br-cGMP. I_sc and PD were further increased by theophylline. Additional radio-isotope flux studies in human colon revealed that ANF did not affect electroneutral sodium and chloride transport either. For comparison, ANF (10^--⁶ m) was administered to large intestinal tissues from young pigs in which ANF induced a significant increase in I_sc which was comparable to the 8–Br-cGMP response in humans. The porcine I_sc response was partly inhibited by chloride-free solution on the serosal side, by serosal application of bumetanide (10^--⁴ m) and BaCl₂ (10^--³ m), and mucosal application of the chloride-channel blocker diphenylamine-2–carboxylate (DPC) (10^--³ m). Mucosal amiloride (10^--⁵ m) pre-treatment reduced baseline I_sc but did not affect the porcine intestinal I_sc response to ANF. In vitro radio-autography demonstrated specific binding sites for ANF in porcine distal colon, whereas no apparent labelling was observed in human distal colon. These findings suggest that the lack of effect of ANF on sodium and chloride transport in human distal ileum and colon is probably due to lack of ANF receptors. In the porcine intestine, however, the I_S0 response induced by ANF seems to involve stimulation of electrogenic chloride secretion, whereas electrogenic sodium absorption seems unaffected.     

Effect of atrial natriuretic factor and cyclic guanosine monophosphate on water and urea transport in the inner medullary collecting duct

We examined the action of high (2×10^–8M) and low (6×10^–9M) concentrations of atrial natriuretic factor (ANF) on water and urea transport in the rat inner medullary collecting duct (IMCD) using the in vitro microperfusion technique. We measured the hydraulic conductivity (Lp ×10^–6 cm/atm per second) and both lumen-to-bath (P _u(lb)) and bath-to-lumen (P _u(bl)) ¹⁴C-urea permeabilities (P _u× 10^–5 cm/s) in the absence and in the presence of vasopressin (VP). High concentrations of ANF were able to inhibit the maximum activity of (50 U/ml) VP-stimulated L _p but physiological concentration of ANF inhibit only submaximum activity (10 U/ml) of VP-stimulated L _p. The hydrosmotic effect of dibutyryl-cyclic 3,5 adenosine monophosphate (cAMP) (10^–4M) was unchanged by high concentrations of ANF (2×10^–8M). Also we found that high (10^–4M) and low (10^–6M) concentrations of exogenous cyclic 3,5-guanosine monophosphate (GMP) while unable to change the Lp in the absence of VP, decreased the maximum activity of VP-stimulated Lp significantly. We also found that ANF inhibits partially and in a reversible manner the VP-stimulated P _u(lb) but not the VP-stimulated P _u(bl). These results demonstrated that plasma concentrations of ANF observed during volume expansion (10^–10M) are able to inhibit submaximum activity of VP-stimulated (10 U/ml) L _p in the rat IMCD, this effect seems to occur before cAMP formation and it appears to be mediated by cGMP. ANF (6× 10^–9M) also reduced the VP-stimulated urea outflux. Therefore, the increase in water excretion produced by ANF could be explained, at least in part, by the inhibition by ANF of vasopressin effects on water and urea transport in the IMCD.This study was presented in part at the VI Latin American Congress of Nephrology, Brazil, October 1985 and at the X^th International Congress of Nephrology, London, July 1987.     

Cytochemical localization of 5'-nucleotidase activity in retinal photoreceptor cells

Further cytochemical studies on the ultrastructural localization of 5'-nucleotidase in the rat retina have revealed activity to be associated with the complex synapses formed by the rod spherules of the receptors and the bipolar and horizontal cell processes. Activity was also seen on the axolemma of receptor fibers. In the rod inner segment strong reaction product is located intracellularly. In the rod outer segment the enzyme appears to be located only on the cytoplasmic side of the disc membrane and not intradiscally . Retinal pigment cells are rich in 5'-nucleotidase. Their microvilli accompany the tips of the receptor cells and show enzyme activity in an ecto position. A role for 5'-nucleotidase is possible in the metabolism of guanylate and adenylate nucleotides both of which are important for visual transduction processes.     

Synaptic efficacy of inhibitory synapses in hypoglossal motoneurons after transection of the hypoglossal nerves

In cat hypoglossal motoneurons after axotomy the synaptic efficacy of inhibitory synapses made by the lingual nerve afferent fibers was studied. The amplitude of the short- and the long-lasting inhibitory postsynaptic potential produced in tongue protruder motoneurons 24 days after axotomy by stimulation of the lingual nerve was significantly reduced in size as compared with the control on the unoperated side. In most protruder motoneurons 40 days after axotomy a large excitatory postsynaptic potential and a spike was produced by stimulation of either the ipsilateral or the contralateral lingual nerve. We have demonstrated that the decline of synaptic efficacy of inhibitory synapses for the short-lasting inhibitory postsynaptic potential was more prominent than that for the long-lasting inhibitory potential in the motoneuron 24 days after axotomy. After the cut axons of protruder motoneurons were re-united to tongue muscles, we have demonstrated that the decline of synaptic efficacy of inhibitory synapses for the short-lasting inhibitory postsynaptic potential was less prominent than that in axotomized protruder motoneurons.