Guanosine triphosphate activation of brain adenylate cyclase: enhancement by long-term antidepressant treatment.

Activation of adenylate cyclase by a stable guanosine 5'-triphosphate analog was augmented in brain membrane preparations from rats treated on a long-term basis with tricyclic antidepressants or electroconvulsive shock. These treatments may facilitate cyclase activation by promoting the interaction of the regulatory and catalytic subunits of the enzyme. This finding suggests a possible mechanism for the changes in sensitivity to various neurotransmitters seen after antidepressant administration.

Bacterial infection induces nitric oxide synthase in human neutrophils.

The identification of human inflammatory cells that express inducible nitric oxide synthase and the clarification of the role of inducible nitric oxide synthase in human infectious or inflammatory processes have been elusive. In neutrophil-enriched fractions from urine, we demonstrate a 43-fold increase in nitric oxide synthase activity in patients with urinary tract infections compared with that in neutrophil-enriched fractions from noninfected controls. Partially purified inducible nitric oxide synthase is primarily membrane associated, calcium independent, and inhibited by arginine analogues with a rank order consistent with that of purified human inducible nitric oxide synthase. Molecular, biochemical, and immunocytochemical evidence unequivocally identifies inducible nitric oxide synthase as the major nitric oxide synthase isoform found in neutrophils isolated from urine during urinary tract infections. Elevated inducible nitric oxide synthase activity and elevated nitric oxide synthase protein measured in patients with urinary tract infections and treated with antibiotics does not decrease until 6-10 d of antibiotic treatment. The extended elevation of neutrophil inducible nitric oxide synthase during urinary tract infections may have both antimicrobial and proinflammatory functions.

Toward a theory of episodic memory: the frontal lobes and autonoetic consciousness.

Adult humans are capable of remembering prior events by mentally traveling back in time to re-experience those events. In this review, the authors discuss this and other related capabilities, considering evidence from such diverse sources as brain imaging, neuropsychological experiments, clinical observations, and developmental psychology. The evidence supports a preliminary theory of episodic remembering, which holds that the prefrontal cortex plays a critical, supervisory role in empowering healthy adults with autonoetic consciousness-the capacity to mentally represent and become aware of subjective experiences in the past, present, and future. When a rememberer mentally travels back in subjective time to re-experience his or her personal past, the result is an act of retrieval from episodic memory.

Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women.

A study was conducted to evaluate the effects on blood lipids and lipoproteins of feeding 21 healthy volunteers, 40-60 yr old, foods commonly eaten in the United States for two 40-day periods. Activities of lactate dehydrogenase (LDH) and LDH isoenzymes, lactate, and pyruvate were monitored. Results showed that LDH activity was significantly lower in all subjects at the end of the 25% fat-calorie period (period I) than at the beginning of the study, but rose above initial levels at the end of the 35% fat-calorie period (period II). While total LDH fell during period I, relative activity of M type subunits of LDH rose significantly in relation to H type in both sexes. This rise is probably indicative of an increase in glycolytic activity as a consequence of the increased intake of dietary carbohydrate. In period I, lactate and pyruvate decreased significantly in males (pyruvate greater than lactate) but not in females. Values for males returned to near initial levels in period II. The ratio of lactate/pyruvate was elevated in both sexes after period I. The greater change in pyruvate relative to lactate with increased dietary carbohydrate suggests increased Krebs Cycle activity. There was a statistically significant positive correlation between lactate, pyruvate, and serum triglyceride for males after they ate the 25% and 35% fat-calorie diets and for females after they ate the 35% fat-calorie diet, but not between lactate, pyruvate, and serum cholesterol for either sex.

Involvement of nitric oxide and cyclic GMP in rabbit urethral relaxation.

Soluble and particulate fractions from rabbit urethra converted [14C]arginine to [14C]citrulline, indicating the presence of nitric oxide synthase activity in these fractions. Both soluble and particulate nitric oxide synthase activities were NADPH dependent, and the soluble activity was Ca2+ dependent. Three nitric oxide synthase (NOS) inhibitors affected transmural nerve stimulation induced relaxation responses in the rabbit urethra and the activity of soluble nitric oxide synthase with the same rank order of potency, i.e., NG-nitro-L-arginine (NNA) > NG-methyl-L-arginine (NMA) > canavanine (CAN). The rank order of potency with respect to particulate NOS activity was CAN > NMA = NNA. The relaxation responses to electrical stimulation were accompanied by increases in cyclic GMP. These results suggest that NOS activity found in the soluble fraction of urethral homogenates produces nitric oxide that in turn increases cyclic GMP levels which mediates the relaxation responses induced by transmural nerve stimulation in the rabbit urethra.

Cyclooxygenase-2 protein and prostaglandin E(2) production are up-regulated in a rat bladder inflammation model.

Cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins and prostaglandin E(2) production are evaluated in a rat model of inflammation in which Escherichia coli lipopolysaccharide is intraperitoneally injected or intravesically instilled into the bladder. While cyclooxygenase-1 mRNA and protein and cyclooxygenase-2 mRNA do not change in bladders treated with lipopolysaccharide, cyclooxygenase-2 protein is elevated in bladders from rats intravesically instilled with lipopolysaccharide or phosphate buffered saline (PBS) or intraperitoneally injected with lipopolysaccharide. Urinary prostaglandin E(2) levels and prostaglandin E(2) synthesis in bladder particulates are elevated by intravesical instillation and intraperitoneal injection of lipopolysaccharide. The nitric oxide donor, S-nitroso-N-acetyl-D,L-penicillamine, increases prostaglandin E(2) synthesis in bladders from lipopolysaccharide intravesically instilled and intraperitoneally injected rats. Lipopolysaccharide increases prostaglandin E(2) synthesis by increasing cyclooxygenase-2 protein levels in rat bladder and prostaglandin E(2) synthesis may be further elevated by increases in nitric oxide caused by an up-regulation of inducible nitric oxide synthase (iNOS).

Biotin status and lipid metabolism in adult obese hypercholesterolemic inbred rats.

A statistically significant inverse association was generally found between plasma total lipid, cholesterol, or phospholipid and biotin status of 300-day-old male inbred BHE (IN-BHE) rats. Plasma, liver, and carcass lipid of both sexes generally had a significant direct association with liver lactate dehydrogenase activity; an inverse association in males resulted with improved biotin status. Elevated plasma lactate indicative of anaerobic glycolysis was found. It is proposed that an increased reductive environment - a consequence of accumulated NADH - could account for enhanced triglyceride synthesis and that this effect could explain the obesity in the IN-BHE rats. After the injection of 300 mug of biotin, plasma levels of lactate and pyruvate fell in male rats, indicating a stimulatory effect of biotin upon the oxidative pathways in these animals.

NG-nitro-L-arginine inhibits non-adrenergic, non-cholinergic relaxation in rabbit urethral smooth muscle.

Electrical field stimulation induced a relaxation response in female rabbit urethral smooth muscle strips precontracted with phenylephrine. The relaxation response was inhibited by tetrodotoxin, but not by atropine, propranolol, or hexamethonium. The relaxation response thus results from stimulation of inhibitory non-adrenergic, non-cholinergic nerves. The electrically induced relaxation response was inhibited by an inhibitor of nitric oxide biosynthesis, NG-nitro-L-arginine. This inhibition was overcome by addition of a precursor of nitric oxide, L-arginine. An inhibitor of soluble guanylate cyclase, methylene blue, reduced the relaxation response, and a selective cyclic GMP phosphodiesterase inhibitor, M & B 22948, potentiated the relaxation response. These data indicate that agents which affect the biosynthesis of nitric oxide are associated with the urethral relaxation response evoked by electrical field stimulation, and that cyclic GMP may mediate the relaxation response.

Identification of wax esters inTetrahymena pyriformis.

Wax esters, isolated fromTetrahymena pyriformis, have been found to contain 45% branched chain alcohols and 76% branched chain fatty acids. No esters of tetrahymanol or of sterols were found.

Clinical correlates of fatigue in spinal cord injury.

STUDY DESIGN: Retrospective chart review. OBJECTIVES: To determine the prevalence of fatigue in an outpatient spinal cord injury population and to examine the clinical variables contributing to that fatigue. SETTING: GF Strong Rehabilitation Centre, Vancouver, British Columbia, Canada. METHODS: Medical charts of 76 individuals admitted to the GF Strong Outpatient SCI Program between December 2004 and December 2005 were reviewed. Data collected included information on clinical characteristics, demographics and Fatigue Severity Scale (FSS) scores. Multivariable analysis was completed to determine the independent association between these variables and fatigue severity. RESULTS: A total of 57% (95% confidence interval (CI)=45-67%) of the sample were found to have fatigue severe enough to interfere with function. People that were admitted for medical reasons; had pain, spasticity, incomplete injuries, and/or were on more that one medication with a known side effect of fatigue had significantly higher FSS scores. Multivariable analysis indicated incomplete injury was the only statistically significant predictor of a higher FSS scores; pain approached significance (P=0.07, CI=-0.09, 2.06). Together these variables account for 18% of the variance in FSS scores in this sample. CONCLUSION: Fatigue among individuals with spinal cord injury who are seeking outpatient rehabilitation is very common. The severity of fatigue was greater for individuals with incomplete lesions. Pain was also a potentially important covariate of fatigue. Further research is required to determine what else contributes to fatigue severity beyond these clinical variables as only minimal variance was accounted for in our model.

Insulin activation of cyclic AMP phosphodiesterase in intact ureteral segments.

Low doses of insulin (0.1-50 nM) when presented to intact ureteral segments increase cyclic AMP (cAMP) phosphodiesterase (PDE) activity in subsequently isolated supernatant and particulate fractions. The stimulation of cAMP PDE occurs within 5 to 10 min of the introduction of insulin. When cyclic GMP or high concentrations of cAMP (greater than 5 microM) are used as substrate, insulin does not increase PDE activity. Although the insulin-increased cAMP PDE exhibits the same sensitivity as control PDE from untreated preparations to isobutylmethyl xanthine, a nonspecific PDE inhibitor, and M & B 22,948, a relatively selective cyclic GMP PDE inhibitor, differences in the degree of inhibition of PDE activity are seen in the insulin-treated and untreated preparations with the low Km cAMP PDE inhibitors Ro20-1724, rolipram, amrinone and milrinone and with cyclic GMP. Pertussis toxin, which modifies GTP regulatory proteins of the adenylate cyclase enzyme and the photoreceptor PDE, blocks cAMP PDE activation by insulin.

Focal retrograde amnesia and the episodic-semantic distinction.

This article reports a review of focal retrograde amnesia (FRA), or the phenomenon of organically based severe memory loss restricted to retrograde, or pretraumatic, memory. Cases of FRA are classified according to the type of memory loss: episodic, semantic, or both. A few different clusters of the disorder were identified. Lesions to either the anterior temporal lobes or the posterior/visual cortex can result in an FRA that devastates retrograde episodic memory, while having smaller effects on semantic memory. A number of left-hemisphere patients have FRA confined to semantic memory. There are several additional examples of FRA following minor cerebral trauma that disrupts either episodic memory alone or both episodic and semantic memory that are not accompanied by evidence of structural brain lesions. We discuss these different profiles of FRA and their implications for the understanding of memory retrieval.

Alterations in G-proteins and beta-adrenergic responsive adenylyl cyclase in rat urinary bladder during aging.

Decreased response of bladder to beta-adrenergic stimulation with aging is related to decreased adenylyl cyclase activity and possibly to changes in guanine nucleotide regulatory protein (G-protein) content or function. G-protein content was quantified by Western blot analysis using antibodies to Gsalpha, Goalpha, and Gialpha in 21-day-old (weanling), 90-day-old (young adult), 6-month-old (adult), and 24-month-old (old) rat bladders. Gi/Go function in bladders with aging was measured by ADP-ribosylation with pertussis toxin. Content of Gsalpha, Goalpha, and Gialpha was lower in 90-day-old bladder than in 21-day-old bladder. Gsalpha content was similar in the 21-day-, 6-month-, and 24-month-old bladders. Gialpha content as well as pertussis toxin-catalyzed ADP-ribosylation was higher in 24-month-old bladders than in 21- and 90-day-old bladders. Pertussis toxin-catalyzed ADP-ribosylation of bladder membranes and treatment of bladder with protein kinase A inhibitors reversed the age-dependent decline in isoproterenol stimulation of adenylyl cyclase. Decreases in beta-adrenergic-induced relaxation response with age in rat bladder are due in part to increases in the content and functional activity of pertussis toxin-sensitive G-protein.

Effect of carbachol and norepinephrine on phosphatidyl inositol hydrolysis and cyclic AMP levels in guinea pig urinary tract.

Muscarinic cholinergic and adrenergic agonist-induced changes in [3H]-phosphatidyl inositol (PI) hydrolysis and cyclic AMP (cAMP) levels were measured in guinea pig ureter, urethra and bladder dome. In the ureter, carbachol, norepinephrine and phenylephrine rapidly increased PI hydrolysis and basal cAMP levels, but did not decrease forskolin-stimulated cAMP levels. In the bladder dome, norepinephrine and phenylephrine produced a rapid but transitory increase in PI hydrolysis, but did not affect forskolin-stimulated cAMP levels. Carbachol produced a rapid and sustained increase in PI hydrolysis and also, at high concentrations, decreased forskolin-stimulated cAMP levels. In the urethra, norepinephrine and carbachol rapidly decreased forskolin-stimulated cAMP levels and later increased PI hydrolysis. Our data suggest that the predominant second messenger system in the ureter, dome, or urethra is more dependent on the tissue than on the agonist. These tissue-specific, agonist-induced rapid changes in second messenger levels may help coordinate the contraction-relaxation phenomena necessary for urinary tract function.

Relaxant effect of forskolin in rabbit detrusor smooth muscle: role of cyclic AMP.

Forskolin caused a concentration dependent relaxation of rabbit detrusor muscle strips. The relaxant effect of forskolin was potentiated by the cyclic AMP sensitive phosphodiesterase inhibitor, Ro20-1274. Pretreatment with the beta-adrenergic antagonist, propranolol, did not inhibit the relaxation of rabbit detrusor induced by forskolin, whereas the relaxation response to forskolin was inhibited in part by the adenylate cyclase inhibitor, SQ22536. Forskolin also increased cyclic AMP levels significantly in rabbit detrusor muscle. These data suggest that detrusor muscle relaxation by forskolin may be mediated by cyclic AMP and that forskolin may activate adenylate cyclase without stimulating beta-adrenergic receptors in detrusor muscle.

Effects of noradrenaline, isoproterenol and acetylcholine on ureteral resistance.

Resistance to fluid flow in the canine ureter can be divided into two categories. The higher resistance is recorded at flow rates less than or equal to 2.16 ml./min. At these rates the ureter is able to completely coapt its walls so that urine is transported in individual boluses. The lower resistance is recorded at flow rates greater than or equal to 5.40 ml./min. At these rates the ureteral walls remained open and urine is transported as a column of fluid. Noradrenaline causes a marked increase in ureteral resistance at low flow rates and a small but statistically significant increase in ureteral resistance at high flow rates. Acetylcholine increases resistance only at the low flow rates. Isoproterenol significantly decreases resistance at both low and high flow rates. These findings are consistent with ureteral resistance to fluid flow being composed of two components. One is the ureteral peristaltic contraction which plays a principal role in urinary bolus transport at low flows; the other is ureteral wall tonus, which plays an important role in the transport of columns of urine by the ureter, which does not coapt its walls, at the higher flow rates.

Sphincteric action of the pelvicalyceal junction and pacemaker activity in human kidney.

The effect of elevation of renal pelvic pressure on pacemaker activity was examined in 5 isolated human kidneys. Pressure fluctuations transmitted from renal pelvic contractions first appeared in pressure tracings from the upper renal calyx as renal pelvic pressure exceeded 25 cm H2O. This finding suggests that the pelvicalyceal junction acts as a sphincter which can withstand pelvic pressures of about 25 cm H2O. The upper renal calyx contracted rhythmically at a rate of 10 times per minute when the pelvic pressure was low. At high pelvic pressures, upper calyceal contraction frequency decreased although its rhythm remained regular. As renal pelvic pressure increased, the frequency of renal pelvic contractions increased to a level that corresponded in a 1:1 ratio with contractions of the upper calyx.