Guanosine 3': 5'-cyclic monosphosphate (cyclic GMP) levels in the ductus deferens of the rat were increased 2-to 3-fold by acetylcholine (10-1000 MM) or by 125 mM KCI, while adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were not changed. After incubation for 30 min in the absence of Ca++, cyclic GMP control levels were decreased by 85% and were not affected by acetylcholine or KCI. The readdition of Ca++ (1.8 mM) for 3 min to Ca++-deprived tissue partially restored basal cyclic GMP levels and the effects of acetylcholine and KCI. The addition of Sr++ (3.6 mM) or of Ba++ (1.8 or 10 mM) also caused an increase in basal cyclic GMP in Ca++.deprived tissue. Cyclic AMP levels were not significantly changed under any of these conditions. The addition of the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (0.1 mM), to ductus deferentes increased the amount of cyclic AMP about 50% and that of cyclic GMP about 2-fold. The latter effect also depended on the presence of Ca++. I-Methyl-3-isobutylxanthine (0.1 mM) increased cyclic GMP and cyclic AMP levels in slices of rat submaxillary glands. Methacholine increased cyclic GMP if added in the presence of methyl isobutylxanthine. Cyclic GMP control levels and the effect of methyl isobutylxanthine were unchanged by Ca + + omission, but the effect of methacholine was abolished.These findings indicate that calcium ions are important for the control of cyclic GMP levels in these tissues.The role of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) as an intracellular mediator in the action of various hormones has been well established (1). Hormones that increase cyclic AMP levels in intact cells can generally be shown to cause an increase in adenylate cyclase activity when added to broken cell preparations (1). While the physiological role of guanosine 3': 5'-cyclic monophosphate (cyclic GMP) is still unclear, the concentration of this nucleotide is increased by cholinergic and other agents in many mammalian tissues (2).The enzyme catalyzing the formation of cyclic GMP from GTP, guanylate cyclase, has been found in both particulate and high-speed supernatant fractions in many tissues (3). Neither of the forms of guanylate cyclase has consistently been affected in cell-free systems by agents that cause an increase in cyclic GMP levels in intact cells. Therefore, we have considered the possibility that the increase in intracellular cyclic GMP concentration in response to acetylcholine Abbreviation: SC-2964, 1-methyl-3-isobutylxanthine. * Present address: Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.t To whom reprint requests should be sent. and other agents might be secondary to altered ion concentrations at the location of guanylate cyclase. The results presented in this paper show that calcium ions are involved in the regulation of cyclic GMP levels by cholinergic and other agents and that Ca++ may also be involved in the regulation of cyclic GMP formation under basal conditions.
MATERIALS AND METHODSMaterials and methods u...
Background
Factors underlying a possible excess of amyotrophic lateral sclerosis (ALS) among military veterans remain unidentified. Limitations of previous studies on this topic include reliance on ALS mortality as a surrogate for ALS incidence, low statistical power, and sparse information on military-related factors.
Objectives
We evaluated associations between military-related factors and ALS using data from a case-control study of U.S. military veterans.
Methods
From 2005 to 2010, we identified medical record-confirmed ALS cases via the National Registry of Veterans with ALS and controls via the Veterans Benefits Administration’s Beneficiary Identification and Records Locator System database. In total, we enrolled 621 cases and 958 frequency-matched controls in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study. We collected information on military service and deployments and 39 related exposures. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We used inverse probability weighting to adjust for potential bias from confounding, missing covariate data, and selection arising from a case group that disproportionately included long-term survivors and a control group that may or may not differ from U.S. military veterans at large.
Results
The odds of ALS did not differ for veterans of the Air Force, Army, Marines, and Navy. We found higher odds of ALS for veterans whose longest deployment was World War II or the Korean War and a positive trend with total years of all deployments (OR = 1.27; 95% CI: 1.06, 1.52). ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with ORs between 1.50 and 7.75.
Conclusions
Although our results need confirmation, they are potentially important given the large number of U.S. military veterans, and they provide clues to potential factors underlying the apparent increase of ALS in veteran populations.
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