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P Aas

Publications and source records attributed to P Aas.

33 records · Page 2Linked to original sources
PubMed1988

The effect of acetylcholinesterase-inhibition on the tonus of guinea-pig bronchial smooth muscle.

The irreversible acetylcholinesterase inhibitor soman (O-[1,2,2-trimethylpropyl]-methyl-phosphonofluoridate) induced contraction of guinea-pig primary bronchial smooth muscle. The apparent affinity (ED50) of acetylcholine (ACh) was altered from control value of 12 microM to 0.3 microM following exposure of the bronchial smooth muscle to 14 microM soman for 15 min in vitro. The ED50 of the cholinergic agonist carbachol was not changed even when the acetylcholinesterase (AChE) activity was inhibited completely. The intrinsic activity (alpha) of ACh and carbachol was not significantly changed after exposure to soman for 15 min. The results demonstrate that the effect of soman is only due to its anticholinesterase activity. Furthermore, the contraction induced by histamine was not altered by concentrations of soman which increase the cholinergic stimulation. This indicates that histamine does not induce contraction of bronchial smooth muscle in guinea pig through the release of ACh or by modulation of muscarinic receptors. Furthermore, soman also inhibited the carboxylesterase activity in the primary bronchi. In respiratory tissue this group of enzymes may have a major protective function, due to their ability to bind several organophosphorus compounds. Compared to studies performed on other species, this study shows that guinea-pig bronchi are very sensitive to the AChE-inhibitor soman. Therefore, exposure to very low concentrations of AChE-inhibitors may induce contraction of bronchial smooth muscle.

Acetylcholinesterase↗
PubMed1988

The toxic effect of an AChE-inhibitor on the cholinergic nervous system in airway smooth muscle.

Excessive cholinergic stimulation of presynaptic muscarinic cholinergic receptors, due to complete inhibition of acetylcholinesterase (AChE) by O-(1,2,2-trimethylpropyl)-methyl-phosphonofluoridate (soman), reduced the release of acetylcholine (ACh) from cholinergic nerves in rat bronchi by almost 25%. Furthermore, long-term (40 h) exposure by inhalation of soman (0.45-0.63 mg/m3) reduced the contraction of bronchi induced by ACh by approximately 70%. This is probably due to reduction of the number of muscarinic cholinergic receptors, since there was a reduction in the binding capacity (Bmax) of [3H]QNB by 40%, without any changes in the dissociation constant (Kd).

Acetylcholine↗
PubMed1987

Acute and sub-acute inhalation of an organophosphate induce alteration of cholinergic muscarinic receptors.

Acute and sub-acute inhalation exposure of rats to the organophosphorus compound soman (O-[1,2,2-trimethylpropyl]-methylphosphonofluoridate) reduced the contraction of the bronchial smooth muscle induced by cholinergic stimulation. Acute exposure to 8.51 mg/m3 of soman for 45 min (total dose of 383 mg X min/m3) inhibited the acetylcholinesterase (AChE) activity of the bronchial smooth muscle by 85% and reduced the contraction induced by ACh and carbachol by 70% and 80% respectively. In spite of the extensive inhibition of AChE and reduction in the contraction following cholinergic stimulation, there was no alteration of the binding capacity (Bmax) or the equilibrium dissociation constant (Kd) to [3H]-quinuclidinyl benzilate ([3H]-QNB) in the rat bronchi following such an acute exposure. After sub-acute exposure (40 hr) to 0.45-0.63 mg/m3 of soman (total dose of 1080-1519 mg X min/m3) there was a reduction in AChE-activity of 94% and in the contraction of the bronchial smooth muscle induced by ACh and carbachol of 70%. Furthermore, also a reduction of the binding capacity to [3H]-QNB of approximately 40% was observed. Following exposure to soman by both acute and sub-acute inhalation exposure there was an increase in the apparent affinity (pD2) to ACh in the bronchial smooth muscle, due to the extensive inhibition of the AChE-activity. Inhalation of soman also induced a substantial inhibition of the AChE-activity in the lung (86%), but somewhat smaller inhibition in the hippocampus (70%) and almost no inhibition in the neostriatum (19%). Moreover, it was only in the lung where sub-acute exposure to soman produced a reduction of the binding capacity to [3H]-QNB and the reduction was approximately 50%. The results therefore show that after sub-acute inhalation of a relatively low concentration of the AChE-inhibitor soman, alterations in the number of cholinergic receptors are only observed in the peripheral cholinergic nervous system.

Acetylcholine↗
PubMed1987

Automated method for the determination of angiotensin-converting enzyme in serum.

A method for the determination of angiotensin-converting enzyme in serum (S-ACE; EC 3.4.15.1.) with use of 3-(2-furylacryloyl)-L-phenylalanyl-glycyl-glycine (FAPGG) as substrate has been adapted for the Cobas Bio microcentrifugal analyser. The method allows 24 determinations per hour in a sample volume of 28 microliters with a within run precision of less than 3% and a between run precision of less than 5%. The reaction is linear up to at least 470 U/l. The reference interval in 92 blood donors has been determined to 14-110 U/l. The method correlates well with the manual method of Hurst & Lovell-Smith (r = 0.982). We have found the method excellently suited for routine assay.

Centrifugation↗
PubMed1987

The effect of soman on potassium evoked 3H-acetylcholine release in the isolated rat bronchi.

The in vitro exposure of rat bronchial smooth muscle to the acetylcholinesterase inhibitor soman (0-[1,1,2-trimethylpropyl]-methylphosphonofluoridate) reduced the potassium (51 mM) evoked release of 3H-acetylcholine (3H-ACh). Exposure to 1.0 and 100 microM soman for 15 min inhibited the acetylcholinesterase (AChE) activity completely and reduced the potassium evoked release by 23.1% and 34.4% respectively. In the presence of scopolamine (0.3 microM), however, there was a large enhancement (87.0%) of potassium evoked release during soman inhibited (100%) AChE-activity. Furthermore, soman (1.0 microM) did not reduce the spontaneous release of 3H-ACh. The results indicate that the presynaptic effect of soman is due to the enhanced concentration of ACh following AChE-activity inhibition in the synaptic region. This induces a stimulation of presynaptic muscarinic receptors and thereby modulation of the ACh release only during evoked release.

Acetylcholine↗
PubMed1986

In vitro effects of soman on bronchial smooth muscle.

The in vitro exposure of rat bronchial smooth muscle to the cholinesterase inhibitor soman (O-[1,2,2-trimethylpropyl]-methyl-phosphonofluoridate) potentiated the rapid and concentration dependent increase in the contraction induced by acetylcholine (ACh). There was a substantial increase in the response to ACh when soman was present in concentrations from 10 nM to 1 microM which correspond to a 65-100% inhibition of acetylcholinesterase (AChE). The apparent affinity (pD2) to ACh increased from 3.7 to 6.7 without any change in intrinsic activity (alpha) in this concentration interval. In contrast, soman did not alter the apparent affinity or intrinsic activity of carbachol, which supports the suggestion that the effect of soman is entirely due to its anticholinesterase activity. Soman by itself induced contraction which begun at 1-10 nM. This may be explained from its anticholinesterase activity and the subsequent increase in the synaptic concentration of spontaneously released ACh. The effect of soman on inhibition of cholinesterase and carboxylesterases have also been examined. The results demonstrate that low concentrations of soman induces contraction of the airway smooth muscle.

Acetylcholine↗
PubMed1986

Presynaptic inhibition of acetylcholine release.

High potassium (51 mM) has been shown to evoke release of acetylcholine ([3H]ACh and endogenous ACh) from cholinergic nerves in rat bronchial smooth muscle. The release of [3H]ACh was reduced by 85% when the Ca2+ concentration was changed from 2 to 0.1 mM. The veratridine-induced release was completely inhibited by tetrodotoxin, but tetrodotoxin did not reduce the potassium-evoked release. The muscarinic agonist, oxotremorine, reduced the potassium stimulated release of [3H]ACh, without affecting the basal release. In contrast, scopolamine substantially potentiated the potassium-evoked release. Adenosine had a dual effect in the rat bronchi. Adenosine inhibited the potassium-evoked release of [3H]ACh and this presynaptic effect of adenosine was antagonized by 8-phenyltheophylline. Adenosine also induced contraction of the bronchial smooth muscle and there was potentiation by adenosine of the ACh-induced contraction. The results indicate that cholinergic nerve terminals in the rat bronchi possess muscarinic receptors which inhibit the release of ACh. Adenosine may have analogous effects, e.g. presynaptic inhibition of transmitter release in addition to postsynaptic enhancement of bronchial smooth muscle contraction.

Acetylcholine↗
PubMed1985

A method for generating toxic vapors of soman: toxicity of soman by inhalation in rats.

A method for administration of highly toxic chemicals by inhalation was developed. The model has three features of special interest: (1) a diffusion cell for producing a constant gas concentration, if necessary for several hours and days, (2) a small rapidly equilibrated inhalation chamber (1100 ml), and (3) complete isolation of the toxic chemicals from the atmosphere. The LCt50 of the anticholinesterase soman [o-(1,2,2 trimethylpropyl)-methyl-phosphonofluoridate] was 400 mg min/m3, registered 24 hr after the end of exposure. The lethal concentration X time of soman was 520 +/- 60 mg min/m3 when exposing the animals until death in the inhalation chamber. The exposure was less than 30 min and the concentration of soman was 21 mg/m3. The inhibition of acetylcholinesterase, cholinesterase, and carboxylesterase activities in different tissues was analyzed to study the possible barrier mechanisms that might exist in the body to soman. There was a large inhibition of the carboxylesterase and cholinesterase activities in bronchi and lungs as well as in blood. Carboxylesterases were important as detoxifying enzymes, as shown by 70% enhancement in toxicity of soman following sc pretreatment with TOCP (tri-ortho-cresyl-phosphate), a carboxylesterase inhibitor.

Acetylcholinesterase↗
PubMed1985

Carboxylesterases, importance for detoxification of organophosphorus anticholinesterases and trichothecenes.

Several different types of experiments, including the use of inhibitors, have shown that carboxylesterases are a major factor in the metabolism and therefore detoxification of organophosphorus compounds such as soman and trichothecene toxins. The development of a new assay method for the enzyme has allowed us to separate the carboxylesterases into two major groups. The carboxylesterases can, however, be further separated by gel filtration, affinity chromatography, isoelectric focusing, and chromatofocusing into several isoenzymes. Liver microsomal carboxylesterases can be separated into five or six isoenzymes whereas guinea-pig plasma contains two isoenzymes. The isoenzymes differ in molecular weights, isoelectric points, substrate specificities, and affinity for inhibitors. Intravenous administration of a carboxylesterase preparation lowered the toxicity of soman in young rats. Carboxylesterases from rat and guinea-pig plasma inhibited by soman could be reactivated by DAM, whereas enzymes from porcine liver were not reactivated. Only one of the isoenzymes from rat liver microsomal preparation was responsible for the metabolism of T-2 toxin to HT-2. The further metabolism of HT-2 was performed by esterases from rat liver cytoplasma. Long-term exposure of the bronchial muscle to low concentration of soman modulate the bronchial contraction.

Animals↗
PubMed1982

Neurotensin receptors in the rat bronchi.

The isolated, circular preparations of the left and right bronchi of the rat were examined for mechanical responses to neurotensin (NT) and other vasoactive peptides. NT caused concentration-dependent increases in the isometric tension of the unstimulated preparations, with an apparent affinity higher than for the cholinergic agonists but with considerably lower intrinsic activity. Pronounced tachyphylaxis to NT was observed. NT potentiated the atropine-sensitive increase in tension resulting from electrical field stimulation. Neither atropine nor methysergide abolished the response to NT in the unstimulated preparations. Bradykinin and to a lesser extent angiotensin II contracted the unstimulated preparations and both systemic peptides enhanced the cholinergic output in response to field stimulation. Substance P and VIP on the other hand were without effects in the stimulated and unstimulated bronchi. The results are consistent with the presence of receptors for NT on the presynaptic cholinergic terminals as well as on the post-synaptic smooth muscles of the rat bronchi.

Angiotensin II↗