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1.
Am J Physiol Lung Cell Mol Physiol ; 281(1): L258-67, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11404269

ABSTRACT

Nitric oxide (NO) is a potent vasodilator, but it can also modulate contractile responses of the airway smooth muscle. Whether or not endothelial (e) NO synthase (NOS) contributes to the regulation of bronchial tone is unknown at present. Experiments were designed to investigate the isoforms of NOS that are expressed in murine airways and to determine whether or not the endogenous release of NO modulates bronchial tone in wild-type mice and in mice with targeted deletion of eNOS [eNOS(-/-)]. The presence of neuronal NOS (nNOS), inducible NOS (iNOS), and eNOS in murine trachea and lung parenchyma was assessed by RT-PCR, immunoblotting, and immunohistochemistry. Airway resistance was measured in conscious unrestrained mice by means of a whole body plethysmography chamber. The three isoforms of NOS were constitutively present in lungs of wild-type mice, whereas only iNOS and nNOS were present in eNOS(-/-) mice. Labeling of nNOS was localized in submucosal airway nerves but was not consistently detected, and iNOS immunoreactivity was observed in tracheal and bronchiolar epithelial cells, whereas eNOS was expressed in endothelial cells. In wild-type mice, treatment with N-nitro-L-arginine methyl ester, but not with aminoguanidine, potentiated the increase in airway resistance produced by inhalation of methacholine. eNOS(-/-) mice were hyperresponsive to inhaled methacholine and markedly less sensitive to N-nitro-L-arginine methyl ester. These results demonstrate that the three NOS isoforms are expressed constitutively in murine lung and that NO derived from eNOS plays a physiological role in controlling bronchial airway reactivity.


Subject(s)
Airway Resistance/physiology , Bronchi/physiology , Nitric Oxide Synthase/physiology , Airway Resistance/drug effects , Animals , Brain/metabolism , Bronchi/drug effects , Cholinergic Agonists/pharmacology , Lung/drug effects , Lung/metabolism , Mice , Mice, Inbred Strains , Mice, Knockout/genetics , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , RNA, Messenger/metabolism , Reference Values , Trachea/drug effects , Trachea/metabolism
2.
Eur J Pharmacol ; 414(2-3): 259-69, 2001 Mar 02.
Article in English | MEDLINE | ID: mdl-11239927

ABSTRACT

In this study, we describe the cardiovascular effects of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-l-yl] ethyl]-1, 2-dihydroquinoline-1-acetamide), a novel 5-hydroxytryptamine (5-HT) receptor antagonist developed for the treatment of cardiovascular disease, in several in vivo models. The haemodynamic profile of SL65.0472 was evaluated in anaesthetised dogs. Following i.v. bolus doses of 0.03 mg/kg i.v. and 0.3 mg/kg, no significant changes in cardiac output, contractility or rate, systemic and pulmonary pressures, regional blood flows and vascular resistances or electrocardiogram were noted. After 1 mg/kg i.v. SL65.0472 significantly reduced arterial blood pressure. In conscious spontaneously hypertensive rats administration of SL65.0472 0.5 mg/kg p.o. had no effect on mean arterial blood pressure or heart rate. Vasoconstriction produced by 5-HT results primarily from the stimulation of two receptor subtypes, 5-HT(1B) and 5-HT(2A) receptors. In anaesthetised dogs SL65.0472 antagonised sumatriptan-induced decreases in saphenous vein diameter (5-HT(1B)-receptor mediated) with an ID(50) of 10.1 microg/kg i.v. (95% c.l. 8.3-12.4). In anaesthetised pithed rats SL65.0472 inhibited 5-HT pressor responses (5HT(2A)-receptor mediated) with ID(50) values of 1.38 microg/kg i.v. (95% c.l. 1.15-1.64) and 31.1 microg/kg p.o. (95% c.l. 22.6-42.6). The duration of the 5-HT(2A)-receptor antagonist effect of SL65.0472 following oral administration was evaluated in conscious rats. SL65.0472 (0.1 mg/kg p.o.) markedly inhibited 5-HT pressor responses 1 and 6 h after administration. Therefore, in vivo, SL65.0472 potently antagonises vasoconstriction mediated by 5-HT(1B) and 5-HT(2A) receptors but has minimal direct haemodynamic effects.


Subject(s)
Hemodynamics/drug effects , Piperazines/pharmacology , Quinolines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Sumatriptan/pharmacology , Vasoconstrictor Agents/pharmacology , Animals , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Blood Pressure/physiology , Dogs , Heart Rate/drug effects , Heart Rate/physiology , Hemodynamics/physiology , Male , Prazosin/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/physiology , Receptors, Serotonin, 5-HT1
3.
Respir Physiol ; 105(3): 225-33, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8931182

ABSTRACT

The present study was designed to point out similarities between the effects on pulmonary circulation caused by hypoxia and by a chemoreceptor stimulant (S1867, an almitrine analog). Isolated rat lungs were perfused at a constant flow with homologous blood and ventilated under normoxic, hypoxic or hyperoxic conditions. (1) At 0.25 microgram/ml, S1867 potentiated the hypoxic pressor response, while at 1 microgram/ml, it induced a significant increase in pulmonary artery pressure (PAP) at 21% O2. (2) Since the expression of an oxygen-binding protein (NADPH-oxidase like) has been demonstrated in the rat carotid bodies, we studied the effects of the NADPH-oxidase inhibitor diphenyleneiodonium (DPI) on HPV and on S1867-induced pulmonary vascular responses. Both responses were totally abolished by DPI (40 microM), whereas the vasoconstriction induced by a thromboxane A2 analog (U46619) remained unchanged. (3) Vascular responses to hypoxia and S1867 (1 microgram/ml) were both reversed by a bolus of the sulfhydryl oxidant diamide (3 mg). (4) The S1867-induced response was prevented and reversed by the supply of inhaled oxygen, which was without action on the vasoconstriction induced by U46619. These results suggest that the almitrine analog and hypoxia act at least partly through the same cellular mechanism, involving a DPI-sensitive protein.


Subject(s)
Almitrine/analogs & derivatives , Hypoxia/etiology , Hypoxia/physiopathology , Respiratory System Agents/pharmacology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid , Almitrine/pharmacology , Animals , Blood Pressure/drug effects , Chemoreceptor Cells/drug effects , Chemoreceptor Cells/physiopathology , Disease Models, Animal , Enzyme Inhibitors/pharmacology , In Vitro Techniques , Male , NADPH Oxidases/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Onium Compounds/pharmacology , Perfusion , Prostaglandin Endoperoxides, Synthetic/pharmacology , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Pulmonary Circulation/drug effects , Pulmonary Circulation/physiology , Rats , Rats, Sprague-Dawley , Thromboxane A2/analogs & derivatives , Thromboxane A2/pharmacology , Vasoconstriction/drug effects , Vasoconstriction/physiology
4.
Eur J Pharmacol ; 310(1): 37-46, 1996 Aug 22.
Article in English | MEDLINE | ID: mdl-8880065

ABSTRACT

The potassium salt of a chemically stabilized dipeptide, {1-[4-(1 H-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-Hyp-Nal-N(methyl)-Bzl , (Hyp = (R)-4-hydroxy-L-proline; Nal = 3-L-(beta-naphthyl)-alanine), S18523, is described as a new water-soluble, potent and selective NK1 receptor antagonist. The low molecular weight antagonist (M(r) = 736) displays nanomolar potency (pA2 = 9.6) in the rabbit vena cava (NK1) bioassay and nanomolar affinity (pKi = 9.1) on the human NK1 receptor expressed by lymphoblastoma cells. It is devoid of mu-opiate affinity (Ki > 10(-4) M with respect to tritiated Tyr-DAla-Gly-MePhe-Gly-ol), has negligible calcium-channel affinity (estimated Ki = 2.6 x 10(-5) M, with respect to isradipine) and does not cause peritoneal mast-cell degranulation. S18523 has strong antinociceptive effects in three classical pain tests in vivo both by i.v. and p.o. routes. The dipeptide potently antagonizes bronchoconstriction provoked by exogenous substance P in the guinea-pig and acts longer than the non-peptide antagonist CP99994, when administered as aerosol. Finally, S18523 displays antiinflammatory properties, since it dose-dependently inhibits substance P-induced plasma extravasation both in the bladder (ID50 = 0.18 mg/kg i.v.) and bronchi (ID50 = 0.14 mg/kg i.v.) of the guinea-pig.


Subject(s)
Dipeptides/pharmacology , Neurokinin-1 Receptor Antagonists , Tetrazoles/pharmacology , Animals , Bronchoconstriction/drug effects , Cell Line/drug effects , Dipeptides/blood , Dipeptides/chemical synthesis , Dipeptides/metabolism , Dose-Response Relationship, Drug , Female , Guinea Pigs , In Vitro Techniques , Male , Mice , Pain Measurement/drug effects , Piperidines/pharmacology , Rabbits , Rats , Receptors, Neurokinin-1/blood , Receptors, Neurokinin-1/metabolism , Substance P/pharmacology , Tetrazoles/blood , Tetrazoles/chemical synthesis , Tetrazoles/metabolism
5.
Eur J Pharmacol ; 294(2-3): 677-84, 1995 Dec 29.
Article in English | MEDLINE | ID: mdl-8750733

ABSTRACT

Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.


Subject(s)
Neurokinin-1 Receptor Antagonists , Oligopeptides/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Animals , Bronchoconstriction/drug effects , Capillary Permeability/drug effects , Cell Degranulation/drug effects , Guinea Pigs , Humans , In Vitro Techniques , Male , Mast Cells/drug effects , Mast Cells/physiology , Oligopeptides/metabolism , Rabbits , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-2/metabolism , Salivation/drug effects , Substance P/pharmacology
6.
J Pharmacol Exp Ther ; 273(3): 1071-7, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7791077

ABSTRACT

The in vitro and in vivo effects of S 16118 [p-guanidobenzoyl-[Hyp3, Thi5,D-Tic7,Oic8]bradykinin (BK)], a new BK receptor antagonist, were studied. S 16118 inhibited the contraction produced by BK in the rabbit jugular vein, but was ineffective in the rabbit aorta, indicating the BK B2 receptor specificity of the compound. In isolated organs from various species including humans, S 16118 was a potent antagonist (Ki, pA2 or pKB value from 9.58-7.37). The effect of S 16118 was specific as it did not show any affinity for a number of other receptors or channels and did not possess residual agonistic properties in most of the tissues studied. Furthermore, S 16118 is a poor secretagogue agent either in the rat or human mast cells and is resistant to degradation with an in vitro half-life in blood from different species, including humans, of more than 24 hr. In vivo, in the rabbit, i.v. injection of S 16118 inhibited the hypotension induced by BK up to 4 hr after administration. In the guinea pig, it was also effective in inhibiting the bronchoconstriction induced by BK, although when administered i.v. it had a shorter duration than in the rabbit. However, in the same species, when aerosolized, S 16118 was effective and long-acting against BK-induced bronchoconstriction. Changes in permeability induced by BK injection in the guinea pig trachea and bronchus, and by BK superfusion in the hamster cheek pouch, were abolished by i.v. pretreatment with S 16118.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bradykinin Receptor Antagonists , Bradykinin/analogs & derivatives , Animals , Antihypertensive Agents/pharmacology , Bradykinin/metabolism , Bradykinin/pharmacology , Bronchoconstriction/drug effects , Capillary Permeability/drug effects , Cell Degranulation/drug effects , Cells, Cultured , Guinea Pigs , Humans , In Vitro Techniques , Male , Mast Cells/cytology , Mast Cells/drug effects , Rabbits , Rats , Receptor, Bradykinin B2
7.
J Pharmacol Exp Ther ; 273(3): 1078-84, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7791078

ABSTRACT

The effects of S 16118 (p-guanidobenzoyl-[Hyp3,Thi5,D-Tic7, Oic8]bradykinin (BK)], a new, potent and long-acting BK B2 antagonist, were tested in some in vivo models of inflammation. In rats, S 16118 (0.1 and 1 mg/kg) given i.v. or s.c. delayed the edema formation induced by intraplantar carrageenan injections up to 4 hr after administration, confirming the involvement of kinins in this inflammatory reaction. In guinea pigs treated with atropine, vagal stimulation induced bronchial microvascular leakage. Aerosolization of S 16118 (5 x 10(-3) M for 20 sec), 4 min before vagus nerve stimulation, induced a 60% decrease in the Evans blue extravasation, demonstrating the modulatory role of BK in neurogenic inflammation. In rats, caerulein infusion (4 nmol/kg/hr) induced hypotension, massive pancreatic edema, hypovolemia due to plasma leakage and an increase in serum lipase and amylase activity. S 16118 (100 nmol/kg s.c.) prevented the hypotension, the pancreatic edema and the hypovolemia and induced a marked increase in the serum lipase and amylase activity. This confirms that BK, acting on BK B2 receptors, is involved in this model of pancreatitis. In rabbits, the injection of lipopolysaccharides (LPS; 600 micrograms/kg i.v.) induced hypotension, metabolic acidosis and leukopenia. S 16118 (1.73 mumol/kg i.v.) did not influence the effects of LPS injection. In mice, i.p. LPS (25 mg/kg) administration induced over 90% mortality in 96 hr. S 16118 (1 mg/kg x 4), given 30 min before LPS injection and 4, 8 and 24 hr after LPS injection, did not influence the mortality rate.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Bradykinin Receptor Antagonists , Bradykinin/analogs & derivatives , Inflammation/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bradykinin/pharmacology , Bradykinin/therapeutic use , Disease Models, Animal , Female , Guinea Pigs , Male , Pancreatitis/drug therapy , Rabbits , Rats , Rats, Sprague-Dawley , Receptor, Bradykinin B2 , Shock, Septic/drug therapy
8.
Cell Biol Toxicol ; 8(2): 171-81, 1992.
Article in English | MEDLINE | ID: mdl-1422926

ABSTRACT

Sulfur mustard (SM) is known to induce cutaneous injury and to cause acute damage to the respiratory tract. Although skin vesication has been demonstrated on human epidermal keratinocytes in culture, no study has been carried out to analyze the effects of SM on the ultrastructural and functional activity of surface respiratory epithelial cells. To evaluate this SM toxicity, we developed an in vitro model of respiratory epithelial cells in primary culture. The study was performed on surface epithelial cells from rabbit trachea cultured according to the explant-outgrowth technique. The functional activity of the cultures was evaluated by measuring the ciliary beating frequency (CBF) of the ciliated cells with a videomicroscopic method. The morphological aspects of the cells were analyzed by light and electron microscopy. Addition of 0.1 mM SM directly into the culture medium produced a sudden and irreversible CBF inhibition, first observed after 2 hr on the ciliated cells of the outgrowth periphery. The arrest of the ciliary beating progressively reached the whole surface of the outgrowth and was simultaneously observed with a detachment of the outgrowth cells. It began at the outgrowth border, leading to the exfoliation of cell sheets, and then to the whole culture after 48 hr. Morphological damage was expressed by intense vacuolisation and disorganization of cytoplasmic and nuclear structures. These findings suggest that the detachment of the respiratory epithelial cells from the matrix represents a major toxic effect of 0.1 mM SM. SM dramatically affects the viability of respiratory epithelial cells in culture. Moreover, the sudden CBF inhibition is more likely due to the death of the ciliated cells than to a specific ciliotoxic effect of SM.


Subject(s)
Mustard Gas/toxicity , Trachea/drug effects , Animals , Cells, Cultured , Cilia/drug effects , Epithelium/drug effects , Epithelium/ultrastructure , Microscopy, Electron , Photomicrography , Rabbits , Trachea/ultrastructure
9.
Fundam Appl Toxicol ; 17(1): 177-85, 1991 Jul.
Article in English | MEDLINE | ID: mdl-1916075

ABSTRACT

To determine the mechanism governing pulmonary edema induced by an organophosphorus compound, S-(2-diisopropylaminoethyl)-O-ethylmethyl phosphonothiolate (VX), lung lymph flow and lymph-to-plasma protein concentration ratio were measured in six anesthetized, open-chest, mechanically ventilated beagle dogs before and after intravenous injection of 6 micrograms/kg of VX. Systemic and pulmonary hemodynamic data (heart rate, aortic blood flow, and left atrial, systemic arterial, pulmonary arterial, and pulmonary capillary pressures) were continuously recorded. Arterial blood gases and pH were measured every 30 min. Histological examinations and lung water content measurements were also carried out. Following VX injection, lung lymph flow increased (from 109 +/- 38 to 179 +/- 66 microliters/min, p less than 0.05) while lymph-to-plasma protein concentration ratio remained unchanged (from 0.64 +/- 0.14 to 0.62 +/- 0.12, N.S.). Neither systemic nor pulmonary hemodynamics were changed. Lung water content expressed as blood-free wet-to-dry weight ratio increased from 4.31 +/- 0.23 to 5.35 +/- 0.26 (p less than 0.05). Histological examinations revealed in many cases diffuse congestion of lungs and interstitial edema. These results suggest that VX injection induces an increase in pulmonary capillary permeability which may lead to a high-permeability edema.


Subject(s)
Organophosphorus Compounds/toxicity , Pulmonary Edema/chemically induced , Acetylcholinesterase/blood , Animals , Blood Gas Analysis , Body Water/metabolism , Cholinesterase Inhibitors/toxicity , Coronary Circulation/drug effects , Dogs , Hydrogen-Ion Concentration , Lung/metabolism , Lymphatic System/drug effects , Male , Organothiophosphorus Compounds/toxicity , Pulmonary Circulation/drug effects , Pulmonary Edema/physiopathology
10.
FEBS Lett ; 281(1-2): 145-8, 1991 Apr 09.
Article in English | MEDLINE | ID: mdl-1849836

ABSTRACT

Serine-specific reagents, anticholinesterase organophosphorus compounds like Vx provoke, in the micromolar range, digitalis-like ventricular arrhythmias of non-cholinergic origin in rodent hearts. The sensitivities of the two rat cardiac Na+,K(+)-ATPase isoforms (alpha 1 and alpha 2) to Vx (0.1-100 microM) were measured in sarcolemma vesicles. At 1 microM Vx, the inhibition of the total activity averaged 18% but never exceeded 75% with 100 microM. When the alpha 2 isoform activity was inhibited by 0.1 microM ouabain, alpha 1 was 35% inhibited by 1 microM Vx, i.e. a 16 +/- 4% inhibition of the total activity. The cardiac alpha 1 being related to the digitalis-induced toxicity, its selective inhibition by a micromolar dose of Vx fully accounts for the cardiotoxicity of Vx. Inasmuch as Vx had no effect on the rat kidney alpha 1, differentially inactivated the cardiac isozymes and specifically reacted with serine residues, the putative binding-site(s) of the organophosphorus compound on the Na+-K(+)-ATPase molecules has been considered.


Subject(s)
Heart/drug effects , Isoenzymes/isolation & purification , Organothiophosphorus Compounds/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Cholinesterase Inhibitors/pharmacology , Kinetics , Myocardium/pathology , Organothiophosphorus Compounds/toxicity , Rats , Rats, Inbred Strains
11.
Arch Int Pharmacodyn Ther ; 300: 218-30, 1989.
Article in English | MEDLINE | ID: mdl-2559669

ABSTRACT

The purpose of this study was to determine whether an anticholinesterase organophosphorous compound, methylphosphonothiolate (VX), could display direct effects on isolated guinea-pig ventricular muscle, and to compare these possible effects with those of carbachol (CCH) and physostigmine (PHYS). Our results confirm the direct positive inotropic effect of CCH (stimulation frequency; 2 Hz) in a concentration range from 10(-7) to 10(-3) M; lack of PHYS or VX-induced modifications was set. In the presence of an adrenergic agonist, isoproterenol (ISO) 10(-7) M, CCH or PHYS modulated the positive inotropic effect of ISO. Even with elevated concentrations of CCH (10(-4) M) or PHYS (10(-3) M), arrhythmias were never depicted. VX-induced modifications are different. Under VX, the development of (1) a positive inotropic effect and (2) two contractile events in response to each stimulation were observed. Electrophysiological studies revealed that VX led to the development of delayed after-depolarizations, and eventually triggered activity. We conclude that, in addition to its anticholinesterase activity, VX could induce a Na+/K+ ATPase inhibition. This effect could be at the onset of ventricular arrhythmias that are observed in vivo in organophosphorous compounds poisoning.


Subject(s)
Arrhythmias, Cardiac/chemically induced , Autonomic Nervous System/drug effects , Heart/drug effects , Organophosphorus Compounds/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Arrhythmias, Cardiac/enzymology , Carbachol/pharmacology , Electrophysiology , Guinea Pigs , In Vitro Techniques , Isoproterenol/pharmacology , Male , Myocardial Contraction/drug effects , Organothiophosphorus Compounds/pharmacology , Papillary Muscles/drug effects , Physostigmine/pharmacology , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/physiology , Sympathetic Nervous System/drug effects
12.
J Pharmacol Methods ; 19(2): 127-33, 1988 Apr.
Article in English | MEDLINE | ID: mdl-3361924

ABSTRACT

Electrocardiogram recording gives much information about cardiac activity and is often required for pharmacological studies. To obtain long-term recordings from laboratory rodents, with neither anesthesia nor stress for the animals, a simple technique was developed. Electrodes were implanted in rats subcutaneously 2 days before experiments. Electrocardiograms could then be recorded for several days without disturbing the rats. Signal quality allowed detection of arrhythmias. The effects of the administration of an organophosphorus compound are presented.


Subject(s)
Electrocardiography/methods , Rats/physiology , Animals , Arrhythmias, Cardiac/physiopathology , Cholinesterase Inhibitors/pharmacology , Male , Organothiophosphorus Compounds/pharmacology , Rats, Inbred Strains
13.
Toxicol Lett ; 37(1): 95-102, 1987 Jun.
Article in English | MEDLINE | ID: mdl-3590234

ABSTRACT

Cardiac toxicity of S-(2-diisopropylaminoethyl)-O-ethylmethyl phosphonothiolate (VX) has been investigated in the dog. Conscious or open-chest anaesthetized animals were subcutaneously injected with VX (1.5, 3.0 or 6.0 micrograms/kg b.w.). Blood cholinesterase activity decreased to 60%, 20% and 18% respectively of initial values. Only in the 6.0 micrograms/kg-treated group, heart rate, arterial and left intraventricular pressures and contractility index slightly but significantly decreased. In some dogs, treated with either 3.0 micrograms/kg or 6.0 micrograms/kg b.w. of VX, the electrocardiogram was changed: the Q-T interval was lengthened and arrhythmias (atrioventricular blocks, ventricular premature complexes. 'Torsade de pointe') were observed. Plasma non-esterified fatty acid concentrations were identical in control and VX-poisoned dogs. This study shows that, besides the expected cardiac effects resulting from muscarinic stimulation, VX can affect ventricular function through a yet unknown mechanism.


Subject(s)
Cholinesterase Inhibitors/toxicity , Heart Rate/drug effects , Hemodynamics/drug effects , Organothiophosphorus Compounds/toxicity , Anesthesia, General , Animals , Cholinesterases/blood , Dogs , Electrocardiography , Fatty Acids, Nonesterified/blood , Female , Male
14.
Toxicol Appl Pharmacol ; 87(2): 206-11, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3029895

ABSTRACT

Cardiac toxicity of methylphosphonothiolate (MPT), an organophosphorus compound, has been investigated in the rat. Subcutaneous injection of MPT (12 micrograms/kg body wt) induced cardiac arrhythmias, the occurrence of which was significantly more frequent than in the control group. Death rate among MPT-treated animals appeared to be in relationship with cardiac arrhythmias. Plasma nonesterified fatty acid concentrations increased in MPT-poisoned rats. cAMP and cGMP contents in myocardial tissue were unchanged 150 min after MPT administration, as compared with control. Similarly, no change has occurred in high energy compound levels.


Subject(s)
Heart/drug effects , Organothiophosphorus Compounds/toxicity , Animals , Arrhythmias, Cardiac/chemically induced , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Electrocardiography , Fatty Acids, Nonesterified/blood , Lethal Dose 50 , Male , Myocardium/metabolism , Rats , Rats, Inbred Strains
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