Attenuation of long-lasting effects of sympathetic stimulation after repeated stimulation.

Neuropeptide Y (NPY) is stored with norepinephrine in sympathetic nerves throughout the cardiovascular system and is released during activation of the sympathetic nervous system in humans and other animals. After stimulation of the cardiac sympathetic nerves in anesthetized dogs, the action of the vagus nerve on heart rate is attenuated for a prolonged period. This attenuation of cardiac vagal action is also seen after injection of NPY. Both sympathetic stimulation and exogenous NPY inhibit cardiac vagal effects by acting on postganglionic vagal nerves. Because the supply of neuropeptides to nerve terminals is by axonal transport, it might be expected that repeated stimulation of cardiac sympathetic nerves would deplete the sympathetic neural factor, proposed to be NPY. In all 11 dogs of this study, repeated episodes of stimulating the cardiac sympathetic nerve (16 Hz for 1 minute each) had a diminishing effect in attenuating cardiac vagal action. However, the episodes of sympathetic stimulation did not show diminishing effectiveness in increasing heart rate. Exogenous NPY had similar inhibitory effects on vagal action whether given at the beginning or the end of the episodes of sympathetic stimulation. Transmural stimulation of sympathetic nerves around rabbit ear arteries produced effects that are also mimicked by NPY. These are prolonged potentiation of contractions evoked by injection of norepinephrine or by brief bursts of transmural stimulation. Repeated stimulations in this case also had diminishing abilities to evoke such potentiations. Both sets of observations are consistent with repeated stimulation of sympathetic nerves causing depletion of a nonadrenergic transmitter, possibly NPY.

Attenuation of vagal action following sympathetic stimulation is modulated by prejunctional alpha 2-adrenoceptors in the dog.

We examined the effect of the alpha 2-adrenoceptor agonist clonidine and the alpha-adrenoceptor antagonist phentolamine on the attenuation of cardiac vagal action seen following stimulation of the cardiac sympathetic nerve. In the presence of phentolamine both the maximum percentage of inhibition of cardiac vagal action and the half-time to recovery were significantly increased. In the presence of clonidine both the maximum percentage of inhibition of vagal action and the half-time to recovery were significantly reduced. The results demonstrate that the inhibition of cardiac vagal action seen following sympathetic stimulation--an effect which is attributed to actions of the co-transmitter neuropeptide Y released during sympathetic stimulation--can be modulated by drugs acting on alpha-adrenoceptors.

Acute and repeated dose inhalation toxicity of para-nitrophenol sodium salt in rats.

Para-Nitrophenol Sodium Salt (PNSP) has relatively low acute inhalation toxicity; the 4-hr Approximate Lethal Concentration in rats is greater than 4.7 mg/l. One subacute study was conducted at 0, 0.34 and 2.47 mg PNSP/l for ten 6-hr exposures. Darker urine, proteinuria and elevated creatinine and SGOT were seen after exposure and were still evident after 14 days recovery. Methemoglobinemia also was seen and was reversible at 0.34 mg/l after 14 days. In addition, exposure to 2.47 mg/l caused elevated erythrocytes, hemoglobin and hematocrit. A second subacute study at 0.03 and 0.13 mg PNSP/l showed reversible methemoglobinemia only at 0.13 mg/l. The repeated dose no-observable effect level was 0.03 mg/l. No compound-related pathologic changes were noted in any of the studies.

Inhalation toxicity of ammonium perfluorooctanoate.

Ammonium perfluorooctanoate (CAS Registry No. 3825-26-1) is a fine white powder which can become airborne; hence its inhalation toxicity was studied in the male rat. The compound was found to be moderately toxic following single 4-hr exposures, with an LC50 of 980 mg/m3. This concentration produced both an increase in liver size and corneal opacity. Both findings diminished with increasing time after exposure. Subchronic head-only inhalation exposures (6 hr/day on 5 days/wk for 2 wk to 0, 1, 8 or 84 mg/m3) suppressed body-weight gain at 84 mg/m3. Reversible liver-weight increases, reversible increases in serum enzyme activities, and microscopic liver pathology, including necrosis, occurred at exposure of 8 and 84 mg/m3. No ocular changes were produced. Concentrations of organofluoride in the blood showed a dose relationship with initial levels of 108 ppm in rats treated at 84 mg/m3 falling to 0.84 ppm after 84 days with a blood half-life of 5-7 days. The no-observed-effect level was 1 mg/m3 and a mean organofluoride blood level of 13 ppm was detected in rats immediately after the tenth exposure to an atmospheric level of 1 mg ammonium perfluorooctanoate/m3.

Inhalation toxicity of dehydrothio-p-toluidine.

The acute inhalation toxicity of dehydrothio -p-toluidine ( DHPT ; CAS Registry No. 92-36-4) was determined by exposing groups of young adult Crl-CD rats for single 4-hr periods. Death resulted when the DHPT concentration reached 3.00 mg/litre. The subchronic effects of DHPT were studied by exposing male rats to 0.6 mg/litre for ten 6-hr periods (five exposure days, two rest days, five exposure days). Body-weight loss during the exposures was followed by normal weight gain during a 14-day recovery period. Salivation, lachrymation , pawing and chewing motions, rapid respiration and red nasal discharge occurred during exposure and continued into the recovery period, although they generally abated as the recovery period progressed. Clinical laboratory measurements on blood from exposed rats suggested a haemolytic anaemia with injury to the liver and kidneys. Liver changes were characterized by hepatocyte hypertrophy and proliferation of bile-duct epithelial cells. A mild degree of renal tubular degeneration was seen and the spleen showed congestion of red pulp with excessive amounts of haemosiderin. These effects persisted throughout the 2-wk recovery period.