Characterization of toxicity involving haemorrhage and cardiovascular failure, caused by parenteral administration of a soluble polyacrylate in the rat.

Adverse effects, involving a combination of hypotension and widespread haemorrhages, as well as evidence of vascullar and other tissue dissociation, associated with various systemic malfunctions (cyanosis, cardiac arrhythmias, neuromuscular disorder and death) were observed in the rat, from parenteral administration of a high-molecular-weight soluble polymer, sodium polyacrylate (EN21). Experiments to elucidate the mechanism of this effect involved comparisons with a low-molecular-weight sodium polyacrylate (EN5), either drug being given to groups of 5-8 rats, male or female, in doses of 5-100 mg/kg i.v., i.p. or s.c., or up to 1000 mg/kg p.o. Effects were observed visually up to the death of the animals, and these plus survivors killed after 10 h were prosected for macroscopic and histopathological examination of internal organs. Characteristic EN21 effects were only observed in animals treated by the i.p. and i.v. routes, death occurring in 4-10 h or rapidly (1 h) after i.v. dosage. No such effects were observed from EN5 by any dose or route. There were no differences between effects in male and female animals. In rats anaesthetized with sodium pentobarbitone and cannulated for blood pressure recording (arterial and venous), no hypertensive effects were observed to explain haemorrhagic effects. Instead, i.v. and i.p. injections gave depressor effects, insidious in the latter case, with a precipitous fall only in the delayed terminal stage. Effects were accompanied by cardiac arrhythmias. Depressor effects were prevented by prior treatment of the animals with calcium chloride solution. These effects could not be evoked by EN5, nor by injection of methylcellulose solutions of equivalent high viscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological actions and acute toxicity of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones.

Some pharmacological actions and acute toxicity effects of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones have been described in experimental animals. The compounds antagonised the contractions evoked by a variety of agonists on several smooth muscle preparations in vitro. They produced inhibitory effects on spontaneously contracting uteri from pregnant rats and relaxant effects on pendular movements of rabbit duodenum and on dog intestinal movements in vivo. The compounds inhibited the castor oil induced diarrhoea in rat and propulsion of charcoal test meal in mice. Phenylbutazone showed similar effect on castor oil diarrhoea. The compounds failed to modify gestation period or parturition in pregnant rats. They antagonised bradykinin-induced bronchospasm in guinea pig. The compounds showed no significant effect on cardiovascular and respiratory systems: CNS and general behaviour were not affected even at high doses. Oral LD50 for both the compounds was greater than 2 g/kg.

Antiinflammatory actions of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones.

Methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones (MHSK and PHSK, resp.) upon oral administration displayed marked antiinflammatory activity in a variety of acute tests viz. carrageenan, histamine, 5-hydroxytryptamine, dextran, bradykinin and prostaglandin (PG) induced oedema in rats and carrageenan evoked swelling in mice; the activity was not altered by adrenalectomy. In subacute test of formaldehyde arthritis, they showed significant reduction in paw swelling but were less effective in granuloma tests. In chronic tests, they produced marked antiarthritic effect both in developing and established adjuvant arthritis. The compounds prevented the inflammation induced increase in serum transaminase levels and leucocyte counts. They inhibited the passive cutaneous anaphylaxis and produced reduction in ADP induced platelet aggregation. The compounds showed weaker antipyretic activity than acetylsalicylic acid in pyretic animals. MHSK showed analgesic activity using the tail clip method and antagonised acetic acid induced writhing syndrome. The compounds lacked any local anaesthetic activity. The low ulcerogenic potential of these compounds in animal models may be related to their relative inability to inhibit PG synthetase.

Comparison of bioassay methods for the estimation of wound-released prostaglandin-like activity.

Methods of bioassay of prostaglandin-like activity (PGLA) released from wounds applied to isolated rat tail skin strips were compared. Administration of multiple bolus doses of PGE2 was used to simulate the response to wound-released PGLA. Estimates of the multiple dose administered were prepared by measuring the peak heights of single bolus and infused doses of PGE2 and also of peak response area measurements of single bolus doses in a three point assay procedure. Comparison of these three methods of measurement demonstrated that peak response height estimates underestimated the simulated wound response value. The mean difference between the bolus dose area estimate and the simulated wound response value was 1.4 +/- 1.2 ng PGE2, and there was a highly significant correlation between the bolus dose area estimates and the simulated wound response values over the range 2.0-12.15 ng PGE2. Data from additional studies using this assay method show that arachidonic acid increased and indomethacin decreased the release of PGLA from wounds and further that wound PGLA release from the skin of diabetic rats was also decreased.

The effects of cadmium ions on blood pressure, dopamine-beta-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation, noradrenaline and tyramine.

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium ((Cd2+) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-beta-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd2+ (0.1-1 microM) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd2+ (0.5, 1 microM) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T10-L1) and tyramine injection (35, 70, 140 nmol kg-1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg-1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd2+.

Hypertension: its effect on the stimulated release of dopamine-beta-hydroxylase in the rat.

Plasma dopamine-beta-hydroxylase (DBH) concentrations have been postulated as providing an index of sympathetic nerve activity. Using a microspectrophotometric assay system, plasma DBH concentrations have been measured in emergent blood from autoperfused heart, spleen and mesentery of normotensive, deoxycorticosterone (doca)/NaCl-treated, Goldblatt (1 kidney) renal and spontaneously hypertensive rats following sympathetic nerve outflow stimulation. Changes in plasma DBH concentrations as a result of sympathetic nerve outflow stimulation rates of 1--25 Hz for the mesentery and spleen and 1--4 Hz for the heart, were found to be frequency-dependent in all groups. Significantly greater amounts of DBH were found in the perfusate from the spleen (1--25 Hz) and mesentery (3--25 Hz) but not the heart (0.5--4Hz) of renal hypertensive rats compared with normotensive controls. Significantly greater concentrations of DBH were released from the spleen but not the mesentery in all hypertensive groups following high stimulation frequencies of 12 and 25 Hz. It is concluded that there is a relation between plasma DBH concentrations and sympathetic nerve activity. Furthermore, greater amounts of the enzyme are released from the spleen and mesentery of chronic renal hypertensive rats following sympathetic nerve stimulation.

Dopamine-beta-hydroxylase release following acute selective sympathetic nerve stimulation of the heart, spleen and mesentery.

In increase in the concentration of dopamine-beta-hydroxylase (DBH) in the blood perfusates of the heart, spleen and mesentery of pithed rats was detected following selective sympathetic nerve stimulation. Furthermore, the concentration of enzyme released by each organ correlated with the stimulation frequency. The results provide further corroborative evidence that the concentration of DBH in the plasma is related to the degree of sympathetic tone. If the sampling methods described were applied to non-spinalized animals, the concentrations of DBH in organ perfusates could be used as an index of sympathetic nervous tone and thus provide a useful preparation for the study of drugs on the sympathetic nervous system.

The effects of anticholinesterases on synaptic transmission through nicotinic and muscarinic receptors in rat sympathetic ganglia in vivo.

1 Stimulation of the entire spinal sympathetic outflow at supramaximal voltage and 25-100 Hz, in the chlorisondamine-treated, pithed, adrenalectomized rat produced a delayed pressor response (late pressor response; LPR).2 The LPR was abolished by phenoxybenzamine, bretylium or a small dose of atropine (25-50 mug/kg), suggesting the involvement of ganglionic muscarinic receptors.3 In the presence of atropine at a dose level (15 mug/kg) which did not influence the LPR, the anticholinesterases physostigmine, neostigmine and Ro 02-0683 but not BW 284C51 markedly enhanced and prolonged the LPR, whereas all of them reduced the pressor responses to AHR-602.4 After blockade of the ganglionic muscarinic receptors with a large dose of atropine (250 mug/kg) the four anticholinesterases did not influence responses to DMPP or noradrenaline and only slightly enhanced responses to preganglionic nerve stimulation at 6 Hz in the absence of chlorisondamine.5 It is concluded that inhibition of butyrylcholinesterase accounts for the enhancement and prolongation of the LPR by anticholinesterases.