Biomedical subjects
Publications and source records attributed to J R Fozard.
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1 The interaction between nor-(-)-cocaine and 5-hydroxytryptamine (5-HT) at autonomic neuronal 5-hydroxytryptamine (5-HT) receptors has been investigated on the rabbit heart and guinea-pig ileum. 2 The chronotropic response to 5-HT mediated through activation of receptors on the terminal sympathetic fibres of the rabbit heart was antagonized selectively and surmountably by nor-(-)-cocaine. Schild analysis yielded a pA2 value for the interaction of 7.79 +/- 0.11, n = 13. 3 On the guinea-pig ileum induced to contract by activation of 5-HT receptors on the intramural cholinergic nerves, nor-(-)-cocaine was also a selective and surmountable antagonist of 5-HT, although the concentrations needed were higher than those shown to be effective on the heart. The pA2 value for the interaction was 6.49 +/- 0.07, n = 16. 4 The differential blocking effect of nor-(-)-cocaine in the two tissues suggests that the receptors for 5-HT on the cholinergic nerves of the ileum and the sympathetic fibres of the heart are different. The data thus lend support to the earlier similar conclusion based on the observation that 5-methoxytryptamine is a potent agonist on the ileum yet inactive on the heart.
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Apomorphine inhibited chronotropic responses of the isolated rabbit heart to 5-HT by 40% at 1.17 micrometers and by 90% at 4.68 micrometers and strongly inhibited the outflow of 3H following preloading of hearts with [3H]- (-)-noradrenaline. Apomorphine, 4.68 micrometers, had no significant effects on transmitter release evoked by DMPP or tyramine but inhibited the responses to SNS at frequencies up to 3.2 Hz. The inhibitory effects of apomorphine on 5-HT were resistant to blockade by chlorpromazine, 1.4 micrometers, haloperidol, 1.6 micrometers, spiroperidol, 2.5 micrometers, or yohimbine, 2.8 micrometers. In contrast, the inhibitory effects of apomorphine on low frequency SNS were abolished by yohimbine. On the guinea-pig ileum treated with methysergide, apomorphine, 1.17-4.68 micrometers, blocked the indirect cholinergic responses to 5-HT less markedly than it blocked the indirect sympathomimetic responses to 5-HT on the rabbit heart. Moreover, the effects were non-selective since responses to DMPP and transmural stimulation of the intramural cholinergic nerves were similarly reduced. Modification of 5-HT receptor function is the most likely explanation for the action of apomorphine with the differential effect on 5-HT in the heart and ileum reflecting differences in the receptors and/or post receptorial events at the two sites.
Spontaneously cycling Sprague-Dawley Rats were treated with the irreversible ornithine decarboxylase (ODC) inhibitor DL-alpha-difluoromethylornithine (DFMO) on the day of proestrus. This treatment completely suppressed both the rise in ovarian ODC and the associated increase in putrescine concentration and increased the number of eggs released the next day by 91%. At the next oestrus (5 days after DFMO) there was a increase of 53% but at the third oestrus after DFMO (9 days) there was no significant change in the number of eggs released. A model is proposed in which ornithine decarboxylase forms part of a local inhibitory feed-back system controlling the number of follicles which develop to maturity and rupture during each cycle.
1. The effects of DL-alpha-difluoromethylornithine (RMI 71782; DFMO) on the tumours induced in female rats by a single oral administration of 20 mg 7,12-dimethyl-benz[a]anthracene (DMBA) have been investigated. 2. Treatment with DFMO (2% aqueous solution as sole drinking fluid) starting 30 days after administration of DMBA resulted in markedly fewer animals with tumours and greater than 90% reduction in the total number of tumours. 3. In rats bearing at least one palpable tumour, treatment with DFMO (2% in the drinking water) slowed significantly the rate of appearance of new tumours but affected to only a minimal extent the growth of existing tumours. Tumour ornithine decarboxylase activities and putrescine concentrations were reduced by treatment with DFMO; the activity of S-adenosyl-L-methionine decarboxylase was increased and the concentration of spermine either remained unchanged or increased depending on the length of treatment. 4. Cyclophosphamide, 100 mg/kg, injected once then repeated after 10 days, altered neither the rate of appearance of new tumours nor the growth of the existing tumours. Combined treatment with DFMO plus cyclophosphamide resulted in regression of the majority of tumours existing at the start of treatment and a marked reduction in the rate of appearance of new tumours. 5. In conclusion, DFMO has clear antitumoral activity against the rat mammary tumour induced by DMBA. The effects are manifested principally as a decreased rate of tumour appearance but meaningful effects on tumour growth are observed if the drug is administered during early tumour development or in combination with cyclophosphamide.
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Clonidine (4.3 X 10(-6) M) and yohimbine (2.8 X 10(-6) M) have been used to stimulate and to block alpha 2-adrenoceptors in the isolated perfused rabbit heart. Transmitter release from the terminal sympathetic fibres as a result of stimulation of the nerves leaving the stellate ganglion (SNS; 0.32-10 Hz) and bolus injections of 5-hydroxytryptamine (5-HT; 2.8-182 nmol) or dimethylphenylpiperazinium (DMPP; 26-418 nmol) was estimated from changes in the chronotropic response of the heart under conditions of constant end organ sensitivity to injected noradrenaline (0.06-15.1 nmol). In accordance with the literature, clinidine inhibited responses to SNS and was more effective against low than against high frequencies of stimulation; similarly, yohimbine enhanced responses to SNS. In contrast, neither clonidine no yohimbine had any effect on the indirect sympathomimetic response to 5-HT. Similarly yohimbine did not alter responses to DMPP. Clonidine produced inconsistent effects on the response to DMPP; the response to 105 nmol was unchanged whereas the response to 209 nmol was reduced. The results suggest that transmitter release from the cardiac sympathetic nerves of the rabbit heart evoked by 5-HT or DMPP is not subject to control through activation of alpha 2-adrenoceptors by the released transmitter. They lend support to the suggestion of Stjärne that alpha 2-adrenoceptor inhibition of transmitter release arises primarily from the suppression of impulse transmission from varicosity to varicosity within the adrenergic ground plexus rather than interference with a Ca2+-dependent step in excitation-secretion coupling.
A procedure is described for the measurement of DL-alpha-difluoromethylornithine (DFMO), a selective irreversible inhibitor of ornithine decarboxylase, in biological specimens. The drug is separated from other amino acids with a commerical amino-acid analyser and detected by formation of its alkylthio-isoindole derivative with o-phthalaldehyde. DFMO concentrations of 0.1 nmol can be determined in a sample volume of 100 microliter. The assay has been used to determine the half-life of DFMO in serum of several species and the relationships between serum and tissue concentrations.
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The activities of ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (SAMDC) and the concentrations of putrescine, spermidine and spermine were measured in mouse uterus placenta and foetus during gestation. The prominent post-implantation biochemical changes in the intact uterus were associated mainly with the deciduomata and significant ODC activity was located in the embryo. Administration of the irreversible inhibitor of ODC, alpha-difluoromethylornithine, DFMO, 2% inthe drinking water during days 5-8 of gestation, abolished the inareases in uterine ODC activity, putrescine and spermidine concentrations and enhanced the activity of SAMDC. Treated animals showed no signs of pregnancy when autopsied on day 18. The alterations in deciduomal weight and the changes in uterine DNA, RNA and protein content indicated that decidualization following DFMO took place normaly but that embryonic growth was arrested. Treatment on single days with DFMO, 200 mg/kg every six h, revealed optimal contragestational effects on day 8 which corresponded exactly to the time of the peak in deciduomal ODC activity. Treatment with DFMO at times other than during the vulnerable period of days 5-8 has less prominent effects on gestation. An increase in ODC activity appears to be an essential factor during a short, but critical, period after implantation for continued murine embryonal growth.
The highly selective, enzyme-activated, irreversible inhibitor of L-ornithine decarboxylase, DL-alpha-difluoromethylornithine, suppresses the increase in uterine L-ornithine decarboxylase activity associated with early embryogenesis in the mouse and arrests embryonic development at that stage. Contragestational effects were confirmed in the rat and rabbit. An increase in L-ornithine decarboxylase activity that leads to a rapid increase in putrescine concentration appears to be essential during a critical period after implantation for continued mammalian embryonal growth.
We investigated the effects on peripheral sympathetic nervous function of monofluoromethyldopa (MFMD, RMI 71963), a selective, enzyme-activated, irreversible inhibitor of L-aromatic amino acid decarboxylase. Three daily injections of 2.5, 25, or 100 mg/kg MFMD to rats reduced the dopamine and norepinephrine concentrations in the heart and increased those of L-dopa. Sedation was seen with the two highest doses of MFMD. Cardiovascular responses in the pithed rat to stimulation of the whole spinal sympathetic outflow and to injections of tyramine were reduced by treatment with MFMD. Both the reduced sympathetic function and the depleted transmitter store were restored by infusions of dopamine. Norepinephrine depletion and functional inhibition were obtained with smaller doses of MFMD (3, 6, and 10 mg/kg daily) given for longer periods (10 days). Blood pressure in spontaneously hypertensive rats was reduced by treatment with MFMD, 25 mg/kg, daily for 3 days. In vitro responses to nerve stimulation of portal veins declined during incubation with MFMD or alpha-methyl-p-tyrosine; responses of atria were unaffected. Changes in norepinephrine concentrations of portal veins and atria closely paralleled the changes in function. MFMD is the first compound which depletes peripheral norepinephrine concentrations by inhibiting transmitter biosynthesis at the decarboxylase step. Such depletion results in inhibition of sympathetic function in vivo and introduces a novel approach to pharmacological manipulation of the activity of the peripheral sympathetic nervous system.
A rational approach to the control of heparinisation during open heart surgery is advocated. Some of the possible and potential shortcomings of the time-based heparin protocols in current use are presented. The use of a recent, simple automated device 'Hemochron' to estimate the Activated Clotting Time is described and it is found to be an economical and efficient method to monitor heparinisation during cardiopulmonary bypass.
The interaction between (--)-cocaine and responses to 5-HT elicited through serotonin receptors on autonomic neurones has been investigated on the rabbit heart and the guinea-pig ileum. Low concentrations of (--)-cocaine or its stereoisomer, (4)-pseudococaine, produced shifts to the right of the 5-HT dose-response curves on heart and ileum with no depression of the maximum responses to electrical stimulation or dimethylphenylpiperazinium remained unaffected. A Schild analysis of data obtained on heart and ileum indicated competitive antagonism of 5-HT by (--)-cocaine. Antagonism of 5-HT by the cocaine isomers cannot be ascribed to local anaesthesia per se since neither lignocaine, tetracaine, benzocaine nor bu tacaine were selective antagonists of 5-HT. Similarly, inhibition of monoamine uptake seems of minimal relevance since desipramine proved only a weak antagonist of 5-HT on the heart and did not influence the 5-HT antagonist potency of (--)-cocaine. Selective blockade of 5-HT neuronal responses is a property shared by several structural analogues of (--)-cocaine and (+)-pseudococaine; nor-(--)-cocaine proved the most potent of these, being active at a concentration of 2 x 10(-8) M. These data indicate that (--)-cocaine and several of its derivatives inhibit 5-HT stimulation of both adrenergic and cholinergic autonomic neurones through competition with the agonist at serotonin receptor sties. Since morphine, the tool normally used to identify responses mediated through neuronal serotonin receptors, acts only at certain "morphine-sensitive" junctions and then, non-discriminately, the cocaine analogues, and particularly nor-(--)-cocaine would seem to offer real advantages as tools for differentiating such responses.
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