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Biomedical subjects

M Weinstock

Publications and source records attributed to M Weinstock.

At least 73 records · Page 4Linked to original sources
PubMed1987

Temporal factors influencing the development of acute tolerance to opiates.

The present study investigated the influence of the extent of drug effect, duration of action and dose interval on the development of acute tolerance to the respiratory and cardiovascular depressant effects of opiates. Morphine (2, 4 and 10 mg/kg i.v.) caused a dose-related reduction in heart and respiratory rates and elevation in PaCO2 which lasted 4 to 4.5 hr. Acute tolerance occurred to the effect of a second dose of 4 or 10 mg/kg but not 2 mg/kg given 4 hr after the first. When the duration of action of the opiate was limited to 75 min by injection of naloxone (0.125 mg/kg) or by the use of a short acting opiate, fentanyl (0.025 mg/kg), tolerance to a second dose of drug still developed provided it was given at least 4 hr later. When naloxone was given at the peak of the morphine effect (30 min) tolerance did not occur. It is concluded that the development of acute tolerance to opiates depends on the degree of initial drug effect and the time of receptor occupancy. The latter must be longer than that required to attain a peak response. A time period of about 4 hr appears to be necessary for the full development of the biochemical processes involved in this phenomenon.

Animals↗
PubMed1986

Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats.

This study investigated the hypotheses that unpredictable prenatal stress has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1-8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.

Animals↗
PubMed1986

Are the effects of gestational stress on motor development and cerebellar cholinesterase activity mediated prenatally?

Prenatal random noise and light stress retards early motor development in the rat. To determine whether this delay is pre- or postnatally mediated and whether the developing cerebellum may play a role in the delay, rats were subjected to this form of stress and their offspring were fostered or cross-fostered onto control rats and vice versa. Their motor development was assessed by a series of behavioral tests between birth and day 10 of life. Prenatally stressed pups (Eo), whether reared by stressed (Em) or control mothers (Cm), showed a retardation in motor development. However, stressed pups matured earlier when reared by a control mother than by a stressed dam. Control pups (Co) raised by stressed mothers showed normal behavioral development. Cerebellar cholinesterase activity, which has been shown to undergo characteristic alterations with normal maturation, did not differ between stressed and control pups at birth. However, on day 10, cholinesterase activity was lower in EmCo than in CmCo pups, whereas that in CmEo and EmEo pups did not differ significantly from controls. It is concluded that three effects of random noise and light stress during pregnancy may be distinguished: (1) A prenatal effect as expressed by a delay in motor development, (2) a postnatal (rearing) effect on motor development and (3) a rearing effect expressed as a decrease in cerebellar ChE activity.

Animals↗
PubMed1986

Mechanism of antagonism by physostigmine of acute flunitrazepam intoxication.

The effect of physostigmine on the loss of consciousness and respiratory depression induced in rabbits by flunitrazepam, 1 mg/kg, was studied to demonstrate whether the restoration of consciousness and respiration rate results from an increase in central cholinergic activity or from an interference by physostigmine with specific binding of flunitrazepam to its receptors. Physostigmine, 0.1-0.4 mg/kg iv, caused a dose-related reversal of consciousness and respiration rate within 15 min of its injection, which lasted 15-30 min depending on the dose. This was associated with peak inhibition of acetylcholinesterase (AChE) in the frontal cortex and medulla, at 15 min, ranging from 35-51%. The analeptic effect of physostigmine in flunitrazepam-treated rabbits was prevented by pretreatment with scopolamine, 1 mg/kg. The effective dose range for physostigmine, 3-12 mumol/kg, is close to concentrations of this agent that inhibit activity in solubilized preparations of AChE from rabbit cortex, 1-3 X 10(-8) M. However, physostigmine, 10(-9) -10(-4) M, failed to displace 3H flunitrazepam from specific binding sites on membranes prepared from rabbit cerebral cortex. It is concluded that physostigmine antagonizes the somnolence and respiratory depression induced by benzodiazepines by restoring cholinergic transmission to normal levels. The effective dose range of physostigmine is small, and serious side effects from overdose can occur as a result of excess cholinergic activity at neuromuscular synapses.

Acetylcholinesterase↗
PubMed1986

Pharmacological evaluation of an injectable prolonged release emulsion of physostigmine in rabbits.

Physostigmine was incorporated in an injectable emulsion in an attempt to prolong its pharmacological activity. Emulsions which remained stable over 6 month storage were prepared using optimal experimental conditions. The in-vitro kinetic examination revealed that the rate-determining step in the release process of physostigmine from the emulsion was its partitioning from the oily phase to the external aqueous phase. The in-vivo results indicated that the physostigmine emulsion was able to inhibit the cholinesterase activity for only 1 to 2 h. The preliminary pharmacokinetic analysis showed that the physostigmine emulsion apparently increased the bioavailability compared with the conventional injectable solution. This could be attributed either to the protection of the sensitive drug from the enzymatic degradation or to improved absorption. The presence of poloxamer micelles in the aqueous phase was shown to enhance the bioavailability of physostigmine without having any effect on its pharmacological activity or duration.

Acetylcholinesterase↗
PubMed1986

A new animal model for action myoclonus.

Morphine was injected into a catheter implanted chronically into the intrathecal space of rats. Three to eight minutes after drug administration, 80% of the rats developed arrhythmic stimulus-sensitive jerks that lasted up to 1 hr. The morphine-induced myoclonic activity was markedly reduced by naloxone. Methadone, pethidine, and etorphine failed to produce the syndrome. In spinally transected rats, morphine injected below the level of transection did not produce the syndrome. No significant changes in PaCO2 and PaO2 were produced by morphine before and throughout the period of myoclonic activity. Neither did induced hypoxia augment the effect of morphine. However, irreversible hypoxic-ischemic cell changes were noticed in some brain regions. The phenomenon described here resembles the human syndrome of action myoclonus and may serve as an animal model for studying the mechanism of that neurological disorder.

Animals↗
PubMed1985

Prenatal stress impairs maternal behavior in a conflict situation and reduces hippocampal benzodiazepine receptors.

Maternal behavior (pup retrieval) was assessed in prenatally stressed rats during control and conflict situations (having to pass through an airstream) when their pups were 4-5 days old. There was no difference in pup retrieval between experimental and control rats under normal conditions but only 52% of the former retrieved their pups during the conflict situation, compared with 96% of the controls. Catecholamine (CA) levels in the arcuate nucleus (Arc.n.) and noradrenaline in the medial preoptic nucleus (POM) were not altered in prenatally stressed females, but their dopamine levels in the POM tended to be lower (p less than 0.1). The number of benzodiazepine (BZ) receptors in the hippocampi of prenatally stressed females was significantly lower than in controls. We conclude from these results that random prenatal noise and light stress increases the vulnerability to stressful situations in the female offspring during adulthood, which may be accompanied by altered CA function in the hypothalamus and BZ binding in the hippocampus.

Animals↗
PubMed1985

Impaired baroreflex sensitivity in the aetiology of salt hypertension in the rabbit.

This study was designed to see whether normotensive rabbits with an impairment in baroreflex control of heart rate due to genetic factors are more susceptible to high salt or deoxycorticosterone acetate (DOCA)-salt hypertension. The baroreflex sensitivity of 27 conscious rabbits was assessed by both the 'steady-state' and 'ramp' methods in response to injections of phenylephrine (2.5-30 micrograms/kg). Animals with differing baroreflex sensitivities were then given 4 weeks treatment with 8% NaCl and 1.3% KCl in food (treatment A), or DOCA (25 mg pellet, subcutaneously) with 0.5% NaCl and 0.13% KCl in drinking water (treatment B). A third group were maintained on a regular diet of food and water (controls). A highly significant negative correlation (r = 0.91, P less than 0.01) was found between the increase in mean arterial pressure (MAP) produced either by treatment A or treatment B and the baroreflex sensitivity before treatment. There was no significant correlation between the increase in MAP and initial MAP; increase in body weight; serum K+ after treatment; baroreflex sensitivity before treatment, when assessed by the 'ramp' method. It is concluded that animals with low baroreflex sensitivity due to a reduced ability to suppress cardiac sympathetic activity in response to a pressor stimulus, are more likely to develop hypertension as a result of salt loading. It remains to be determined whether the susceptibility to salt of rabbits with lower baroreflex sensitivity is also associated with a difference in the renal excretion of Na+ ions.

Animals↗
PubMed1985

Seasonal variation in the development of stress-induced systolic hypertension in the rat.

Seasonal variation in blood pressure in human hypertensives prompted us to investigate whether such a phenomenon also occurs in rats made hypertensive by environmental stress. Groups of eight to 20 rats, housed in stress chamber under natural light conditions at 21 +/- 1 degree C, were subjected to noise (85-105 dB) and light stress for 4 h three times per week for 16 weeks, over 4 years. Systolic pressure increased by 14-25 mmHg after 6-8 weeks of stress from October to January. Artificial environmental light for 15 h prevented development of hypertension by stress, which could also be reversed by acute administration of propranolol. Hypertensive rats had significantly greater relative heart and adrenal weights. This phenomenon can be explained by amplification of sympathetic pressor activity by stress hormones, adrenaline, corticosterone and prolactin, under the influence of melatonin.

Animals↗
PubMed1984

The effects of prenatal exposure to predictable or unpredictable stress on early development in the rat.

Pregnant rats were exposed to different schedules of noise and light stress, and the development of their offspring was studied during the first 2 weeks of life. Motor development was measured by different tests: Righting reflex (Days 2-4); cliff avoidance (Days 4-10); turning on an inclined plane (Days 5-10); and swimming behavior (Days 6-10). Development of motivation-involved behavior was measured with a home-seeking test (Days 6-16). Other developmental landmarks such as acoustic response (Days 12-14) and eye-opening (Days 14-17) were also recorded. Thrice-weekly random stress resulted in a delay in the development of all behaviors studied. Daily stress exposure throughout pregnancy resulted in smaller litters with heavier pups, but otherwise normal behavioral and physical development. Rats exposed to daily stress during the last week of pregnancy only produced litters that did not differ in size and body weight, but that displayed accelerated development of all parameters (except for eye-opening) from Day 6 onwards. It is concluded that the unpredictable nature of prenatal stress is responsible for delays in behavior of offspring.

Animals↗
PubMed1984

Oral flunitrazepam in the prevention of local anaesthetic-induced convulsions in mice.

The present study determined whether oral flunitrazepam was effective reducing CNS toxicity of lidocaine and bupivacaine. Pretreatment of mice with flunitrazepam, 0.065-0.25 mg X kg-1, significantly reduced or prevented convulsions and mortality induced by lidocaine 106 and 209 mg X kg-1 or bupivacaine 58 and 90 mg X kg-1 injected intraperitoneally. The doses of flunitrazepam used did not cause measurable sedation in mice. The efficacy of oral flunitrazepam in preventing local anaesthetic-induced convulsions is similar to that previously reported by intraperitoneal or intramuscular injections in mice. Flunitrazepam could be useful for oral premedication of patients before regional anaesthesia.

Administration, Oral↗
PubMed1984

Endogenous opiates mediate cardiac sympathetic inhibition in response to a pressor stimulus in rabbits.

Two different patterns of response to a pressor stimulus occurred in conscious rabbits. This difference was not apparent when a depressor stimulus was applied. At levels of mean arterial pressure exceeding 120 mmHg one group of animals exhibited a marked bradycardia which was due to sympathetic inhibition in addition to vagal activation while this sympathetic component appeared to be lacking in the second group of animals. Naloxone (0.1 mg/kg i.v.) markedly reduced the sympathetic inhibition elicited by phenylephrine but had no significant effect on the reflex vagal stimulation. Naloxone thereby abolished the difference in sensitivity of baroreflex control of heart rate in response to a pressor stimulus between the two groups of rabbits. Naloxone did not influence the sensitivity of the reflex response to nitroprusside. Morphine (2 mg/kg) increased the vagal component of the baroreceptor reflex in response to a pressor stimulus and the sensitivity of the reflex response to nitroprusside in all the rabbits, and this was antagonized by naloxone (0.1 mg/kg). Morphine also potentiated and naloxone antagonized the bradycardic response at levels of MAP exceeding 120 mmHg, in those rabbits which appeared to lack the cardiac sympathetic inhibitory component of the reflex. The results show that endogenous and exogenous opiates can increase the reflex bradycardia in response to a pressor stimulus in the conscious rabbit. The difference in baroreflex sensitivity in different animals may result from their varying ability to activate endogenous opioid systems which depress cardiac sympathetic activity.

Animals↗
PubMed1984

Baroreflex sensitivity and susceptibility to systolic hypertension induced by DOCA-salt in the Sabra rat.

Rats of the salt-resistant Sabra strain (SBN) have a more sensitive baroreflex control of heart rate than do normotensive hypertension-prone salt-sensitive (SBH) rats. To test the hypothesis that increased baroreflex sensitivity confers resistance to hypertension, aortic baroreceptor deafferentation (ABD) was performed in 7- to 10-wk-old SBN rats. This treatment reduced the slope of the mean arterial pressure-heart period (MAP-HP) relationship in response to infusions of increasing doses of phenylephrine in conscious rats, from 1.92 +/- 0.21 to 0.66 +/- 0.11 ms X mmHg-1 (P less than 0.01). The latter value did not differ significantly from that of untreated SBH rats (0.56 +/- 0.07 ms X mmHg-1). Treatment of uniphrectomized SBH, SBN-ABD, and sham-operated SBN rats for 3 wk with deoxycorticosterone acetate (DOCA; 25-mg pellet) and 0.9% NaCl + 0.4% KCl (to maintain normal serum K+ values) as drinking fluid caused increases in systolic blood pressure from 126 +/- 3 to 147 +/- 5 mmHg and 104 +/- 6 to 130 +/- 8 mmHg in the former two groups, respectively, but no significant change (105 +/- 3 to 110 +/- 4 mmHg) in SBN rats when measured by an indwelling arterial catheter in the tail artery. The slopes of the MAP-HP relationships of each of the above three groups of rats were not significantly altered by DOCA-salt treatment. It is concluded that a decrease in baroreflex control of the heart by ABD can render SBN rats sensitive to DOCA-salt-induced systolic hypertension.

Animals↗
PubMed1984

Sympathetic component of baroreflex control of heart rate is impaired in hypertension-prone (SBH) Sabra rats.

Baroreflex control of heart rate in response to phenylephrine was studied in conscious Sabra hypertension-prone (SBH) rats, at a prehypertensive stage, and hypertension-resistant (SBN) rats. Baroreflex sensitivity as determined from the slope of the relationship of mean arterial blood pressure and heart period was significantly lower in SBH rats (0.58 +/- 0.06 versus 1.71 +/- 0.11 ms/mmHg in SBN rats, P less than 0.01) before the development of hypertension. Sympathetic nerve blockade with guanethidine (15 mg/kg) significantly reduced the slope of the mean arterial blood pressure-heart period relationship in SBN rats to 0.45 +/- 0.05 ms/mmHg (P less than 0.01) and increased the pressor response to phenylephrine, without having any effect on these parameters in SBH rats. Atropine methyl nitrate (1 mg/kg) abolished reflex vagal bradycardia in response to phenylephrine in both groups of rats. This suggests that SBH rats are unable to withdraw the sympathetic cardiac component of the baroreflex in response to a pressor stimulus and appear to rely only on increased vagal activity to effect bradycardia.

Animals↗