Altered responsiveness to autonomic transmitters of hearts from neonatal spontaneously hypertensive rats

Responsiveness to autonomic neurotransmitters of isolated hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared in 1-day-old and 4-week-old neonates and adults. Chronotropic responses to norepinephrine (NE) and acetylcholine (Ach) were examined using right atrial preparations. There was no difference in the basal beating rate between SHR and WKY at all ages tested. The maximum beating rate produced by NE was higher in SHR only at 1 day after birth; there was no difference in the 4-week-old neonate and the adult. The sensitivity (pD2 values) to Ach was lower in SHR at both 1 day and 4 weeks after birth, but not in the adult. Inotropic responses to NE were examined using right ventricular preparations. The sensitivity was slightly higher in SHR at 1 day after birth, but no difference was observed in the 4-week-old neonate and the adult. These results suggested that the neonatal SHR heart has an increased function due to altered responsiveness to autonomic neurotransmitters, which may play a role in the initiation of hypertension.     

Increased sensitivity to picrotoxin as an index of physical dependence on alcohol in the mouse

A relatively simple and rapid method has been developed to induce tolerance to and dependence on alcohol in mice. Alternating intraperitoneal injections of metabolically stable tert-butanol and ethanol for 4 consecutive days resulted in a physical dependence on alcohol, which was quantified by the latency and ED₅₀ of picrotoxin-induced CNS hyperexcitability — myoclonic and tonic seizures and mortality — during the withdrawal period. The data indicate that alcohol-dependent animals in the withdrawal period are more susceptible than alcohol-naive controls to picrotoxin. Withdrawal hyperexcitability can be quantified by the ED₅₀ of picrotoxin.     

Increased sensitivity to warfarin in elderly Hispanics

It has been suggested that aging enhances the pharmacologic effect of warfarin, but there is little information about the effects of warfarin in aging minority populations. The authors examine the response of an aging Hispanic population to warfarin. Charts in their anticoagulation clinic were retrospectively examined for the following information: age, sex, weight, duration of anticoagulant therapy, number of medical problems, number of medications, number of minor or major bleeding episodes, prothrombin time, warfarin dose, and international normalized ratio (INR). The dose-adjusted prothrombin time ratio (PTR) and dose-adjusted INR were calculated by dividing the PTR and INR by the mean warfarin dose. Four groups were compared by age: < 50, 50 to 59, 60 to 69, and > or = 70. A total of 243 charts were reviewed: 113 female, 130 male; 90% were Hispanic. The most common indication for anticoagulation was atrial fibrillation. Elderly patients had more medical problems (3.1 vs. 2.4) and took more medications (3.4 vs. 2.4) than younger patients. The dose-adjusted PTR and dose-adjusted INR increased with aging (0.59 vs. 0.38 and 0.85 vs. 0.59, p < .05 ANOVA). In a multiple linear regression analysis, only age remained significantly associated with the anticoagulant effect. These results are consistent with previous reports on the effect of warfarin in aging patients and extend these data to the Hispanic population.     

Increased sensitivity to phenprocoumon during methyltestosterone therapy

Summary Abnormal sensitivity to phenprocoumon in a castrated male who was receiving substitution therapy with methyltestosterone, has been studied and compared with pharmacokinetic data obtained from six control subjects, all of whom had cardiac disorders. The concentration-effect relationship for phenprocoumon in the castrated patient was evaluated by the mathematical model described by Nagashima et al. (1969). The possible mechanisms involved in sensitization by methyltestosterone of the response to phenprocoumon are discussed. It is suggested that methyltestosterone increases the affinity of the receptor sites in the liver for phenprocoumon, an effect which has previously been attributed to other C17-alkyl-substituted androgens.     

Differential effects of drugs interacting with autonomic transmitters on responses of rat vas deferens to field stimulation

1. Frequency-response curves (0.1-30 Hz) were obtained in the epididymal portion of rat vas deferens. At low frequencies (0.1-1 Hz), the parameters evaluated were the first twitch and the fourth twitch at each frequency. The responses to trains of stimuli at intermediate (2-5 Hz) and high (10-30 Hz) frequencies were biphasic consisting of phase I (the first rapid phase of tetanus) and of phase II (the secondary slowly developing one). 2. Prazosin inhibited the first and the fourth twitch but not when the frequency was < 1 Hz. Suramin inhibited the first twitch while substantially depressing the fourth one. The combination of prazosin and suramin almost completely abolished all the twitches evoked by a train of stimuli at low frequencies. Nifedipine left almost unaltered the first twitch while markedly depressing the fourth one, especially at relatively high frequency (1 Hz). Verapamil was devoid of any inhibitory action. Papaverine depressed the first twitch while only at the highest concentration used (1 x 10(-4) M) markedly inhibited the fourth one. Chloroethylclonidine (CEC) depressed the first twitch and increased the fourth. 3. When intermediate (2-5 Hz) and high (10-30 Hz) frequencies are considered, prazosin and suramin partially inhibited both phase I and phase II, while in combination they almost completely abolished both phases. Nifedipine and verapamil selectively suppressed phase II, leaving phase I unaffected. Papaverine completely abolished both phase I and phase II. CEC was able to completely abolish phase I but increased phase II. 4. These results suggest that the response to the first twitch of a train at low frequency is prevailingly noradrenergic, prazosin-sensitive, while when the twitches are close enough (i.e. at 1 Hz) a summation of stimuli takes place and a predominant purinergic component, both suramin- and nifedipine-sensitive, becomes evident. 5. At high frequencies, both phases are due to the concomitant release of noradrenaline and adenosine triphosphate (ATP). The noradrenergic component of phase I is nifedipine-insensitive and CEC-sensitive, resembling the pharmacological profile of the endogenously released noradrenaline by single pulse, while that of phase II, nifedipine-sensitive and CEC-insensitive, is similar to that produced by exogenously applied noradrenaline.     

Increased sensitivity to nitrazepam in old age.

The effects of a single 10 mg oral dose of nitrazepam were compared with those of a placebo in healthy young and old people. Both the young and the elderly slept better on three successive nights after nitrazepam but they felt less awake at 12 and 36 hours (P less than 0-01). Elderly people made significantly more mistakes in a psychomotor test than did the young, despite similar plasma concentrations of nitrazepam and half lives in the two groups. This difference in response to psychomotor testing is probably explained by an increased sensitivity of the ageing brain to the action of nitrazepam.     

Increased sensitivity to chronic ethanol in isolated mice

Isolated C57BL/10 mice fed liquid diet as their only nutritional supply consumed 44% more diet than did groupedhoused mice. A similar increase due to isolation of 36% for C57BL/10 mice and of 89% for DBA/1 mice was demonstrated when the sucrose in the liquid diet was replaced by an equicaloric (6% v/v) amount of ethanol. The ethanol-drinking isolated mice suffered a higher mortality rate than the grouped mice. When isolated mice were given a restricted amount of ethanol diet to match the consumption of the grouped mice, their death rate still remained higher. It was concluded that isolation increased the sensitivity to ethanol effects. The observed changes in the sensitivity to ethanol effects may have been mediated by the known isolation-induced changes in the levels of brain amines and corticosterone. Generally, DBA/1 mice were more susceptible to chronic ethanol than C57BL/10, and the young more susceptible than the adults.     

Cardiac response to autonomic drugs in atria of diabetic mouse

Abstract— Comparisons of chronotropic effects of sympathomimetic and parasympathomimetic agents were made in isolated atria from alloxan-induced diabetic and age-matched control mice. In atria from mice rendered diabetic for three months, the cardiac response to bethanechol was potentiated compared with that of the age-matched control atria. However, the cardiac responses of atria from alloxan-treated mice to noradrenaline, 3-isobutyl-1-methylxanthine and 1,1-dimethyl-4-phenyl piperazinium iodide were similar to those of the controls.     

Increased sensitivity of mice to tremorogenic agents following MPP+

The behavioral effects following intrastriatal MPP⁺, the neurotoxic metabolite of MPTP, were evaluated in mice. Bilateral injections of 10 cro;g MPP⁺ to mice previously trained in the shuttle box paradigm produced a 66% decrease in striatal dopamine and significant deficits in all measures of conditioned avoidance responding. In addition, although these mice showed no deficits in baseline rotorod performance, challenge with the cholinergic agonist oxotremorine revealed that MPP⁺-treated mice exhibited an increased sensitivity to the disruptive effects of the drug at each dose and time point. Finally, MPP⁺-treated mice also exhibited an increase in tremor induced by 0.1 and 0.15 mg/kg oxotremorine. These observations are discussed in reference to idiopathic parkinsonism.     

Increased sensitivity to nifedipine of smooth muscle from hypertensive rats

The sensitivity of smooth muscle from aortas of spontaneously hypertensive rats (SHR), renal hypertensive rats: two kidney-one clip and one kidney-one clip (2K-1C, 1K-1C) and DOCA salt hypertensive rats to the relaxant effect of nifedipine (NIF) was studied. A parallel leftward shift of the concentration-relaxation curve was detected in the K-precontracted aortic smooth muscle from hypertensive rats. This increased sensitivity seems to be related to the degree of hypertension and independent of the experimental method used to produce the high blood pressure level. No change in sensitivity was detected either in SHR or in renal hypertensive rats when nitroglycerin was used as a vasodilator.     

Inotropic effects of histamine on developing chick heart: release of transmitters from autonomic nerve terminals

Inotropic effects of histamine were examined in isolated ventricular preparations from late embryonic and hatched chick hearts. In 19 day-old embryonic preparations, histamine had little effect on the contractile force. In preparations from 1 to 2 day-old hatched chick, histamine produced a transient decrease in contractile force followed by a sustained increase. The negative and positive responses were antagonized by atropine and propranolol, respectively, but not by histamine antagonists terfenadine, cimetidine or thioperamide. Acetylcholine produced positive Inotropic responses in the embryo while negative responses were observed after hatching. In myocardium of hatched chicks, compound 48/80, which releases histamine from mast cells, produced a transient decrease in contractile force followed by a sustained increase with a similar magnitude and time course to the case of exogenously applied histamine. The negative and positive responses were inhibited by atropine and propranolol, respectively, but not by terfenadine, cimetidine or thioperamide, which was similar to the case with the responses to histamine. The present results suggest that histamine, either applied exogenously or released from myocardial store sites, produces negative and positive inotropic responses in hatched chick myocardium which are due to release of acetylcholine and norepinephrine, respectively, from autonomic nerve terminals.     

Effects of hemicholinium and bretylium on the release of autonomic transmitters in the isolated sino-atrial node

1. In the isolated, spontaneously beating, sino-atrial node of the rabbit selective electrical excitation of intranodal autonomic nerve fibres results in a biphasic chronotropic response. This chronotropic response (negative followed by positive chronotropism) is due to the release of the autonomic transmitters (acetylcholine and noradrenaline, respectively) from intranodal nerve fibres.2. In the presence of 2 x 10(-4) g/ml hemicholinium, the negative chronotropic (cholinergic) response is abolished while the positive chronotropic (adrenergic) response is unaltered.3. In the presence of 5 x 10(-6) g/ml bretylium, the positive chronotropic response is abolished while the negative chronotropic response is little affected.4. After blockade of the negative chronotropic response by hemicholinium, bretylium abolishes the remaining positive chronotropic response. The effect of bretylium is not altered in the presence of hemicholinium.5. Considering currently accepted mechanisms of action for hemicholinium and bretylium, the results of these experiments do not lend support to the cholinergic link hypothesis of adrenergic neuro-effector transmission.     

Metabolic activation capacity of neonatal mice in relation to the neonatal mouse tumorigenicity bioassay

The neonatal mouse tumorigenicity bioassay is a well-developed animal model that has recently been recommended as an alternative tumorigenicity bioassay by the International Conference on Harmonization (ICH) for Technical Requirements for the Registration of Pharmaceuticals for Human Use. There are sufficient data to conclude that this animal model is highly sensitive to genotoxic chemical carcinogens that exert their tumorigenicity through mechanisms involving the formation of covalently bound exogenous DNA adducts that lead to mutation. On the other hand, it is not sensitive to chemical carcinogens that exert tumorigenicity through a secondary mechanism. The metabolizing enzymes present in the neonatal mouse, particularly the cytochromes P450, are critical factors in determining the tumorigenic potency of a chemical tested in this bioassay. However, compared to the metabolizing enzymes of the adult mouse and rat, the study of the metabolizing enzymes in neonatal mouse tissues has been relatively limited.     

Increased vulnerability of neonatal rats and mice to 1-nitronaphthalene-induced pulmonary injury

The postnatal period of lung development is a critical window of susceptibility to environmental toxicants, including polyaromatic hydrocarbons (PAHs) and furans. To determine whether the increased susceptibility of neonatal lung injury due to environmental toxicants is a universal response across species and also applies to nitrated compounds, adult and 7-day-old male mice and rats were given a single intraperitoneal dose (0, 12.5, 25, 50, or 100 mg/kg) of 1-nitronaphthalene and killed 24 h later. Exposure to 1-nitronaphthalene, a nitro-polyaromatic hydrocarbon, results in pulmonary lesions in both adult rats and mice, although the severity of the injury is species-specific (greater in rats than in mice). Pulmonary lesions, as assessed by quantitative histopathology, included dose-dependent vacuolization and exfoliation of both ciliated and nonciliated airway epithelial cells throughout the airway tree in both rats and mice. In both species, the 7-day-old animals were more susceptible to injury by 1-nitronaphthalene than adult animals. In contrast to adult response, neonatal mice were more susceptible to 1-nitronaphthalene-induced pulmonary injury than neonatal rats. This indicates that neonatal susceptibility to environmental pollutant-induced lung injury cannot be reliably predicted based on adult susceptibility.     

Increased sensitivity to serotonergic agonists after repeated electroconvulsive shock in rats

The effect of single and repeated electroconvulsive shock (ECS) (once daily for 7 days) on head twitches produced by 5-HT agonists (LiCl, 5-hydroxytryptophan; 5-HTP and 5-methoxytryptamine; 5-MT) was investigated 1 hr, 24 hr, 5 days and 10 days after the last ECS, while locomotor activity induced by serotonergic agonists (fenfluramine, 3-chlorophenylpiperazine; m-CPP) and antagonists (metergoline, cyproheptadine) was only investigated after 24 hr. 5HT and 5-HIAA concentrations were measured 0.5, 1 and 24 hr after a single ECS and up to 10 days after repeated ECS. Head twitches induced by LiCl were significantly depressed 1 hr after both single and repeated ECS. The number of head twitches produced by LiCl, 5-HTP or 5-MT given 24 hr after single or repeated ECS did not change but it rose significantly 5 and 10 days after the last shock. Repeated ECS increased locomotor activity 24 hr after the last shock. This increase was significantly enhanced by serotonergic antagonists. Biochemical assays showed that a single ECS did not significantly change brain 5-HT and 5-HIAA concentrations 0.5, 1 or 24 hr after the ECS. On the other hand, repeated ECS raised brain 5-HIAA 0.5, 1 and 24 hr or 5 and 10 days and 5-HT 0.5 hr after the final ECS. It is concluded that a single or repeated ECS both depress the serotonergic system response to LiCl but repeated ECS facilitates the response to serotoninomimetics.     

Increased sensitivity to the stimulus properties of morphine in food deprived rats

Recent research has shown that food deprivation increases opiate self-administration; in this line a first purpose of the present experiments was to determine whether the food deprivation effect could be replicated by the use of place conditioning, an alternative procedure for the study of drug reinforcement. It was found that the conditioned reinforcing properties of morphine (2.5 mg/kg IP) paired cues are greater in food deprived rats both after 1 and 3 conditioning sessions. A second objective of the work was to examine the possibility that food deprivation could also influence the discriminative stimulus properties of opiates. To this end rats trained to discriminate 10 mg/kg IP of morphine from saline were submitted to morphine generalization tests when food deprived or after 15 min supplemental feeding in the home cages. The ED50 value was significantly lower for food deprived (6.09 mg/kg) than for partially satiated (7.79 mg/kg) rats. It was concluded that food deprived rats are mores sensitive to both the reinforcing and the discriminative stimulus properties of morphine.     

Increased sensitivity to alprazolam in females with a paternal history of alcoholism

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.