Extra-vesicular binding of noradrenaline and guanethidine in the adrenergic neurones of the rat heart: a proposed site of action of adrenergic neurone blocking agents.
1 The binding and efflux characteristics of [14C]-guanethidine and [3H]-noradrenaline were studied in heart slices from rats which were pretreated with reserpine and nialamide. 2 Binding of both compounds occurred at extra-vesicular sites within the adrenergic neurone. After a brief period of rapid washout, the efflux of [14C]-guanethidine and [3H]-noradrenaline proceeded at a steady rate. The efflux of both compounds appeared to occur from a single intraneuronal compartment. 3 (+)-Amphetamine accelerated the efflux of [14C]-noradrenaline; this effect was inhibited by desipramine. 4 Unlabelled guanethidine and amantadine also increased the efflux of labelled compounds. Cocaine in high concentrations increased slightly the efflux of [14C]-guanethidine but not that of [3H]-noradrenaline. 5 Heart slices labelled with [3H]-noradrenaline became refractory to successive exposures to releasing agents although an appreciable amount of labelled compound was still present in in these slices. 6 It is suggested that [14C]-guanethidine and [3H]-noradrenaline are bound at a common extravesicular site within the adrenergic neurone. Binding of guanethidine to the extra-vesicular site may be relevant to its pharmacological action, i.e., the blockade of adrenergic transmission. (+info)
Myocardial uptake of digoxin in chronically digitalized dogs.
1 The time course of myocardial uptake of digoxin, increase in contractility and changes in myocardial potassium concentration was studied for 90 min following an intravenous digoxin dose to long-term digitalized dogs. 2 Nineteen dogs were investigated by the use of a biopsy technique which allowed sampling before and after administration of digoxin. 3 Ten minutes after administration of digoxin the myocardial concentration increased from 60 to 306 nmol/kg tissue, the myocardial concentration of digoxin was significantly lower (250 nmol/kg tissue) after 30 min and then increased again. 4 The transmural myocardial distribution of digoxin was uniform before and 90 min after administration of digoxin in long-term digitalized dogs but at 10 min after administration, both the subepicardial and the subendocardial concentration of digoxin were significantly lower than that of the mesocardial layer. 5 During the first 10 min the dp/dtmax increased to 135% of the control level. The increase remained unchanged during the rest of the study. 6 Myocardial potassium decreased throughout the study. 7 The M-configuration of the myocardial uptake curve and the non-uniformity of myocardial distribution of digoxin observed at 10 min after administrating digoxin to long-term digitalized dogs indicate that the distribution of myocardial blood flow may be changed during chronic digitalization. (+info)
Quantification of baroreceptor influence on arterial pressure changes seen in primary angiotension-induced hypertension in dogs.
We studied the role of the sino-aortic baroreceptors in the gradual development of hypertension induced by prolonged administration of small amounts of angiotensin II (A II) in intact dogs and dogs with denervated sino-aortic baroreceptors. Short-term 1-hour infusions of A II(1.0-100 ng/kg per min) showed that conscious denervated dogs had twice the pressor sensitivity of intact dogs. Long-term infusions of A II at 5.0 ng/kg per min (2-3 weeks) with continuous 24-hour recordings of arterial pressure showed that intact dogs required 28 hours to reach the same level of pressure attained by denervated dogs during the 1st hour of infusion. At the 28th hour the pressure in both groups was 70% of the maximum value attained by the 7th day of infusion. Both intact and denervated dogs reached nearly the same plateau level of pressure, the magnitude being directly related both the the A II infusion rate and the daily sodium intake. Cardiac output in intact dogs initially decreased after the onset of A II infusion, but by the 5th day of infusion it was 38% above control, whereas blood volume was unchanged. Heart rate returned to normal after a reduction during the 1st day of infusion in intact dogs. Plasma renin activity could not be detected after 24 hours of A II infusion in either intact or denervated dogs. The data indicate that about 35% of the hypertensive effect of A II results from its acute pressor action, and an additional 35% of the gradual increase in arterial pressure is in large measure a result of baroreceptor resetting. We conclude that the final 30% increase in pressure seems to result from increased cardiac output, the cause of which may be decreased vascular compliance. since the blood volume remains unaltered. (+info)
Evaluation of the force-frequency relationship as a descriptor of the inotropic state of canine left ventricular myocardium.
The short-term force-frequency characteristics of canine left ventricular myocardium were examined in both isolated and intact preparations by briefly pertubing the frequency of contraction with early extrasystoles. The maximum rate of rise of isometric tension (Fmas) of the isolated trabeculae carneae was potentiated by the introduction of extrasystoles. The ratio of Fmas of potentiated to control beats (force-frequency ratio) was not altered significantly by a change in muscle length. However, exposure of the trabeculae to isoproterenol (10(-7)M) significantly changed the force-frequency ratio obtained in response to a constant frequency perturbation. Similar experiments were performed on chronically instrumented conscious dogs. Left ventricular minor axis diameter was measured with implanted pulse-transit ultrasonic dimension transducers, and intracavitary pressure was measured with a high fidelity micromanometer. Atrial pacing was performed so that the end-diastolic diameters of the beats preceding and following the extrasystole could be made identical. Large increases in the maximum rate of rise of pressure (Pmas) were seen in the contraction after the extrasystole. The ratio of Pmax of the potentiated beat to that of the control beat was not changed by a 9% increase in the end-diastolic diameter, produced by saline infusion. Conversely, isoproterenol significantly altered this relationship in the same manner as in the isolated muscle. Thus, either in vitro or in situ, left ventricular myocardium exhibits large functional changes in response to brief perturbations in rate. The isoproterenol and length data indicate that the force-frequency ratio reflects frequency-dependent changes in the inotropic state, independent of changes in length. (+info)
Acquisition of nicotine discrimination and discriminative stimulus effects of nicotine in rats chronically exposed to caffeine.
Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and D3 (PD 128,907) dopamine-receptor agonists in water- and caffeine-drinking rats. The dopamine-release inhibitor CGS 10746B reduced the discriminative effects of 0.4 mg/kg nicotine in water-drinking rats, but not in caffeine-drinking rats. There was no evidence of development of tolerance or sensitization to nicotine's effects throughout the study. In conclusion, chronic caffeine exposure (average, 135 mg/kg/day) did not affect the rate of acquisition of the nicotine discrimination, but it did reduce the dopaminergic component of the nicotine-discriminative cue. The reduction of the dopaminergic component of the nicotine cue was permanent, as this effect was still evident after the caffeine solution was replaced with water in caffeine-drinking rats. That nicotine could reliably serve as a discriminative stimulus in the absence of the dopaminergic component of its discriminative cue may differentiate nicotine from "classical dopaminergic" drugs of abuse such as cocaine and amphetamine. (+info)
Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine.
Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. One conclusion of these studies was that when low- and high-intensity stimuli induce responses of similar magnitude in nociceptive neurons, low-intensity stimuli must be as painful as the high-intensity stimuli. The present study investigates in anesthetized rats the significance of the changes in the responses of central trigeminal neurons (i.e., in nucleus caudalis) by correlating them with the occurrence and type of the simultaneously recorded cardiovascular responses. Before chemical stimulation of the dura, simultaneous increases in neuronal firing rates and blood pressure were induced by dural indentation with forces >/= 2.35 g and by noxious cutaneous stimuli such as pinching the skin and warming > 46 degrees C. After chemical stimulation, similar neuronal responses and blood pressure increases were evoked by much smaller forces for dural indentation and by innocuous cutaneous stimuli such as brushing the skin and warming it to >/= 43 degrees C. The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine. (+info)
Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices.
To understand the elementary unit of synaptic communication between CNS neurons, one must know what causes the variability of quantal postsynaptic currents and whether unitary packets of transmitter saturate postsynaptic receptors. We studied single excitatory synapses between hippocampal neurons in culture. Focal glutamate application at individual postsynaptic sites evoked currents (I(glu)) with little variability compared with quantal excitatory postsynaptic currents (EPSCs). The maximal I(glu) was >2-fold larger than the median EPSC. Thus, variations in [glu]cleft are the main source of variability in EPSC size, and glutamate receptors are generally far from saturation during quantal transmission. This conclusion was verified by molecular antagonism experiments in hippocampal cultures and slices. The general lack of glutamate receptor saturation leaves room for increases in [glu]cleft as a mechanism for synaptic plasticity. (+info)
Reproductive experience and opioid regulation of luteinizing hormone release in female rats.
The objective of the present study was to determine whether reproductive experience that produces shifts in opioid regulation of prolactin secretion and behavioural functions also alters opioid regulation of LH during the oestrous cycle or lactation. In Expt 1 the effect of naloxone administration (i.v.) on LH was compared between age-matched, nulliparous and primiparous, catheterized female rats on dioestrus II. In Expt 2, the effects of multiple reproductive experiences on opiate control of LH were investigated using cyclic, nulliparous and multiparous (three litters) rats. In both experiments, no differences in naloxone-stimulated LH release were found between groups even though multiple reproductive experiences resulted in the prolongation of oestrous cyclicity. In Expt 3, day 8 lactating primiparous rats were administered 2, 5, 10 or 25 mg naloxone kg-1 i.v. The three lowest naloxone doses, but not the 25 mg kg-1 dose, significantly increased LH concentrations. The possible effects of prior reproductive experience on opioid control of LH during lactation were then investigated. Naloxone at 0.5 mg kg-1, but not at 2 mg kg-1 or 10 mg kg-1, stimulated a significantly greater rise in LH in multiparous (two litters) than in primiparous females. Overall, these data indicate that while modest differences were found in naloxone-induced LH responses between multiparous and primiparous animals during lactation, reproductive experience did not significantly alter opioid regulation of LH during subsequent oestrous cycles at the naloxone doses examined. Hence, the effects of reproductive experience on opioid regulation of LH are less pronounced than those previously found for opioid regulation of prolactin and behaviour. (+info)