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Biomedical subjects

S Kalsner

Publications and source records attributed to S Kalsner.

At least 55 records · Page 3Linked to original sources
PubMed1982

Positive feedback regulation of noradrenaline release from sympathetic nerves: a questionable hypothesis.

The effects of known agonists and of an antagonist on the stimulation-induced efflux of [3H]noradrenaline from left atria of guinea pigs was assessed. This was done to evaluate the hypothesis of presynaptic beta receptors mediating a positive feedback system. Isoproterenol (1.2 X 10(-8) M) enhanced the efflux of tritium with 50 pulses at all four test frequencies and did so to a similar extent at three of them. Exogenous noradrenaline (1.8 X 10(-6) M) inhibited efflux and isoproterenol was ineffective as an enhancer of efflux in its presence. Propranolol (1 X 10(-7) M) did not reliably increase the inhibitory effect of added noradrenaline on stimulation-induced efflux nor did the antagonist by itself under a variety of test conditions decrease the stimulation-induced efflux of tritium. It is concluded that the synaptic quantities of transmitter do not determine the magnitudes of the effects of exogenous agents on tritium efflux and that positive feedback, for both theoretical and empirical considerations, does not function during neurosecretion.

Animals↗
PubMed1982

Termination of responses to sympathetic nerve stimulation and to noradrenaline in a perfused arterial preparation: the role of neuronal and extraneuronal uptake.

Perfused branch vessels of bovine radial artery in vitro responded to sympathetic nerve stimulation and to noradrenaline added extralumenally and intralumenally with constrictions monitored as flow reductions. Cocaine and 17 beta-estradiol, inhibitors of neuronal and extraneuronal uptake, respectively, enhanced responses to exogenous noradrenaline given by either route. An analysis of response recovery rates, namely termination of action, revealed that the extraneuronal and neuronal uptake process each accounted for between 35 to 50% of the total inactivation capacity of the perfused neuroeffector system for noradrenaline. Responses to periarterial nerve stimulation over a 0.5 to 10 Hz frequency range, involving minimal to moderate flow reductions, were substantially magnified by cocaine and by 17 beta-estradiol. An analysis of response duration and recovery rates showed that extraneuronal processes were more significant than neuronal uptake in terminating noradrenergic transmitter action over the frequency band of 0.5 to 10 Hz.

Animals↗
PubMed1981

The role of calcium in the effects of noradrenaline and phenoxybenzamine on adrenergic transmitter release from atria: no support for negative feedback of release.

1 The relation of calcium ion influx into nerve terminals to presynaptic adrenoceptor function and the possible masking, by desensitization due to intraneuronal calcium accumulation, of the effects of adrenoceptor agonists and antagonists on presynaptic alpha-adrenoceptors was investigated in guinea-pig atria previously incubated with [(3)H]-noradrenaline.2 Atria were stimulated with 100 pulses at various frequencies (1 to 15 Hz) in standard (2.3 mm), low (0.26 mm) and high (6.9 mm) calcium-Krebs solution in the absence and then the presence first of noradrenaline and subsequently phenoxybenzamine.3 The per pulse overflow of tritium was directly related to the calcium concentration of the Krebs solution, being much reduced and substantially increased in 0.26 and 6.9 mm calcium-Krebs solutions respectively.4 Noradrenaline inhibited the overflow of tritium in low calcium-Krebs solution, to a relatively constant extent, independently of frequency. In addition, the agonist had a greater maximal inhibitory effect in standard than in reduced calcium-Krebs. The catecholamine was as effective an inhibitor of overflow at the lowest and highest frequencies in high as it was in standard calcium-Krebs solution. Phenoxybenzamine invariably increased the tritium overflow but was generally less effective both in low and in high calcium-Krebs solution. The patterns of inhibition and enhancement of stimulation-induced tritium overflow by these two agents do not indicate an intimate relationship between calcium influx and adrenoceptor activation; nor does desensitization appear to be an adequate explanation of the relationship between frequency of stimulation and the intensity of agonist and antagonist effect in the three different calcium concentrations.5 It is concluded that the perineuronal levels of adrenergic transmitter do not establish the magnitudes of effect of exogenous adrenoceptor agonists and antagonists on tritium overflow and that a negative feedback regulation of release by transmitter is exceedingly unlikely under ordinary conditions of neurotransmission.

Animals↗
PubMed1980

The effects of (+)- and (-)-propranolol on 3H-transmitter efflux in guinea-pig atria and the presynaptic beta-adrenoceptor hypothesis.

The effects of isoprenaline and of the (+)- and (-)-isomers of propranolol on the stimulation-induced overflow of 3H-transmitter was assessed in guinea-pig atria to evaluate the hypothesis of presynaptic beta-adrenoceptors. 2 Isoprenaline (1.2 x 10(-8) M) enhanced the efflux of tritium at 2 and 5 Hz with 100 pulses and did so to a similar extent at both frequencies. 3 The (-)-isomer of propranolol (1.0 x 10(-7) M) blocked the enhancing effect of isoprenaline but did not by itself modify transmitter efflux. 4 The (+)-isomer of propranolol, almost devoid of beta-adrenoceptor blocking properties, was also effective at 1.0 x 10(-7) M in blocking the enhancement of tritium efflux by isoprenaline. 5 The (-)-isomer of propranolol (1.0 x 10(-7) M) blocked almost entirely the inotropic response to isoprenaline (3 x 10(-7) M) but even 3.0 x 10(-6) M (+)-propranolol was ineffective in antagonizing the beta-adrenoceptor-mediated contractile responses to the catecholamine. 6 It is concluded that the presynaptic site of isoprenaline action does not show the requisite stereo-specificity of beta-adrenoceptors and that a 'non-specific' action of the antagonist probably accounts for its reduction of the effect of isoprenaline.

Animals↗
PubMed1980

Inhibition by dopamine of the stimulation-induced efflux of [3H]noradrenaline in renal arteries: limitations of the unitary hypothesis of presynaptic regulation of transmitter release.

The supposition was tested that a pattern of agonist inhibition of 3H-labelled transmitter efflux which shows a decline in intensity as the frequency of stimulation rises provides major evidence for the existence of a functional autoinhibitory feedback loop mediated by released transmitter and located on adrenergic nerve terminals. For these experiments dopamine was used, as it is not released in significant quantities in the ordinary course of sympathetic nerve activation and it appears to act presynaptically in several tested tissues at a locus discrete from that acted on by noradrenaline. Dopamine (3 X 10(-7) and 3 X 10(-6) M) inhibited the stimulation-induced efflux of [3H]noradrenaline from cattle renal arteries and did so to a declining extent with increasing frequency (1-15 Hz). Known antagonists of dopamine action, pimozide and metoclopromide, antagonized this effect of dopamine but did not by themselves enhance stimulation-induced transmitter efflux or block the inhibiting effects of exogenous noradrenaline on efflux, establishing the specificity of dopamine action in renal artery and indicating the absence of an operative negative feedback loop mediated by dopamine. This interpretation was substantiated by the finding that although dopamine reduced the magnitude of contractile responses to nerve stimulation neither pimozide nor metoclopromide enhanced the amplitude of nerve-induced contractions. It thus appears that a pattern of agonist effect on transmitter efflux which manifests a diminution in intensity as the frequency of stimulation climbs is not derived from the operation of an ongoing autoinhibitory feedback system regulating transmitter release but by a yet to be established factor.

Animals↗
PubMed1980

Limitations of presynaptic adrenoceptor theory: the characteristics of the effects of noradrenaline and phenoxybenzamine on stimulation-induced efflux of [3H]noradrenaline in vas deferens.

The effects of noradrenaline and phenoxybenzamine on the stimulation-induced efflux of 3H-transmitter were examined in guinea-pig vasa deferentia to assess how they conform to the expectations of presynaptic receptor theory. The vasa were stimulated transmurally with 0.5, 1.0, 3.0 and 10.0 Hz and with two different train lengths (10 and 50 pulses), in the presence of either the agonist or the antagonist. Noradrenaline (3 X 10(-7) M) depressed the stimulation-induced overflow of tritium by about 60% at each test frequency with 10 pulses and about 30% with 50 pulses, except at 0.5 Hz. Phenoxybenzamine (3 X 10(-5) M) increased the efflux of tritium to a diminishing extent with increasing frequency, with both the 10 and 50 pulses, and the effect was not sensitive to train length. The finding that the effect of phenoxybenzamine decreased with frequency and that of noradrenaline was essentially independent of frequency suggests that these compounds do not function as agonist and antagonist at a presynaptic adrenoceptor regulating transmitter output. Further, the distinctly different profiles of effect for noradrenaline and phenoxybenzamine, with frequency and train length, raises the possibility that they do not have a common mechanism or site of action in achieving their effects.

Animals↗
PubMed1979

An examination of the negative feedback function of presynaptic adrenoceptors in a vascular tissue.

1 The hypothesis was examined that presynaptic alpha-adrenoceptors exert a negative feedback function regulating noradrenergic transmission.2 Renal artery strips from cattle, pre-incubated with [(3)H]-noradrenaline, were stimulated with 300 pulses at 5 different frequencies, spanning the physiological range, and the efflux of tritium assessed both in the absence and presence of functional presynaptic receptors.3 Considerable variation in the synaptic level of free and active noradrenaline with increasing frequency was apparent from the rates of development and the magnitudes of the mechanical responses but the overflow of tritium was constant at 1, 2, 10 and 15 Hz and slightly elevated at 5 Hz, providing no evidence for presynaptic modulation of release.4 Phenoxybenzamine (3.3 x 10(-5) M) enhanced the overflow of tritium most at the lowest frequency tested and to a similar extent at the other test frequencies, except 10 Hz where its effect was slightly reduced.5 The conditions of the present experiments appeared optimal for the operation of the negative feedback system and the failure to observe an increased effectiveness of the antagonist with increasing frequency indicates that the physiological relevance of such a system is highly questionable and suggests that it may not function at all.

Animals↗
PubMed1979

Single pulse stimulation of guinea-pig vas deferens and the presynaptic receptor hypothesis.

1 The effect of phenoxybenzamine on the efflux of [3H]-noradrenaline and the mechanical response to single pulse excitation of superfused guinea-pig vas deferens was determined to examine the validity of the currently accepted hypothesis of a presynaptic negative feedback system on adrenergic nerve terminals. 2 The adrenoceptor antagonist enhanced both the outflow of tritium and the mechanical response to single pulse stimulation. The efflux of labelled material and the responses to 4 pulses were also enhanced, as expected. 3 Blockade of neuronal and extraneuronal uptake did not by itself increase nerve-induced outflow or the mechanical response nor dated within the framework of a hypothesis that proposes that the enhancement of response and tritium efflux by phenoxybenzamine results from blockade of a feedback system whereby noradrenaline released by previous impulses inhibits its own subsequent release.

Animals↗
PubMed1979

The effects of periarterial nerve activation on coronary vessel tone in an isolated and perfused slab of beef ventricle.

The direct effects of extrinsic nerve stimulation on coronary artery tone are unclear because of the complications arising from alterations in myocardial dynamics which themselves alter flow. An isolated and perfused nonbeating slab of beef ventricle was utilized in the present experiments to eliminate secondary complications and the efects of periarterial nerve activation on coronary perfusion pressure were examined. It was found that stimulation induced vasoconstrictor responses which were enhanced by physostigmine, a cholinesterase inhibitor, and blocked by atropine. These responses were duplicated by exogenous acetylcholine both in the perfused preparation and in isolated strips of coronary artery. Although added noradrenaline gave vasodilatation, no response attributable to the release of noradrenaline from nerves was obtained. It is concluded that the coronary vasculature of the beef receives a cholinergic innervation and that its activation, especially under conditions of reduced transmitter degradation, may induce considerable coronary vessel constriction.

Acetylcholine↗
PubMed1979

Adrenergic presynaptic receptors: examination of a hypothesis in guinea pig vas deferens.

The hypothesis was examined that phenoxybenzamine enhances both the overflow of noradrenaline and the mechanical response in guinea pig vas deferens by blockade of presynaptic inhibitory receptors located on adrenergic nerve terminals which serve a negative-feedback function. Preparations were stimulated with a constant small number of pulses but at three different frequencies (1, 5, and 15 Hz) and the relative effectiveness of phenoxybenzamine in enhancing overflow assessed. According to the presynaptic receptor hypothesis inhibition of transmitter output should increase with increasing frequency due to increased activation of receptor sites by endogenously released noradrenaline. The antagonist enhanced the overflow of tritium but did so to a similar extent at all three frequencies, regardless of the length of the interval between pulses. Similarly, no evidence for a greater sensitization of the mechanical response by phenoxybenzamine at the higher frequencies was obtained. The conditions of the present experiment were considered optimal for the operation of the negative-feedback system and the results indicate that the physiological relevance of such a system is questionable.

Action Potentials↗
PubMed1979

Noradrenaline inhibition of transmitter efflux in a renal artery preparation and the presynaptic receptor theory.

The effect of noradrenaline on the stimulation-induced efflux of tritium in cattle renal arteries preincubated with [3H]noradrenaline was determined. Preparations were stimulated transmurally, with 300 shocks over a range of frequencies (1--15 Hz) in the presence and absence of noradrenaline (3 X 10(-6) M). The agonist inhibited the efflux most at 1 Hz but the extent of the inhibition did not vary with frequency between 2, 5, and 15 Hz. It is concluded that a negative feedback system, modulating neurotransmitter release, and increasingly activated by endogenously released noradrenaline as the frequency of stimulation rises, cannot account for the pattern of efflux inhibition induced by exogenous noradrenaline.

Animals↗
PubMed1978

Prostaglandin mediated relaxation of coronary artery strips under hypoxia.

Strips of beef coronary branch arteries, maintained in vitro, respond to decreased PO2 in the bathing medium with relaxations which are much attenuated by pretreatment with indomethacin or aspirin. It was determined that these hypoxia-induced relaxations are sustained until strips are returned to an environment of high PO2 and that the mechanism involved does not fatigue readily with repetitive exposure to hypoxic stress (53 mm Hg). It was also established that the reduced relaxations observed in the presence of inhibitors of prostaglandin synthesis were not enlarged with time by the development of an alternate process of relaxation independent of prostaglandins. Other experiments showed that when prostaglandin intervention is blocked with inhibitors the strips maintain a given level of tone to potassium chloride under a PO2 of 53 mm Hg, and do so without significant impairment over an observation period of one hour. Similarly, complete concentration-response curves to potassium did not differ under high (515 mm Hg) or low (53 mm Hg) PO2. This confirms that hypoxia-induced relaxation in beef coronary artery strips is a specific process, apparently mediated by a prostaglandin, rather than any consequence of the failure of the energetics of contraction.

Acetylcholine↗
PubMed1978

Mechanisms of inactivation of noradrenaline in the iris sphincter, tracheal muscle and facial artery of cattle: implications for beta-adrenoceptor-mediated responses.

1 The role of neuronal and extraneuronal pathways of amine inactivation in regulating the inhibitory actions of noradrenaline was investigated in three bovine smooth muscle preparations in which the primary adrenoceptor is of the beta-type.2 The extraneuronal uptake inhibitor, 17beta-oestradiol, sensitized the inhibitory responses to noradrenaline in the facial artery, the iris sphincter and in tracheal muscle preparations, indicating a major role for non-neuronal processes in agonist-inactivation in all three preparations. Cocaine also increased responses to noradrenaline, pointing to a role for neuronal uptake either as a terminating mechanism or as a process limiting access of exogenous agonist molecules to their site of action.3 Cocaine did not enhance significantly responses to isoprenaline, a potent beta-adrenoceptor agonist which is not taken up neuronally. Further, relaxations to metaraminol, a sympathomimetic amine which is taken up extraneuronally, but much less so than noradrenaline, were also less enhanced by 17beta-oestradiol in the three preparations tested. These findings support the specificity of action of cocaine and 17beta-oestradiol as neuronal and extraneuronal uptake inhibitors in the present experiments.4 Studies of the uptake of [(3)H]-noradrenaline revealed that 17beta-oestradiol reduced the uptake of amine in the presence of cocaine, confirming a cocaine-resistant site of action for the steroid in all three preparations.5 It is concluded that extraneuronal uptake sites are located sufficiently close to the beta-adrenoceptors to modulate the concentration and duration of action of noradrenaline at these sites of action. It is proposed that in smooth muscles which contain a preponderance of beta-receptors, extraneuronal metabolism is a key event in terminating the inhibitory effects produced.

Animals↗