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S Kalsner

Publications and source records attributed to S Kalsner.

At least 37 records · Page 2Linked to original sources
PubMed1990

Presynaptic receptors and autonomic effectors.

Agonist interactions with release processes do not validate autoreceptor operation. Instead, the data suggests that autoreceptors function as homoreceptors. Declining efficacy of agonist inhibition of transmitter release with increasing stimulation "intensity" is not assignable to competition with endogenous transmitter for a finite population of receptors. Heteroreceptor activation also reveals a pattern of declining efficacy with increasing intensity. Inhibition of stimulation-induced release by agonists also does not correlate inversely with that of antagonist effectiveness, as it should if both effects are linked to biophase levels of transmitter. Further, per pulse release of transmitter, in the absence of drugs, does not comply with expectations for autoinhibition. Experiments with tetrodotoxin, and study of the magnitudes of agonist and antagonist effects suggest that in the periphery putative autoreceptors may actually be homoreceptors, e.g., sympathetic nerve terminal receptors responsive to circulating catecholamines. In the central nervous system the paracrine secretion of transmitter may invoke homoreceptor activation rather than autoreceptors. Such activation may include, for example, the release of adrenaline from one set of fibers in the hypothalamus to act on dopaminergic or noradrenergic fibers or the release of noradrenaline from the terminals of some noradrenergic fibers in the cortex to activate alpha2 receptors on other cortical noradrenergic fibers, the latter with a somewhat different function in the same brain region. The action of antagonist drugs to enhance transmitter release may be direct on nerve membranes in particular on sodium channels, and often unrelated to feedback regulation. This possibility is discussed by me elsewhere in this volume. It is shown that yohimbine and a low concentration of veratridine have similar and nonadditive effects on transmitter release.

Animals↗
PubMed1990

The problem with autoreceptors.

There are numerous problems with the concept that antagonists enhance transmitter release by blockade of feedback. It was shown that antagonist enhancement of transmitter release does not correlate satisfactorily with the intensity of stimulation or with other indices of biophase transmitter concentration. Wide variations were shown to exist between antagonists in the amount of enhancement of release they induce. Also, antagonists enhance transmitter release or the effector response with a single stimulation pulse, a condition under which no feedback is possible. A study of agonist/antagonist relationships indicates different sites of action, and it was determined that the antagonist effect has negligible or minimal latency and that enhancement by antagonists is maximal under minimal condition of stimulation. Antagonists were shown to enhance release by a direct action, not by passive occupancy of agonist sites. Experiments were described in which acetylcholine and cold selectively antagonized antagonist but not agonist effects. Further, experiments with pulse duration shifts and with veratridine pointed to a direct action of antagonists on Na+ (also Ca++?) channel gating mechanisms, which results in a shift in the voltage dependence of activation. If antagonists, in some particular instances, enhance release by blockade of sites involved in negative feedback this is likely lost or mired in their more prominent direct actions on neurosecretion--and these must be sorted out. The acceptance of the fact that antagonists act directly to alter transmitter release (and not only as passive occupiers of presynaptic receptors), as the present study shows, both in the central nervous system and in the periphery, opens a new area for future investigation, and may be exploitable for therapeutic purposes and to gain an enriched understanding of the mechanism of neurosecretion.

Adrenergic alpha-Antagonists↗
PubMed1989

Cholinergic constriction in the general circulation and its role in coronary artery spasm.

The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of liberation of endothelium-derived relaxing factor (EDRF) from endothelial cells. Some blood vessels contain a substantial population of medial constrictor receptors for acetylcholine, and the implications of this presence for vascular control systems has been largely ignored, although it needs to be considered. A survey of the evolution of vasomotor control systems indicates that acetylcholine serves principally as an excitatory transmitter to blood vessels. Neurally mediated cholinergic constriction and not dilation is found in fish, amphibians, reptiles, and birds, with responses initiated by medial muscarinic receptors. Acetylcholine constricts many vascular preparations from these lower animals, but some vessels relax, reflecting the emergence of an EDRF responsive to acetylcholine. An examination of cholinergic responses in mammalian vessels reveals that cholinergic (neurogenic) dilation is limited to a very few vascular beds and to only a few species. Both experimental evidence and evolutionary considerations support the likelihood that cholinergic (neural) constriction operates in some vascular regions in mammals and, in particular, in the coronary circulation of some species, including humans. In fact, constriction, and not dilation, may be the dominant vascular response to activation of the cholinergic axis in most mammals, including humans. The complications and contradictions introduced by the simultaneous presence of both EDRF and a cholinergic constrictor innervation involving medial muscarinic receptors are discussed. A variety of evidence is also presented that implicates cholinergic constriction in at least some instances of coronary artery spasm and sudden death.

Acetylcholine↗
PubMed1989

Cholinergic contraction to field stimulation in coronary arteries of cattle.

Epicardial coronary artery strips of cattle hearts mounted in vitro respond to transmural stimulation with a neurogenic constriction, attributable to the endogenous release of acetylcholine. These responses were elicited with frequencies as low as 1.0 Hz and with pulse durations as low as 100 microseconds. The magnitude of the contractile response increased with increasing frequency of stimulation. Blockade of adrenergic neuronal mechanisms with guanethidine (5 x 10(-6) M) increased the size of the contractile responses at 10 Hz and they were antagonized markedly by the muscarinic antagonist atropine (4.3 or 8.6 x 10(-7) M), but not by the adrenergic antagonist phentolamine (3.6 x 10(-7) M). Contractions to field stimulation were increased greatly by the cholinesterase inhibitor physostigmine (1.1 x 10(-6) M). Blockade of neuronal sodium channels with tetrodotoxin (9.4 x 10(-7) M) reduced severely the contractions to field stimulation, as did cold storage of coronary vessels for 5 or 6 days. The contractile responses to stimulation were not inhibited significantly by antagonists of prostaglandin synthesis, or were they enhanced by denudation of the endothelium. It is concluded that cholinergic constrictor mechanisms, linked to medial muscarinic receptors, operate in the large coronary arteries, which are associated in humans with coronary spasm.

Animals↗
PubMed1989

Nonneurogenic relaxation to field stimulation in coronary arteries.

Coronary artery strips of cattle hearts in vitro respond to transmural stimulation with two potent but distinctly different responses. A neurogenic constriction, attributable to the endogenous release of acetylcholine, is predominant under conditions of minimal and moderate tone. During a high degree of spontaneous tone, and in the presence of near maximal contractions induced by 5-hydroxytryptamine, the response to field stimulation is relaxation rather than constriction. This process was studied more clearly after blockade of the cholinergic effects with atropine. The relaxation response elicited by 5 Hz stimulation for 2 min consisted of two components, one occurring during stimulation and the other promptly after its cessation. The overall relaxation was sufficient to almost obliterate a spontaneous contraction or a near-maximal contraction to 5-hydroxytryptamine. The relaxation to transmural stimulation was unaltered by tetrodotoxin, adrenergic blockade, indomethacin or 5 days cold storage of tissue. Relaxation was elicitable even by a single pulse. With a few pulses, the maximal effect was achieved at 0.5 Hz. Repeated application of three pulses, in strips with spontaneous tone, led to substantial but transient relaxations, which simulated spontaneous rhythm. Removal of the endothelium was without effect on the relaxations, and they were unaltered by inhibition of guanylate cyclase. In the presence of elevated potassium (30 mM), contractions to 5-hydroxytryptamine and those generated spontaneously did not relax to field stimulation. Inhibition of Na+-K+-ATPase with ouabain (5 microM) partially antagonized both components of the relaxation response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Presynaptic interactions between acetylcholine and adrenergic antagonists on norepinephrine release.

A previously unknown interaction between acetylcholine (ACh) and adrenergic mechanisms is described, which increases the likelihood of a physiological association between the two divisions of the autonomic nervous system. In particular, ACh had a novel effect to disengage the neuronal mechanism that is purported to regulate the release of norepinephrine from sympathetic nerves. Brief exposure to ACh (1.4 X 10(-7) M-1.4 X 10(-5) M) inhibited the stimulation-evoked release of [3H]norepinephrine from guinea pig atria and ureter and rabbit aorta but higher concentrations (8.8 X 10(-5) or 1.4 X 10(-4) M) or prolonged exposure to moderate concentrations either had no visible effect or enhanced release. ACh blocked the ability of yohimbine, the presynaptic alpha receptor antagonist, to enhance the liberation of 3H-transmitter during field stimulation at 2 and 5 Hz, and it did so in all three of the test tissues. This effect was not attributable to a direct competition between ACh and yohimbine for presynaptic alpha sites and ACh did not act like yohimbine to increase transmitter release. The antagonistic effect of ACh bore no relation to the direct effect of ACh on adrenergic neurotransmitter release and occurred regardless of whether ACh itself inhibited, enhanced or did not affect transmitter liberation. Atropine blocked the effect of ACh on 3H-transmitter efflux and restored the capacity of yohimbine to enhance transmitter release. Inhibition of neurotransmitter release by norepinephrine was partially antagonized by ACh and this antagonism was also countered by atropine. Enhancement of norepinephrine release by phenoxybenzamine was also blunted by ACh. These findings cannot be incorporated into a model of neurotransmitter regulation that interprets the enhancement of norepinephrine release by adrenergic antagonists as the result of interruption of an on-going negative feedback system. The action of yohimbine appears linked to activation of presynaptic sites and not simply to their passive occupancy. A working model is offered to account for the interaction between ACh and adrenergic antagonists.

Acetylcholine↗
PubMed1985

Is there feedback regulation of neurotransmitter release by autoreceptors?

Neurotransmitter release does not seem to be regulated by neuronal receptors mediating feedback and the mechanism of action of presynaptically active agents is still uncertain. In a recent set of papers [27, 82], experiments were described in which major modifications were made to the amount of neurotransmitter released per impulse, with all other parameters of field stimulation, such as pulse number, voltage and frequency, fully controlled. These studies done with a number of sympathetically innervated tissues give some insight into an antagonist action presynaptically which is independent of the ambient concentration of extracellular transmitter. It appears to involve, instead, the gating mechanisms which control neuronal membrane depolarization and repolarization. It was found that the effects of yohimbine and also of phenoxybenzamine on stimulation-induced efflux appeared to be essentially "all or none". That is, the absolute total release of tritiated transmitter with 100 pulses was elevated to roughly the same dpm value by the presynaptic antagonist at each of the pulse durations between 50 and 1000 microsec, in a variety of test tissues. The declining percentage effect of the antagonist on tritium efflux, as the pulse duration was enlarged between 50 and 1000 microsec, referred to earlier (Fig. 3), was due to rising values for transmitter release in the controls not matched by proportionally similar increases in the antagonist-treated tissues. Values for the amount of transmitter released during stimulation in the presence of yohimbine, at pulse lengths between 50 and 1000 microsec, were all in the range of values achieved in the absence of yohimbine with long pulse lengths (1000-2000 microsec). In other words, prolongation of the pulse duration from 50 to 1000 microsec and the exposure of tissues to a presynaptic antagonist, such as yohimbine or phenoxybenzamine, may involve a common mechanism, and the effects of these two procedures are not additive. In fact, with much prolonged pulse durations (2000-5000 microsec), the presynaptic antagonists are virtually ineffective. It is known that the release of transmitter from sympathetic nerves is directly related to the duration of the action potential. If it is prolonged, the calcium channels stay open longer leading to greater entry of calcium and to an increased release of transmitter [45, 46]. Yohimbine and phenoxybenzamine may prolong the duration of depolarization by indirect modification of the calcium gating mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Clonidine and presynaptic adrenoceptor theory.

The effects of clonidine, a presumed selective presynaptic alpha 2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. Clonidine inhibited efflux at 3 X 10(-8)M to 3 X 10(-7)M by about 30%. Yohimbine, at a concentration (10(-6)M) which caused a 3 fold increase in the release of 3H-transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. At 10(-6)M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10(-6)M), inhibited efflux by over 50%. The inhibitory effect of noradrenaline (10(-6)M) on 3H-transmitter efflux was antagonized by clonidine at 10(-6)M but not at 10(-8)M, although neither concentration of clonidine alone inhibited transmitter efflux. The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic alpha 2-adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.

Animals↗
PubMed1985

Cholinergic mechanisms in human coronary artery preparations: implications of species differences.

Acetylcholine dilates most arteries, including dog coronaries, if the endothelium is intact. The present study has shown only contraction of human coronary arteries to acetylcholine. Both strip and ring preparations of human coronary epicardial vessels, the latter done particularly to protect the intimal surface from unintentional denudation, contracted to acetylcholine at low to high concentrations (6.84 X 10(-9)-2.05 X 10(-5) M). These responses were blocked by atropine (3.45 X 10(-6) M). Acetylcholine contracted the arteries about as much as ergonovine and considerably more than noradrenaline. Field stimulation of coronary artery strips caused a vasoconstriction which was partially antagonized by atropine (3.45 X 10(-6) M). The release of [3H]noradrenaline from superfused coronary artery preparations during field stimulation was inhibited by methacholine (6.24 X 10(-6) M), a stable muscarinic analogue of acetylcholine. Dog coronary arteries relaxed to acetylcholine but not if the endothelium was intentionally denuded, in which case there was either no response at all or a weak relaxation. Coronary arteries of sheep, pig and cattle always contracted to acetylcholine, and those of monkey contracted in two out of three responsive preparations. Histological examination of the intimal surface of human coronary vascular segments confirmed the presence of an intact endothelial cell layer. Rabbit aorta gave dilator responses to acetylcholine even after being left in the animal for as long after death as the human arteries had been; they did not give dilator responses after the endothelium was rubbed off. It is concluded that cholinergic vasoconstriction of coronary arteries occurs in humans, though not in the dog, and is probably important in some cases of coronary artery spasm.

Acetylcholine↗
PubMed1985

Coronary artery reactivity in human vessels: some questions and some answers.

Spasm of a conduit coronary artery, converting it into a major resistance vessel impeding myocardial blood flow, may have severe short- or long-term effects on cardiac rhythm and systolic ejection of blood. It is now clear that human coronary arteries in vitro contract to acetylcholine but that relaxation is the only response observed in dog coronary vessels. Acetylcholine is as powerful a constrictor of human coronary arteries, in terms of tension induced, as 5-hydroxytryptamine (5-HT) or histamine and is a substantially more powerful constrictor than norepinephrine. Field stimulation of coronary artery strips caused a vasoconstriction that was partially antagonized by atropine (3.45 X 10(-6) M). An enhanced reactivity of the epicardial arteries of cardiac and older patients to several agonists was also observed and appears to provide a background against which a number of vasoactive agents might induce spasm. Coronary tissue from cardiac patients also contains stores of 5-HT and histamine, and the histamine levels are substantially increased above the values in vessels from noncardiac patients. Coronary artery spasm or contraction probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no one agent or entity is causative in all cases.

Acetylcholine↗
PubMed1984

A hypothesis to explain the presynaptic effects of adrenoceptor antagonists.

The hypothesis of negative feedback regulation of transmitter release was examined in a range of tissues obtained from three species. Tissues were transmurally stimulated with 100 pulses at 2 Hz with pulse durations from 50 microseconds to 5,000 microseconds, and the efflux of [3H]-noradrenaline determined. The stimulation-induced efflux of tritium increased with increasing pulse duration, but yohimbine, a prototypal alpha 2-antagonist had an effect which was consistently contrary to expectations for a negative feedback system. Enhancement of efflux by the antagonist, supposedly correlated directly with the extent of ongoing auto-inhibition, became smaller rather than larger as the stimulation-induced efflux rose with increases in pulse duration, with all other parameters of stimulation maintained constant. Similar findings were obtained in rat spleen with the haloalkylamine antagonist, phenoxybenzamine. It is concluded that the presynaptic effects of adrenoceptor antagonists do not involve a negative feedback function nor do they relate, in any detectable way, to the extracellular concentration of transmitter. The effects on stimulation-induced tritium efflux of yohimbine, phenoxybenzamine and enlargment of the pulse duration, in a variety of tissues, support the previously described hypothesis of a common action to enhance efflux. The antagonists increased efflux to approximately the same value between 50 and 1,000 microseconds pulse durations and that value was equivalent to that obtained in each given tissue with pulses of 1,000-2,000 microseconds in the absence of the antagonist. Tetraethylammonium, an inhibitor of stimulation-induced potassium efflux from nerves had an effect on transmitter efflux in rat spleen essentially like that of the adrenoceptor antagonists. These findings provide further support for an alternative to the hypothesis of negative feedback. Yohimbine and other presynaptic antagonists may prolong the period of potassium efflux from nerve varicosities, and by this means prolong depolarization and the associated period of transmitter release, rather than act by disrupting an ongoing system sensing and responding to fluctuations in extracellular transmitter levels.

Animals↗
PubMed1984

Limitations of presynaptic theory: no support for feedback control of autonomic effectors.

Only limited evidence, much of it repetitious, has supported the hypothesis that transmitter release is regulated by negative and positive feedback. It is shown here that the theory fails to satisfactorily predict the outcome of experimental tests that examine transmitter efflux critically, over an array of test conditions in several effector organs. Experimentally established inadequacies relate to: the observed effects of agonists and antagonists on stimulation-induced efflux; presynaptic site specificity; per pulse output of transmitter in the absence and presence of drugs; single-pulse stimulation; synaptic dimensions and efflux; lack of coincidence between enhancement of efflux and blockade of amine-induced inhibition and between effector response size and efflux alterations. Theoretical considerations about negative and positive feedback that render their routine operation unlikely are also discussed. It is concluded that, despite repeated observations that norepinephrine and some antagonists exert presynaptic actions to decrease and enhance transmitter output, the unitary hypothesis that assigns these effects to interactions with functional autoinhibitory and excitatory systems mediated by alpha- and beta-adrenergic receptors is probably not correct.

Adrenergic alpha-Agonists↗
PubMed1983

The effects of yohimbine on presynaptic and postsynaptic events during sympathetic nerve activation in cattle iris: a critique of presynaptic receptor theory.

1 The effects of presynaptic alpha-adrenoceptor blockade on both the efflux of 3H-transmitter and on the magnitude of the effector response were measured simultaneously in a smooth muscle preparation which responds to field stimulation with noradrenergic beta-receptor-mediated relaxation. 2 In the presence of atropine, the circular muscle of cattle iris relaxes in response to noradrenaline and to field stimulation at 2 Hz with 10, 20, 50 and 100 pulses. 3 Yohimbine (3 x 10(-6) M), a potent presynaptic alpha-adrenoceptor antagonist, increased the stimulation-induced efflux of tritium to about 2.0 times control values and, contrary to theory, did so to a similar extent regardless of pulse number and with apparent indifference to the synaptic concentration of transmitter, as confirmed by the varying size of the postsynaptic response. 4 In most cases, yohimbine had no significant effect on the magnitude of the relaxations to nerve stimulation. 5 It is concluded that negative feedback regulation of transmitter release, if it functions at all, and this itself seems doubtful, would not have a substantial impact on the size of the effector response.

Animals↗
PubMed1983

The effect of magnesium deficiency and excess on bovine coronary artery tone and responses to agonists.

1 The hypothesis that magnesium deficiency, linked to the magnesium content of drinking water, induces major tone increases in coronary arteries and enhances their responses to vasoactive agents to an extent sufficient to explain sudden death associated with ischaemic heart disease was examined in an in vitro preparation. 2 The spontaneous tone of cattle coronary arteries was not increased during a 30 min exposure to Mg2+-deficient Krebs until the mineral was omitted entirely from the bathing medium, and even then the observed increase was small. Only in strips maintained under extremely deficient conditions for a prolonged period, namely Mg2+ concentration of 0.2 mM and 0.0 mM for 3 h, was tone substantially greater than in controls in standard (1.2 mM) Mg2+-Krebs. 3 Responses to acetylcholine and to noradrenaline were not increased in Mg2+-free Krebs but those to potassium and to 5-hydroxytryptamine were enlarged over the lower parts of their concentration-response curves. Responses to potassium and to 5-hydroxytryptamine were also examined in Krebs containing very low concentration of Mg2+ (0.4 and 0.2 mM) and only modest increases in contraction size were detected. Increases in the Mg2+ concentration of the Krebs (to 4.8 mM) depressed responses to potassium and 5-hydroxytryptamine. 4 It is concluded that Mg2+ deficiency must be nearly complete (0.4-0.0 mM) to induce even moderate tone increases in coronary vessels, or to sensitize them to agonist responses, and that there is no reason to link marginally subnormal Mg2+ levels, occasionally reported in humans with heart disease, to marked changes in coronary dynamics.

Acetylcholine↗
PubMed1983

Yohimbine and prolongation of stimulation pulse duration alter similarly 3H-transmitter efflux in heart: an alternative to the negative feedback hypothesis.

The hypothesis of negative feedback regulation of noradrenaline release was studied in guinea-pig left atrial halves mounted in vitro. Tissues were transmurally stimulated with 30, 100 or 300 pulses at 2 Hz with pulse durations ranging from 50 mus to 2,000 mus, and the efflux of 3H-transmitter determined. The efflux of tritium increased with increasing pulse duration as was anticipated, but the effects of supposed presynaptic antagonism by yohimbine were opposite to expectations for a negative feedback system. The magnification of efflux by yohimbine, compared to untreated controls was less rather than more as stimulation-induced transmitter efflux climbed with increases in pulse duration, and with all other parameters of stimulation held constant. It is concluded that the neuronal effect of yohimbine is not linked to negative feedback or to any other system sensing the perineuronal concentration of previously released transmitter. Analysis of the effects on tritium efflux of yohimbine and of prolongation of the stimulation pulse duration, reveals a similarity in the way that they promote transmitter release. Yohimbine increased efflux to approximately the same value at all pulse durations between 50 and 1,000 mus and the value reached was equivalent to that obtained in untreated atria during stimulation with very long pulses (2,000 mus duration). It is suggested that yohimbine prolongs the outward current attributable to the efflux of potassium from axon terminals, and by this means prolongs depolarization and the period of transmitter release. Tetraethylammonium (TEA), a quaternary ion known to plug potassium efflux channels, had an effect on transmitter efflux that was, in some ways, similar to that of yohimbine but of greater magnitude. The present findings provide, for the first time, an alternative to the hypothesis of negative feedback, that might explain the presynaptic effects of adrenoceptor antagonists and possibly other compounds.

Animals↗
PubMed1983

Evidence that transmitter release in sympathetic nerves is not set by feedback via presynaptic receptors.

The possibility of negative feedback regulation of noradrenaline release was studied in the sympathetically innervated ureters of the guinea pig mounted in vitro. Tissues were transmurally stimulated with 300 pulses at 2 Hz over a range of voltages, from 10 to 60 V. It was determined that the output of transmitter increased with increasing voltage but that the effects of supposed presynaptic antagonism by yohimbine and presynaptic agonism by added noradrenaline did not fulfill the requirements of presynaptic theory governing negative feedback. It is concluded that the presynaptic effects of these drugs is neither linked to the operation of a negative feedback system nor sensitive to the perineuronal concentrations of free and active neurotransmitter.

Animals↗
PubMed1982

Evidence against the unitary hypothesis of agonist and antagonist action at presynaptic adrenoceptors.

1 The concept that presynaptic receptors regulate noradrenergic transmitter release via a system of inhibitory receptors mediating negative feedback relies on a supposed association between increases in stimulation-induced efflux of [3H]-noradrenaline by antagonists and blockade by them of the inhibitory effects of exogenous noradrenaline. 2 It was shown in guinea-pig ureter, that yohimbine (3 X 10(-7)M), a presumed selective presynaptic antagonist, increased transmitter efflux substantially at 1 Hz and 5 Hz with 100 pulses, purportedly representing antagonism of the inhibitory effect of locally released noradrenaline but did not reduce the inhibitory effect of exogenous noradrenaline (1.8 X 10(-6)M or 1.8 X 10(-7)M) except in one case. 3 Additionally, the inhibitory effect of oxymetazoline (1.0 X 10(-7)M or 1.0 X 10(-8)M) on stimulation-induced efflux was in no way antagonized by yohimbine (3 X 10(-7)M). 4 It is concluded that the increased efflux of [3H]-noradrenaline produced by antagonists and the decreased efflux produced by exogenous agonists may represent actions at different loci and that the hypothesis of presynaptic feedback regulatory sites is still not substantiated.

Animals↗