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S Kalsner

Publications and source records attributed to S Kalsner.

At least 19 recordsLinked to original sources
PubMed2001

Rate-independent inhibition by norepinephrine of 5-HT release from the somadendritic region of serotonergic neurons.

Endogenous adrenergic drive regulates the firing rate of serotonergic neurons. However, advocates of feedback theory assert that 5-hydroxytryptamine (5-HT) released in the somatodendritic region of raphe neurons regulates both rate and release of 5-HT. Experiments were done to determine if the somatodendritic region might have receptors for norepinephrine that inhibit release of 5-HT independently of rate, as this would allow for discrete effects of norepinephrine on rate and release, even in the presence of functional feedback by 5-HT. The release of 5-HT at fixed frequencies of stimulation was substantially reduced when norepinephrine (1 and 3 x 10(-7) M) was present. Norepinephrine also inhibited the release of 3H-5-HT with delivery of a single stimulation pulse ruling out a remote action of the catecholamine. The alpha(1) antagonist prazosin did not modify the profile of norepinephrine inhibition. Further, the alpha(1) agonist phenylephrine had no effect on 3H-5-HT efflux. The alpha(2) antagonist yohimbine antagonized almost entirely the inhibition by norepinephrine at 1 Hz, and reduced it substantially at 3 Hz. Blockade of 5-HT(1) receptor sites with methiothepin did not reduce the inhibitory effect of norepinephrine on 3H-5-HT efflux. It is proposed that release of endogenous norepinephrine at synapses with 5-HT neurons could activate 5-HT neuron firing rate through alpha(1) receptors located at the soma and simultaneously short-circuit ongoing 5-HT feedback inhibition by inhibiting release through adrenergic alpha two receptors likely located at the dendrites.

Adrenergic alpha-Agonists↗
PubMed2001

Regarding the unitary theory of agonist and antagonist action at presynaptic adrenoceptors.

1. The linkage between potentiation of field stimulation-induced noradrenaline release and blockade of the presynaptic inhibitory effect of exogenous noradrenaline by a presynaptic antagonist was examined in superfused rabbit aorta preparations. 2. Rauwolscine clearly potentiated the release of noradrenaline in response to 100 pulses at 2 Hz but reduced the capacity of noradrenaline to inhibit transmitter release to a questionable extent, and then only when comparisons were made with untreated, rather then to rauwolscine-treated, controls. 3. Aortic preparations exposed for 60 min to rauwolscine followed by superfusion with antagonist-free Krebs for 60 min retained the potentiation of stimulation-induced transmitter release but no antagonism of the noradrenaline-induced inhibition could be detected at either of two noradrenaline concentrations when comparisons were made with rauwolscine treated controls. 4. Comparisons of the inhibitory effect of exogenous noradrenaline (1.8 x 10-6 M) on transmitter efflux in the presence and absence of rauwolscine pretreatment revealed that the antagonist enhanced rather than antagonized the presynaptic inhibition by noradrenaline. 5 It is concluded that the unitary hypothesis that asserts that antagonist enhancement of transmitter release and its blockade of noradrenaline induced inhibition are manifestations of a unitary event are not supportable.

Adrenergic Agonists↗
PubMed2001

Autoreceptors do not regulate routinely neurotransmitter release: focus on adrenergic systems.

The theory that neurotransmitter release is regulated locally at the individual terminals of neurons has achieved a rapid and seemingly secure status in our understanding of neuronal function both in the periphery and in the central nervous system. This concept of negative feedback control through the monitoring of the perineuronal concentration of previously released transmitter has been extended to a multiplicity of transmitters and utilized to explain the mechanisms of action of diverse classes of drugs, ranging from antihypertensives to antidepressants. It is my view that negative feedback by terminal and by somadendritic receptors cannot account for the existing body of experimental work. Analyses of the profiles of action of agonists and antagonists, and of the per pulse release of transmitter in the absence of drugs in a variety if peripheral organ systems, as well as in superfused brain slices, demonstrates the need for alternate interpretations of the available data. Evidence is provided that the actions of agonists to inhibit transmitter release and that of antagonists to enhance release occur at different cellular loci and that the purported unitary action of these two classes that is so central to the validity of presynaptic theory is unsupportable.

Adrenergic alpha-Antagonists↗
PubMed2000

The question of feedback at the somadendritic region and antidepressant drug action.

Presynaptic receptor theory has been expanded to encompass the regulation of the firing rate of serotonergic neurons through negative feedback mediated by the somadendritic release of transmitter. This has encouraged hypotheses as to the mechanisms of action of several classes of antidepressants and anxiolytics. One conspicuous example is the attribution of the clinical efficacy of 5-HT uptake inhibitors, such as fluoxetine and paroxetine, to desensitization of somadendritic 5-HT autoreceptors. An examination of the available evidence, mainly observations made with agonists, antagonists, monoamine oxidase inhibitors and uptake blockers, taken along with the theoretical expectations for a negative feedback loop, and the operational characteristics of inactivation pathways, indicates that negative feedback does not function at somadendritic sites to set firing rate or transmitter density, and suggests that the process may not function at all physiologically. The attribution of the effectiveness of neuroactive drugs to desensitization of raphe 5-HT inhibitory receptors, or to other interactions with feedback, is highly speculative and unlikely.

Animals↗
PubMed1997

Vasodilator action of calcium antagonists in coronary arteries in vitro.

Calcium antagonists have routinely been assumed to inhibit the contractions of arterial smooth muscle through block of membrane channels. The effects of nifedipine and diltiazem on contractions were examined in in vitro preparations of cattle coronary artery, one of the key therapeutic targets of calcium antagonists, to determine if alternate mechanisms of action are involved. Contractions elicited in calcium-free Krebs, in the presence of U 46619, to potassium channel inhibitors (4-aminopyridine and tetraethylammonium) and to a Na(+)-K(+)-ATPase inhibitor (ouabain), were antagonized by low concentrations of nifedipine (3 x 10(-9)-3 x 10(-8) M) and by diltiazem (3 x 10(-8) and 1 x 10(-7) M). Contractions produced in calcium-free Krebs to KCl (50 mM) were antagonized similarly by calcium antagonists. Contractions to depolarizing agents in calcium-free Krebs were antagonized at lower concentrations of nifedipine than comparably elicited responses in Krebs containing 2.3 mM calcium. In addition, higher concentrations of nifedipine were required to antagonize contractions to extracellular calcium, produced in preparations maintained in calcium-free Krebs in the presence of KCl (50 mM), than were needed to block contractions to KCl or to potassium channel inhibitors elicited in calcium-free Krebs. Pretreatment of preparations in calcium-free Krebs with ryanodine (30 microM) did not reduce the nifedipine-sensitive contractions elicited in calcium-free Krebs. It is concluded that at least some of the therapeutic effects of calcium antagonists on arterial tone may be the consequence of antagonism at vascular smooth muscle cell site(s) at which calcium is released or interacts, rather than of block of calcium entry through membrane L channels.

Animals↗
PubMed1995

Coronary artery spasm. Multiple causes and multiple roles in heart disease.

Myocardial infarction and sudden cardiac death may be initiated by a sudden intense localized contraction of coronary artery smooth muscle. When this event occurs around a vulnerable eccentric lipid-filled plaque, rupture and extrusion of plaque contents and exposure of collagen occur. This may sometimes be a silent and self-limiting event; other times it leads to thrombus formation. A second wave of spasm due to accumulated platelet and inflammatory mediators may compound the contractile consequences of the initiating event. Spasm involves intrinsic smooth muscle cell electrical mechanisms, hyper-responsive cells, and multiple agonists that synergize their actions, and the involvement of each mechanism varies at different times in the sequence of vascular occlusion. Study of spasm requires vascular systems that adequately model coronary artery responses of the ageing human heart. As previously emphasized, tissues obtained postmortem, and when possible from recipients during heart transplants, must be integral to theory building, alongside animal models, despite the experimental limitations such tissues impose. A multidisciplinary approach, at all levels of vascular physiology and pharmacology, will be necessary to understand coronary motor activity and human heart disease.

Animals↗
PubMed1995

Hypoxic relaxation in functionally intact cattle coronary artery segments involves K+ ATP channels.

Functionally intact coronary artery segments studied in vitro responded to 15 min of hypoxia with relaxations of preexisting contractions. The hypoxic relaxations were obtained in preparations routinely denuded of endothelium and were unaffected by tetrodotoxin, by indomethacin or by the blockers of calcium-dependent potassium channels, apamin and charybdotoxin. Relaxations from contractions to the calcium channel opener Bay K 8644 and to spontaneous tone were attenuated most by hypoxia, and those to carbamylcholine and 5-hydroxytryptamine were inhibited to an intermediate extent. Contractions to the thromboxane A2 analog U 46619, dependent largely on intracellular calcium, were the least reduced during 15 min of hypoxia. Pretreatment of contracted preparations with glibenclamide, the potent antagonist of ATP-dependent potassium channels, before exposure to 95% N2/5% CO2 significantly attenuated, but did not eliminate, hypoxic relaxations. Hypoxic relaxations from contractions to the calcium channel opener Bay K 8644 and to spontaneous tone were antagonized most by glibenclamide, and those to U 46619 were reduced the least. In the presence of the calcium channel antagonist nifedipine, tissues contracted with carbamylcholine or 5-hydroxytryptamine relaxed during hypoxia, but these relaxations were insensitive to glibenclamide. Contractions of cattle radial artery and rabbit aorta were variably reduced during hypoxia but were insensitive to glibenclamide. We conclude that K+ ATP channels participate in hypoxia-induced coronary artery smooth muscle relaxation and may do so particularly with contractions that utilize principally extracellular calcium.

Adenosine↗
PubMed1994

Propranolol antagonizes coronary artery relaxation by a potassium channel opener.

Coronary artery preparations from cattle hearts responded with stable contractions to the thromboxane A2 analogue, U 46619. These contractions were progressively reduced by increasing concentrations of the prototypical potassium channel opener pinacidil (3.8 x 10(-8) to 1.1 x 10(-4) M). Pinacidil-induced relaxations were antagonized significantly by d,l-propranolol (1.2 x 10(-6) to 1.2 x 10(-5) M). Forskolin-induced relaxations of coronary preparations were also antagonized by d,l-propranolol, but those to nitroprusside were not. d-Propranolol also antagonized relaxations to pinacidil but only when used in higher concentrations than the I-isomer. Nadolol and metoprolol, two other beta receptor antagonists with differing profiles of action, also antagonized to some extent the vasodilator action of pinacidil. The known potassium channel antagonist, glibenclamide, shifted the concentration-relaxation curve for pinacidil to the right, but d,l-propranolol produced an additional antagonistic effect in the presence of glibenclamide. Relaxations of contracted tracheal ring preparations of guinea pig by pinacidil, however, were not antagonized by d,l-propranolol, suggesting specificity for vascular tissue. Isoproterenol increased significantly the cyclic AMP levels in coronary tissue, but pinacidil had no such effect, ruling out an adrenergic component to pinacidil action. Pinacidil increased the efflux of 86Rb in isolated coronary preparations, and this effect was blunted by propranolol. It is concluded that beta receptor antagonists inhibit relaxations to a potassium channel opener by a mechanism independent of beta adrenergic receptors and that this effect may have therapeutic implications.

Adrenergic beta-Agonists↗
PubMed1994

Non-neurogenic contractions in isolated coronary arteries by brief electrical pulses.

OBJECTIVE: The aim was to describe a novel form of non-neurogenic coronary artery contraction. METHODS: Superfused cattle coronary artery preparations in vitro were placed between platinum electrodes and stimulated. RESULTS: The preparations responded to exceedingly brief transmural stimulation (a single ten thousandth of a second pulse) with long lasting [150(SEM 18.5) s] contractions. These previously undescribed contractions were not reduced by neural blockade nor did they involve free radicals, prostaglandins, or the endothelium. In contrast to the rapid loss of responses to KCl in zero calcium Krebs solution, responses to stimulation were only progressively diminished over many minutes, suggesting involvement of internal calcium stores. The L channel calcium antagonists nifedipine and diltiazem markedly reduced contractions to KCl but did not materially alter those to 1, 5, or 10 stimulation pulses, nor did the T channel antagonist tetramethrin, further supporting the involvement of stored calcium in contractions to stimulation. Evidence was obtained that neither Na+/K(+)-ATPase nor the Na+/Ca+ exchanger are involved in the contractions to stimulation. Ryanodine in zero calcium Krebs solution potentiated contractions to stimulation with 10 pulses and also to endothelin, but depressed contractions to U 46619. CONCLUSIONS: Stimulation at excitation parameters well below those associated with neurotransmitter release activates a highly effective contraction sequence that may use a ryanodine insensitive pool of bound calcium. This novel process may have physiological and pathophysiological relevance and provides a means of activating contraction in a coronary artery and studying its time course and contributory components, without the complicating participation of an agonist drug.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Coronary artery spasm and no spasmogens?

Traditionally coronary artery spasm, which is implicated in the pathogenesis of angina, myocardial infarction and sudden death, has been perceived as involving either a powerful spasmogen or larger quantities of a less potent stimulant. The present essay proposes that spasm may occur in the complete absence of any inciting chemical or spasmogen. Sudden intense coronary artery constriction may reflect an abnormality in an intrinsic system of tone regulation involving pacemaker cell discharge, intercellular conduction through gap junctions to adjacent cells, and the cycling of extracellular and bound calcium. Defects in spontaneous tone generation and recovery, may be primary factors in the causation of clinically occurring coronary artery spasm and its sequela.

Aging↗
PubMed1993

Cocaine sensitization of coronary artery contractions: mechanism of drug-induced spasm.

Illicit cocaine use has been associated with a high incidence of cardiovascular complications including coronary spasm, arrhythmias, myocardial infarction and sudden death. Adverse effects of cocaine have been attributed routinely to the consequences of increased concentrations of the adrenergic transmitter at its sites of action including the coronary vasculature. The present study examined non-neurogenic postsynaptic sites of cocaine action in cattle coronary arteries that could account for its clinical profile. It was found that cocaine (3.3 x 10(-5) M) greatly increased responses to potassium chloride (by 98.4 +/- 13.8%) that are totally dependent on extracellular calcium. However, contractions to a thromboxane A2 analog, which are much less dependent on extracellular calcium influx, were not increased significantly by cocaine. Cocaine (3.3 x 10(-5) M) more than doubled the magnitude of non-neurogenic responses to field stimulation, but these responses were not enhanced in the presence of a calcium channel antagonist. Spontaneously generated tone was magnified significantly by cocaine (3.3 x 10(-5) M) (by 127.5 +/- 45.2%), and this enhancement also was selectively antagonized by nifedipine. Subthreshold concentrations of the calcium channel opener, Bay K 8644, also were increased greatly by cocaine, and this magnification was antagonized by nifedipine. Cocaine did not magnify responses to norepinephrine that are inhibitory in cattle coronary arteries, and desmethylimipramine, a potent inhibitor of catecholamine uptake, had no sensitizing effects on responses to potassium chloride, norepinephrine or field stimulation. It is concluded that cocaine has a potent action on the calcium L channels, magnifying the effects of stimuli that make use of these channels in contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Adrenergic presynaptic antagonists and their mechanism of action in smooth muscle.

The effects of veratridine and of yohimbine on the efflux of norepinephrine from guinea pig ureters was examined to gain insight into presynaptic receptor function. Ureter segments were stimulated at 1 and 2 Hz with 100 pulses in the absence and presence of yohimbine, veratridine, or the combination. Veratridine (4.5 or 6 x 10(-7) M) increased transmitter release. The enhancements of release by the adrenergic antagonist yohimbine and by veratridine were not additive, suggesting a common site of action. The lack of additivity was not linked to a ceiling effect since tetraethylammonium, which increases release by block of potassium channels, had an additive effect with veratridine. Protection experiments, done with veratridine as the protecting agent against phenoxybenzamine blockade, supported the interpretation that adrenergic antagonists and veratridine act at a common locus to enhance transmitter efflux. Although veratridine enhanced transmitter efflux like yohimbine, it only slightly reduced the inhibitory capacity of norepinephrine, confirming the likelihood of discrete sites of agonist and antagonist action. Veratridine and alpha-receptor antagonists might combine presynaptically with sites on the sodium channels of sympathetic nerve terminals to alter channel gating, namely the shifting of sodium channel activation to more negative potentials, and in this way increase the liberation of norepinephrine.

Animals↗
PubMed1992

Activation of a relaxation cascade in isolated coronary arteries by brief electrical pulses.

Superfused cattle coronary artery rings contracted with endothelin or with a thromboxane A2 mimetic respond to transmural stimulation with relaxation. These relaxations are not reduced by denudation of the endothelium, or by combined pretreatment with quanethidine, atropine and propranolol, nor do they involve free radicals. Stimulation at 0.5 Hz with an increasing number of pulses, from 1 to 50, each of 500 microseconds in duration, produced progressively greater and more prolonged relaxations. Human coronary arteries, denuded and pretreated with guanethidine or tetrodotoxin, also showed prominent relaxations of both spontaneous and induced contractions with minimal transmural stimulation at 0.5 Hz. The delivery of 10 pulses briefly depressed near-maximal contractions to combinations of two or even three spasmogens in the cattle preparations. Reduction of extracellular potassium to near zero did not reduce stimulation-induced relaxations, but decreases in extracellular calcium did. The participation of ATP-sensitive potassium channels in stimulation-induced relaxations was unlikely because glibencamide did not reduce them, although it antagonized the relaxation produced by the potassium channel opener pinacidil. Tetraethylammonium blocked the relaxations to stimulation, indicating the involvement of calcium-dependent potassium channels, but block of small to moderate conductance SK channels with apamin was ineffective in antagonizing relaxations, making it likely that activation of large conductance SK channels or maxi-K channels was involved. Blockade of stimulation-induced relaxation in low sodium Krebs', but not by vanadate (1 mM), indicated the likely involvement of the Na+/Ca++ exchanger rather than a Ca(++)-ATPase as the calcium extrusion component of the relaxation process. Restoration of prestimulation tone required calcium influx through nifedipine-sensitive channels. It is concluded that a highly effective relaxation cascade is initiated by the delivery of one to five 0.5-msec pulses at 0.5 Hz, whose effects long outlast the stimulation parameters. The significance of this finding for coronary pathophysiology and as a means of selectively activating a relaxation cascade in an intact coronary artery segment is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗