Neurotransmitter release in an arterial preparation and the action of alpha-adrenoceptor antagonists.

1 This study examined the potentiating effects of competitive antagonists of the adrenergic alpha2 receptors and of phenoxybenzamine (POB) an irreversible antagonist, on the stimulation-induced efflux of [3H]-noradrenaline in arterial tissue of rabbit. This was done to determine if the lack of concordance of efflux potentiation by antagonists with the expectations of presynaptic negative feedback theory can be attributed to increasingly successful competition from rising perineuronal transmitter concentrations, when stimulation parameters are increased, in the presence of a fixed concentration of competitive antagonist. 2 Tissues were stimulated with a fixed pulse number and frequency, to rule out confounding factors, and major alterations in the concentration of released transmitter were achieved through variations in the pulse duration.

Decrements in per pulse release of norepinephrine, antagonist potentiation of release and presynaptic receptor theory.

In recent decades the theory that amine transmitter release at nerve terminals is routinely regulated through negative feedback systems sensing and responding to the instantaneous perineuronal concentration of previously liberated transmitter has assumed pre-eminence. However, observations indicate a major drop off in per pulse transmitter release when only two or four stimulation pulses are administered, reflecting the unexpectedly prompt operation of feedback inhibition. We explored this quandary in our understanding of control of transmitter release by axonal depolarization versus terminal feedback using isotopic norepinephrine and in vitro slices of rabbit hippocampus.

Rate-independent inhibition of 5-HT release by 5-HT in the somadendritic regions of raphe neurons.

The somadendritic regions of raphe neurons respond to exogenous 5-hydroxytryptamine (5-HT) with an inhibition of spontaneous rate and a consequent reduction in local transmitter release, providing evidence for the operation of negative feedback regulation of spontaneous rate. Experiments were done to determine if a release process for 5-HT might also operate in the somadendritic regions that is independent of negative feedback and rate regulation. Slices of rabbit brain containing medullary or midbrain raphe nuclei, were stimulated in vitro at predetermined frequencies and the efflux of 3H-transmitter determined.

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.

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.

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.

Autoregulation of neurotransmitter release at autonomic nerve terminals: a questionable theory.

1. The evidence for feedback regulation of neurotransmitter release by means of autoreceptors is questioned. 2.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.