Local modulation of adrenergic neuroeffector interaction in the blood vessel well.
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Adenosine Triphosphate↗
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Development of neuroeffector mechanisms in the carotid artery of the fetal lamb.
A survey has been made of mechanisms associated with vascular adrenergic neuroeffector transmission in the lamb fetuses between 53 days and term gestation. The common carotid artery was isolated for studies of enzymic activities, uptake of norepinephrine (NE) and reactivity to vasoactive agents. The extra-neuronal NE uptake, monoamine oxidase and catechol-O-methyltransferase activities were present in the carotid artery of the youngest fetuses. The contractile responses to NE and serotonin and neuronal NE uptake preceded the response to adrenergic nerve stimulation during fetal growth. These results suggest that the mechanisms for adrenergic transmitter inactivation, transmitter action on vascular smooth muscle cells, and neuronal transmitter delivery develop in that sequence.
Animals↗
Neuroeffector function of isolated portal vein from spontaneously hypertensive and wistar-kyoto rats: dependence on external calcium concentration.
The calcium dependence of the vascular neuroeffector function has been studied in the portal vein of spontaneously hypertensive Okamoto rats (SHR) and Wistar-Kyoto rats (WKY). The noradrenaline (NA) sensitivity of veins of both species, expressed in terms of ED50, was decreased to the same extent in relation to the reduction in Ca2+ ion concentration below 2.5 mM. The responses to individual NA concentrations at subnormal Ca2+ concentrations were better maintained, however, in portal veins from SHR than from WKY, indicating that the excitation contraction coupling mechanism is less dependent on external Ca2+ concentrations in the portal vein from SHR than from WKY. In both strains of rats the spontaneous myogenic activity of the vessel was depressed in low Ca2+ concentrations to a greater extent than responses to nerve stimulation, which, in turn, were more reduced than the excitatory responses to exogenous NA or acetylcholine (ACh). Transmitter release (fractional overflow of 3H-NA/impulse) was less dependent on Ca2+ concentrations than the contractile nerve stimulation response. The persistence of all responses in reduced Ca2+ concentrations was significantly greater in the portal vein of SHR. It is concluded that the phasic, spontaneously active smooth muscle of the rat portal vein is highly dependent on the external calcium concentration and that various induced responses persist to a varying degree in reduced Ca2+ concentrations. It is suggested that this is due to interference with electromechanical coupling as well as myogenic spread of activation. Induced responses of the portal vein from SHR are, in general, less affected by decreased Ca2+ concentrations than the WKY portal vein, indicating an altered vascular smooth muscle excitation-contraction coupling mechanism in spontaneous hypertension. Possibly an increased efficiency of the coupling mechanism may contribute to augment vascular responses in the development of hypertension and promote structural vascular changes.
Animals↗
Local control of blood pressure by purines.
Dual control of local blood flow by purines is described: adenosine 5'-triphosphate (ATP) released as a cotransmitter with noradrenaline from perivascular sympathetic nerves acts on P2X-purinoceptors on smooth muscle cells to produce vasoconstriction; ATP released from endothelial cells during hypoxia (and ADP released from aggregating platelets) acts on P2Y-purinoceptors on endothelial cells which results in production of endothelium-derived relaxing factor and subsequent vasodilatation. It is suggested that the endothelial-mediated vasodilatation is a pathophysiological mechanism to protect the host tissue (e.g. brain or heart) from damage produced by hypoxia following ischaemia. The ATP released from the endothelial cells is rapidly broken down to adenosine which augments this protective mechanism by acting directly on P1-purinoceptors on vascular smooth muscle to produce a longer lasting component of vasodilatation and on perivascular sympathetic nerve terminals to inhibit release of excitatory neurotransmitters. The possibility that impairment of normal endothelial-mediated responses in atherosclerosis and hypertension can lead to local vasospasm is considered.
Animals↗
Quantitative ultrastructural measurement of innervation density, neurotransmitter vesicles and neuromuscular cleft width in the rabbit central ear artery and its main side branch.
The purpose of this study was to provide anatomical information about innervation density and the neuromuscular relationship in the rabbit central ear artery and its main side branch, so that, when combined with functional observations, a better understanding of neuroeffector mechanisms in these vessels could be established. Electron-microscopic methods were used to measure number and size of axon varicosities, their content of vesicles, the sizes of dense cores in the small vesicles and the neuromuscular cleft width. For each 100 micron of the outer circumference of the tunica media, the central ear artery contained 4 varicosities with a total cross-sectional area of 2.2 micron 2, and the main side branch about 9 varicosities with a total cross-sectional area of 4.1 micron 2. On the average, the varicosities of the central and branch arteries contained 93.6 and 95.1 small, and 2.3 and 1.9 large vesicles, respectively, per micron. The diameter of dense cores in the small vesicles was significantly smaller in the main side branch (18.3 vs. 16.7 nm). In the central ear artery, the mean cleft width was 5.27 micron, and 3% of all clefts were narrower than 1 micron. In the main side branch, the mean cleft width was 2.77 micron, and 22% were narrower than 1 micron. Thus, the innervation of the main side branch is closer to the vascular smooth muscle cells and is characterized by a larger number of smaller varicosities per unit circumference. Although vesicle density is the same as in the central artery, the dense cores are smaller in diameter. These data do not provide an explanation as to why the response of the main side branch to nerve stimulation in vitro is proportionally weaker. The reasons for this apparent contradiction are not clear, but we offer some possible explanations.
Adrenergic Fibers↗
Mechanism of action of indirectly acting sympathomimetic amines.
The mode of action of indirectly acting sympathomimetic amines was analysed in the rat vas deferens (preloaded with 3H-(-)-noradrenaline). When monoamine oxidase (MAO), catechol-O-methyltransferase and vesicular uptake were inhibited (i.e., when the concentration of 3H-noradrenaline in the axoplasm was high), all substrates of neuronal uptake induced a carrier-mediated outward transport of 3H-noradrenaline, in strict dependence on the Km for neuronal uptake of the substrate. However, when MAO and vesicular uptake were not inhibited, some of the substrates of neuronal uptake were better releasers of 3H-noradrenaline than others; obviously, when the axoplasmic 3H-noradrenaline concentration is very low (intact vesicular uptake, intact MAO), a 'mobilization' of vesicular 3H-noradrenaline is a prerequisite for substantial release.
Animals↗
Effect of endogenous tachykinins on neuro-effector transmission of vagal nerve in guinea-pig tracheal tissue.
To elucidate the effect of endogenous tachykinins on neuro-effector transmission of vagal nerves, we performed in vitro experiments using guinea-pig tracheal smooth muscle. The subthreshold dose (the highest dose which did not induce any smooth muscle contraction) of capsaicin (10(-8) to 10(-7) M) increased the amplitudes of contractions evoked by electrical field stimulation (EFS) significantly, but not those by acetylcholine (ACh). The inhibitor of neutral endopeptidase, phosphoramidon (10(-7) to 10(-6) M), increased the contractions evoked by EFS significantly. The inhibitor of cholinesterase, physostigmine (10(-6) to 10(-5) M), induced smooth muscle contractions, but such contractions were inhibited by atropine, suggesting the spontaneous release of ACh from the vagal nerve terminals. The subthreshold dose of substance P or capsaicin increased the contractions evoked by physostigmine. These results indicated that endogenous tachykinins increase the spontaneous ACh release as well as the ACh release in response to vagal stimulation from the nerve terminals. Furthermore, it is suggested that the excitatory effects of the tachykinins on the vagal neuro-effector transmission may be modulated by neutral endopeptidase in the guinea pig.
Acetylcholine↗
Effects of procaterol, a beta-2-adrenoceptor stimulant, on neuroeffector transmission in human bronchial tissue.
It has been reported that low concentrations of noradrenaline or isoprenaline reduce the resting tension of the smooth muscle cells and suppress acetylcholine release from the vagal nerve terminals through activation of beta 2-adrenoceptors. Procaterol, beta 2-adrenoceptor stimulant, has a high potency and selectivity for airway smooth muscle tissues. However, there is little documentation on the prejunctional actions of this chemical in airway smooth muscle, especially in man. In the present study, the effects of procaterol on excitatory neuroeffector transmission in the human bronchus were investigated. Procaterol (10(-10) to 10(-7) M) dose dependently reduced the amplitude of the contractions evoked by electrical field stimulation in the presence of indomethacin (10(-5) M), FPL-55712 (10(-6) M), and guanethidine (10(-6) M). By contrast, procaterol (10(-10) to 10(-9) M) had no effect on the postjunctional response of smooth muscle cells to exogenously applied acetylcholine. Pretreatment with ICI-118551 (10(-7) M), a beta 2-adrenoceptor-blocking agent, reduced the inhibitory action of procaterol on the amplitude of twitch contractions evoked by field stimulations in the human bronchus. These results indicate that procaterol at low concentrations has a prejunctional action, inhibiting the excitatory neuroeffector transmission and presumably suppressing transmitter release from the vagal nerve terminals through beta 2-adrenoceptors in the human bronchial tissue. The prejunctional action of procaterol explains partly its potent bronchodilator effects in clinical use.
Acetylcholine↗
Age-related changes in beta-adrenergic neuroeffector systems in the human heart.
BACKGROUND: Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. METHODS AND RESULTS: Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. CONCLUSIONS: There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.
Adenylyl Cyclases↗
Arterial neuroeffector responses in early and mature spontaneously hypertensive rats.
Intramural sympathetic neuroeffector responses and presynaptic regulation of neurotransmission by amine uptake and alpha 2-adrenergic receptors were examined in young (5-week-old) and mature (12-week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar-Kyoto (WKY) control rats. Electrical field stimulation (20 V, 0.2-msec pulse width, 3-second pulse train each minute, 5-100 Hz) elicited contractile responses from isolated mesenteric arteries mounted in a myograph. There was a significant difference between the sensitivity of arteries to electrical field stimulation in the two age groups, with arteries from 12-week-old rats being more sensitive than arteries from 5-week-old animals. Also, there was a significant age-strain interaction: the sensitivity of arteries from SHR to electrical field stimulation increased dramatically with age compared with that of WKY rat arteries. Cocaine significantly increased the sensitivity to electrical field stimulation after inhibition of presynaptic alpha 2-adrenergic receptors, and had a significantly greater effect in arteries from 5-week-old SHR compared with WKY controls. This would reflect an overactive neuronal amine uptake mechanism in young SHR. At 12 weeks there was no significant interstrain difference in the effect of cocaine. Yohimbine increased the sensitivity to electrical field stimulation both before and after inhibition of neuronal amine uptake, but there was no difference in its effect with age or strain. Therefore, although sensitivity to sympathetic nerve stimulation varies with age in the SHR, there is no evidence that this can be ascribed to alpha 2-adrenergic receptor function.
Animals↗
Beta-adrenergic neuroeffector mechanisms in cardiac hypertrophy of renin transgenic rats.
We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2d gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of beta 1-adrenergic receptors, an increase of inhibitory G protein alpha-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein alpha-subunits and beta 2-adrenergic receptors was unchanged. Desensitization of adenylyl cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages.
Adenylyl Cyclases↗
Decreased release of norepinephrine in the isolated kidney of the adult spontaneously hypertensive rat.
Renal resistance vessels of the mature spontaneously hypertensive rat (SHR) exhibit an increased reactivity to exogenous norepinephrine, but a normal response to renal nerve stimulation. This difference could be due either to depression of the exocytotic process or to accelerated disposition of the released transmitter. We compared the overflow of norepinephrine in isolated perfused kidneys from adult SHR and normotensive rats. After previous incubation with 3H-norepinephrine, renal nerve stimulation caused smaller increases in the overflow of intact tritiated transmitter and its metabolites in kidneys form SHR than in those from normotensive controls. A similar difference was found when the amounts of endogenous norepinephrine were measured radioenzymatically. The tissue content of norepinephrine was comparable in kidneys from both hypertensive and normotensive animals. The uptake of 3H-norepinephrine was comparable in kidneys from SHR and normotensive controls; cocaine caused a comparable depression of the 3H-uptake in which then explains the normal vasoconstrictor response to renal nerve stimulation despite the increased responsiveness of the vascular smooth muscle cells to norepinephrine.
Adrenergic Fibers↗
Hedqvist P, Stjärne L,+STJARNE L: Effects of hypothermia on norepinephrine release and effector response in isolated perfused cat spleen.
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Animals↗
Phasic effects of repetitive vagal stimulation on atrial contraction.
The vagus nerves of anesthetized dogs were stimulated once each cardiac cycle with a brief burst of pulses, and the timing of the stimulus bursts was changed by a fixed increment on successive cardiac cycles. The effects of such vagal stimulation on atrial contraction depended on the number of pulses per stimulus burst, on the interval between pulses within the burst, and on the timing of the stimulus bursts within the cardiac cycle. The vagal stimulus bursts had the least negative inotropic effect when they were given less than 100 msec before the next atrial depolarization, and they were most effective when given about 330 msec before the next atrial depolarization. This dependence of the inotropic response on the timing of the vagal activity within the cardiac cycle indicates that the following conditions must prevail with respect to the vagal innervation of the atrium: (1) the acetylcholine released from the vagal nerve endings is hydrolyzed at a critically rapid rate in the atrial tissues, (2) the neurally released acetylcholine must exert its major influence on atrial contraction during some preferential fraction of the cardiac cycle (presumably, during depolarization), and (3) after a vagal stimulus of a given strength, the concentration of acetylcholine in the region of the myocardial cells will attain its maximum value during this critical phase of the cardiac cycle when the vagal stimuli are given at the optimal time in the cardiac cycle.
Acetylcholine↗
Vascular adrenergic neuroeffector function does not decline in aged rats.
To investigate adrenergic control of blood vessels during aging, rats aged 6, 12, 20, and 27 months were studied using in vitro techniques. Accumulation of [3H]norepinephrine, one index of adrenergic nerve density, did not alter with age in the femoral or renal arteries or renal vein. In the femoral vein [3H]norepinephrine accumulation was greater at 6 and 27 months of age. Norepinephrine sensitivity was determined in both an innervated vessel, the femoral artery, and a non-innervated vessel, the carotid artery. In both cases, sensitivity to norepinephrine did not alter with age. In the renal and femoral arteries and veins, no significant changes in maximum responses to norepinephrine (10(-5) M), potassium chloride, or transmural nerve stimulation were seen with advancing age. Furthermore, frequency response curves (2-16 Hz, 200 pulses) did not differ with age for any of the four vessels studied, with one exception. The response to stimulation at 4 Hz of the femoral vein from 6-month-old rats was significantly larger than responses at other ages. During nerve stimulation, the renal vein exhibited rapid contractions superimposed upon the maintained contractile response. This type of rapid contraction occurred only rarely (1 out of 5) in the renal vein from 27-month-old rats. In summary, neither adrenergic nerve density as reflected by [3H]norepinephrine accumulation nor norepinephrine sensitivity decline with age. As the net effect of various components, the ability of vascular smooth muscle to respond to adrenergic nerve stimulation is also maintained during advancing age.
Aging↗
Prejunctional control of excitatory neuroeffector transmission by prostaglandins in the airway smooth muscle tissue.
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Acetylcholine↗
Intraepithelial vagal sensory nerve terminals in rat pulmonary neuroepithelial bodies express P2X(3) receptors.
The neurotransmitters/modulators involved in the interaction between pulmonary neuroepithelial bodies (NEBs) and the vagal sensory component of their innervation have not yet been elucidated. Because P2X(3) purinoreceptors are known to be strongly expressed in peripheral sensory neurons, the aim of the present study was to examine the localization of nerve endings expressing P2X(3) purinoreceptors in the rat lung in general and those contacting pulmonary NEBs in particular. Most striking were intraepithelial arborizations of P2X(3) purinoceptor-immunoreactive (IR) nerve terminals, which in all cases appeared to ramify between calcitonin gene-related peptide (CGRP)- or calbindin D28k (CB)-labeled NEB cells. However, not all NEBs received nerve endings expressing P2X(3) receptors. Using CGRP and CB staining as markers for two different sensory components of the innervation of NEBs, it was revealed that P2X(3) receptor and CB immunoreactivity were colocalized, whereas CGRP-IR fibers clearly formed a different population. The disappearance of characteristic P2X(3) receptor-positive nerve fibers in contact with NEBs after infranodosal vagal crush and colocalization of tracer and P2X(3) receptor immunoreactivity in vagal nodose neuronal cell bodies in retrograde tracing experiments further supports our hypothesis that the P2X(3) receptor-IR nerve fibers contacting NEBs have their origin in the vagal sensory nodose ganglia. Combination of quinacrine accumulation in NEBs, suggestive of the presence of high concentrations of adenosine triphosphate (ATP) in their secretory vesicles, and P2X(3) receptor staining showed that the branching intraepithelial P2X(3) receptor-IR nerve terminals in rat lungs were exclusively associated with quinacrine-stained NEBs. We conclude that ATP might act as a neurotransmitter/neuromodulator in the vagal sensory innervation of NEBs via a P2X(3) receptor-mediated pathway. Further studies are necessary to determine whether the P2X(3) receptor-expressing neurons, specifically innervating NEBs in the rat lung, belong to a population of P2X(3) receptor-IR nociceptive vagal nodose neurons.
Adenosine Triphosphate↗
Probable pre- and postsynaptic modifications by 5-hydroxytryptamine of contractile responses to electrical stimulation of isolated guinea-pig vas deferens.
Two kinds of electrical stimulation, low frequency stimulation (5 Hz, 1 msec, 5 pulses, every 20 sec) and high frequency stimulation (30 Hz, 0.05-0.1 msec, 10 pulses, every 20 sec), produced contractions in the isolated guinea-pig vas deferens. These responses were blocked by tetrodotoxin but not hexamethonium. Phentolamine potentiated the contractions produced by low frequency stimulation, while it reduced the contractions produced by high frequency stimulation. Diametrically, 5-hydroxytryptamine reduced the contractions produced by low frequency stimulation, while it potentiated the contractions produced by high frequency stimulation. These inhibitory and potentiating actions of 5-hydroxytryptamine were reversed by cyproheptadine and 2-bromolysergic acid diethylamide. Moreover, that 5-hydroxytryptamine produced a depolarization of the smooth muscle membrane was shown by the sucrose gap technique. The results suggest that a 5-hydroxytryptamine receptor exists pre- and postsynaptically in the neuroeffector transmission of the guinea-pig vas deferens, that the stimulation of the presynaptic receptor by 5-hydroxytryptamine inhibits the release of a transmitter from noradrenergic nerves, and that the stimulation of the postsynaptic receptor by a high concentration of 5-hydroxytryptamine produces a depolarization of the smooth muscle membrane, and this relates to the potentiation of contractile responses.
Animals↗