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Age-related changes of dopamine receptor protein immunoreactivity in the rat mesenteric vascular tree.

Dopamine D1-D5 receptor protein immunoreactivity and tyrosine hydroxylase (TH) immunoreactivity were investigated on the mesenteric arterial tree by immunohistochemistry. The density of various dopamine receptors and TH immunoreactivity was compared between young (6-month-old), adult (15-month-old) and senescent (24-month-old) Fischer 344 rats by computer-assisted microdensitometry. The dopamine D1-like (D1 and D5) receptors were localized on the tunica media of different sized mesenteric artery branches. The D2-like (D2, D3 and D4) receptors as well as TH immunoreactivity were localized only on the adventitia-media transitional zone of mesenteric arterial tree. Expression of the D1 and D5 receptors was decreased in both adult and senescent rats compared to the young rats, suggesting an age-related decline in these receptors. Of the D2-like receptors, the expression of the D2 receptor was decreased as a function of age, while the D3 receptor was unchanged in the senescent rats compared to the young rats. Expression of the D4 receptor was increased in adult, but was unchanged in the senescent rats compared to young animals. TH immunoreactivity was increased as a function of age. The above data suggest that reduction in the D1, D2 and D5 receptor expression may contribute to the deficiency in the dopamine-mediated vasorelaxation and hence blood flow in the mesenteric vascular tree in aging. The different sensitivity to aging of sympathetic neuroeffector junctions labeled by TH and of dopamine D2-like receptors that are known to be prejunctional, suggests that age-related changes of dopamine receptor expression in the mesenteric vasculature reflect more complicated mechanisms than simple up- or down-regulation phenomena.

Aging↗

Specificity in the organization of the autonomic nervous system: a basis for precise neural regulation of homeostatic and protective body functions.

Experimental investigations of the lumbar sympathetic outflow to skin, skeletal muscle and viscera and the thoracic sympathetic outflow to the head and neck have shown that each target organ and tissue is supplied by one or two separate pathways which consists of sets of pre- and postganglionic neurons with distinct patterns of reflex activity. This probably applies to all sympathetic and parasympathetic systems. The specificity of the messages that these peripheral pathways transmit from the central nervous system arises from integration within precisely organized pathways in the neuraxis. The messages in these discrete functional pathways are transmitted to the target tissues often via organized neuroeffector junctions. Modulation in the periphery can occur within each pathway, both in ganglia and at the level of the effector organs. This organization is the basis not only for precise neural regulations of all homeostatic body functions in which the autonomic nervous system is involved but also the basis of one main component in the regulation of protective body functions: (a) Elementary defense behaviors which are organized in the mesencephalon (confrontational defense, flight, quiescence), (b) regulation of the immune system by the sympathetic nervous system, and (c) adaptive autonomic motor responses during basic emotions require precisely working autonomic, in particular sympathetic, systems. In this sense, the concept of the functioning of the sympathetic nervous system in an "all-or-none" fashion, without distinction between different effector organs, and of simple functional antagonistic organization between sympathetic and parasympathetic nervous system is misleading, inadequate and untenable.

Animals↗

Modulation of purinergic neurotransmission.

During the past 25 years ATP has become accepted as an important neurotransmitter at a wide variety of neuroeffector junctions, usually acting as a cotransmitter with NA, ACh, nitric oxide or a neuropeptide such as NPY or VIP. The details of the storage and release of ATP with its cotransmitters has yet to be resolved. However, recent studies indicate that there is more than one population of storage vesicles in the nerves, since the release of the various cotransmitters varies over time and can be differentially modulated by drugs. The subclassification of P2 receptors has advanced dramatically in the past few years due to the use of molecular biology methods allowing the cloning and expression of 14 different subclasses of P2 receptors, seven P2X and seven P2Y. Determination of the functional significance of the various receptor subtypes would be helped by the development of selective agonists and antagonists. The neurotransmitter action of ATP at visceral and vascular smooth muscle P2X receptors has been elucidated in considerable detail. ATP induces a transient inward current via ligand-gated channels, which produces EJPs, action potentials and a phasic contraction of the effector tissue. ATP's neurotransmitter actions appear to be curtailed by the action of ATPases. It has been assumed that this ATPase activity is due to membrane bound ecto-ATPases on the surface of the effector tissue, however, the recently identified soluble ATPase released during nerve stimulation could also be involved in inactivation of ATP. The relative importance of ecto-ATPase and the releasable ATPase is yet to be determined.

Adenosine Triphosphate↗

NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31]NPY24-36, reduces renal vasoconstrictor activity in anaesthetised dogs.

The actions of neuropeptide Y (NPY) at the autonomic neuroeffector junction have been attributed to two main receptor subtypes. At NPY Y1 receptors, located postsynaptically, NPY has been shown to produce vasoconstriction, or to potentiate the action of other vasoconstrictor agents. At NPY Y2 receptors, located presynaptically on nerve terminals, NPY inhibits the release of neurotransmitter from autonomic nerve terminals. In these experiments we have used the specific NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31]NPY, which lacks local constrictor activity, and have demonstrated inhibition of nerve-evoked vasoconstriction in the renal circulation of anaesthetised dogs in a way that suggests an intra-renal regional specificity. Under control conditions stimulation of the renal sympathetic nerves over a range of frequencies (1-5 Hz) reduced renal vascular conductance and glomerular filtration rate (GFR). Following the injection of the selective NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31]NPY24-36, nerve-evoked reductions in renal conductance were reduced by over 45%. At the lowest stimulation frequencies, reduced vasoconstrictor activity was associated with a marked increase in GFR in the presence N-acetyl [Leu28,Leu31]NPY24-36. At both higher levels of stimulation N-acetyl [Leu28,Leu31]NPY24-36 significantly inhibited vasoconstrictor activity and attenuated the nerve-evoked reductions in GFR. Full recovery of both variables was observed 20 min after N-acetyl [Leu28,Leu31]NPY24-36 injection. N-acetyl [Leu28,Leu31]NPY24-36 produced a similar inhibition of renal vasoconstrictor activity when the renal nerves were left intact and activated reflexly. These results suggest that NPY can act via NPY Y2 receptors to inhibit sympathetic vasoconstrictor activity in the renal circulation of dogs. On the basis of the demonstrated dissociation of effects on vascular conductance and GFR, we suggest that this might result from a preferential action of the NPY Y2 agonist on sympathetic nerves supplying the afferent arteriole of the kidney.

Anesthesia↗

Muscarinic stimulation of airway smooth muscle cells.

1. Acetylcholine, the principal neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors. This review focuses on the effects of postjunctional muscarinic stimulation of airway smooth muscle. 2. On pharmacological criteria, four distinct subtypes of muscarinic cholinoceptor, denoted M1, M2, M3 and M4 receptors, have been identified by use of selective antagonists. Cloned muscarinic cholinoceptors are members of the family of GTP-binding protein-coupled receptors, which are characterized by seven transmembrane (TM) regions connected by intra- and extracellular loops. Between the fifth and the sixth TM regions, muscarinic receptors possess a large intracytoplasmic loop that is considered to be responsible for G-protein-coupling selectivity and exhibits high divergence between the different subtypes. 3. At the site of the smooth muscle itself, both binding and Northern blot studies have demonstrated, in a variety of species, that muscarinic receptor subtypes present are M2 and M3. M2 receptors are coupled to Gi proteins and adenylyl cyclase inhibition and thus to cAMP signaling. M3 receptors are coupled to Gq/11 protein and phosphoinositide hydrolysis and thus to calcium signaling. 4. Muscarinic-induced contraction of airway smooth muscle is mediated by M3 receptors. M2-mediated inhibition of adenylyl cyclase contributes to the prevention of bronchodilation. Cross-talk between muscarinic and beta2 adrenoceptors is likely to be present in airway smooth muscle. The pathophysiological role of this cross-talk requires further investigation.

Cholinergic Agents↗

In vitro continuous amperometry with a diamond microelectrode coupled with video microscopy for simultaneously monitoring endogenous norepinephrine and its effect on the contractile response of a rat mesenteric artery.

Continuous amperometry with a diamond microelectrode and video microscopy were used to record (in vitro) endogenous norepinephrine release simultaneously with the evoked contractile response of a mesenteric artery from a healthy Sprague Dawley rat. Norepinephrine (NE) is a vasoconstricting neurotransmitter released from sympathetic nerves that innervate the smooth muscle cell layers surrounding arteries and veins. Using these two techniques along with several drugs, the NE released at sympathetic neuroeffector junctions nearby the microelectrode was measured as an oxidation current. Key to the amperometric measurement was the use of a diamond microelectrode because of the response sensitivity, reproducibility, and stability it provided. NE release was elicited by electrical stimulation at frequencies between 1 and 60 Hz, with a maximum response seen at 20 Hz. Confirmation that the oxidation current was, in fact, associated with endogenous NE came from the results of several drugs. Tetrodotoxin (TTX, 0.3 microM), a voltage-dependent sodium channel antagonist that blocks nerve conduction, abolished both the oxidation current and the arterial constriction. The alpha(2)-adrenergic autoreceptor antagonist, yohimbine (1.0 microM), caused an increase in the oxidation current and the corresponding constriction. The addition of cocaine (10 microM), an antagonist that inhibits neuronal NE reuptake, caused both the oxidation current and the contractile response to increase. These results, combined with the fact that the hydrodynamic voltammetric E(1/2) for endogenous NE was identical to that for a standard solution, confirmed that the oxidation current was due to NE and that this compound caused, at least in part, the contractile response. The results demonstrate that continuous amperometric monitoring of NE with a diamond microelectrode and video imaging of vascular tone allow real time local measurement of the temporal relationship between nerve-stimulated NE release and arterial constriction.

Animals↗

Excretion of amines and their metabolites by two patients in hepatic coma treated with L-dopa.

Two patients in hepatic coma were treated with L-dopa. The first patient showed clear clinical improvement, but the second patient did not. Analyses of urinary metabolites indicated that L-dopa was not absorbed by the second patient. There was evidence that L-dopa had the following beneficial effects in the first patient: (1) increased production of urine, which could have been accompanied by increased excretion of toxins; (2) displacement of tyramine from transmitter sites (because increased excretion of p-hydroxyphenylacetic acid, a major metabolite of tyramine, occurred during L-dopa treatment in patient 1); (3) replenishment of dopamine, and to a much lesser extent, norepinephrine, at central or peripheral neuroeffector junctions; and (4) scavenging of methyl groups by L-dopa, because ratio of methylated amines to catecholamines was higher than normal in both comatose patients before L-dopa treatment, and this ratio decreased during L-dopa treatment in patient 1.

Dopamine↗

Sympathetic vasoconstriction as a mechanism of action of ouabain in forearm arterioles of hypertensive patients.

1. The interaction of ouabain, a Na+/K+ adenosine 5'-triphosphatase inhibitor, with sympathetic mechanisms of vasoconstriction, as well as its possible site(s) of action, were investigated in forearm arterioles of patients with uncomplicated hypertension. 2. Intra-arterial infusion of ouabain per se decreased forearm blood flow without changes in systemic arterial pressure or contralateral flow. However, the vasoconstrictor effect of the glycoside was abolished after local pretreatment with either phentolamine, a competitive alpha-adrenoceptor antagonist, or bretylium tosylate, a neurotransmitter blocker. 3. To exclude a non-specific effect due to the vasodilatation, a similar protocol was performed using histamine, which acts independently of sympathetic mechanisms. The vascular effect of ouabain was maintained in spite of histamine-induced increases in forearm blood flow even greater than those obtained from either blocker. 4. To discriminate between pre- and post-synaptic site(s) of action of ouabain, exogenous noradrenaline was infused intra-arterially after inactivation of local neurotransmitter release by bretylium, thus causing direct postsynaptic vascular alpha-adrenoceptor stimulation. Under these conditions, noradrenaline decreased forearm blood flow irrespective of the presence or absence of ouabain. 5. Thus, local sympatholysis by drugs acting on different levels of the sympathetic neuroeffector junction abolished the effect of ouabain, whereas histamine did not influence it. The data provide positive evidence for an effect of ouabain on sympathetically mediated vasoconstriction. This action is apparently not exerted at a postsynaptic site but possibly by enhancing neurotransmitter release. 6. If a circulating endogenous ouabain-like Na+/K+ adenosine 5'-triphosphatase inhibitor is relevant to the development of hypertension in man, it might act through a similar mechanism.

Arterioles↗

Neurophysiological analysis of target-related sympathetic pathways--from animal to human: similarities and differences.

The sympathetic nervous system regulates many different target tissues in the somatic and visceral domains of the body in a differentiated manner, indicating that there exist separate sympathetic pathways that are functionally defined by their target cells. Signals generated by central integration and channelled through the preganglionic neurons into the final sympathetic pathways are precisely transmitted through the para- and prevertebral ganglia and at the neuroeffector junctions to the effector cells. Neurophysiological recordings of activity in postganglionic neurons in skin and muscle nerves using microneurography in human subjects and in skin, muscle and visceral nerves, using conventional recording techniques in anaesthetized animals, clearly show that each type of sympathetic neuron exhibits a discharge pattern that is characteristic for its target cells and, therefore, its function. These findings justify labelling the neurons as muscle vasoconstrictor, cutaneous vasoconstrictor, sudomotor, lipomotor, cardiomotor, secretomotor neurons, etc. The discharge patterns monitor aspects of the central organization of the respective sympathetic system in the neuraxis and forebrain. They can be dissected into several distinct reflexes (initiated by peripheral and central afferent inputs) and reactions connected to central signals (related to respiration, circadian and other rhythms, command signals generated in the forebrain, etc). They are functional markers for the sympathetic final pathways. These neurophysiological recordings of the discharge patterns from functionally identified neurons of sympathetic pathways in the human and in animals are the ultimate reference for all experimental investigations that aim to unravel the central organization of the sympathetic systems. The similarities of the results obtained in the in vivo studies in the human and in animals justify concluding that the principles of the central organization of sympathetic systems are similar, if not identical, at least in the neuraxis, in both species. Future progress in the analysis of the central neuronal circuits that are associated with the different final sympathetic pathways will very much depend on whether we are able to align the human models and the animal models. Human models using microneurography have the advantage to work under awake conditions. The activity in the postganglionic neurons can be correlated with various other (afferent, centrally generated) signals, effector responses, perceptions, central changes monitored by imaging methods, etc. However, human models have considerable limitations. Animal models can be divided into in vivo models and various types of reduced in vitro models. Animal models allow using various methodological approaches (e.g., neurophysiological, pharmacological, modern anatomical tracing methods; behavioural animal models; transgenic animals), which cannot be used in the human. Interaction of the research performed in the human and animals will allow to design animal models that are relevant for diseases in which the sympathetic nervous systems is involved and to trace down the underlying pathophysiological mechanisms. The scientific questions to be asked are formulated on the basis of clinical observations resulting in testable hypotheses that are investigated in the in vivo human and animal models. Results obtained in the in vivo models lead to the formulation of hypotheses that are testable in reduced in vivo and particularly in vitro animal models. Microneurographic recordings from sympathetic postganglionic fibres in the human will keep its place in the analysis of the sympathetic nervous system in health and disease although only relatively few laboratories in the world will be able to keep the standards and expertise to use this approach. Experimental investigation of the organization of the sympathetic nervous system in animal models has changed dramatically in the last 15 years. The number of in vitro models and the methodological diversity have increased. In vivo experimentation on larger animals has almost disappeared and has been replaced by experimentation on rats, which became the species for practically all types of studies on the central organization of the sympathetic nervous system.

Action Potentials↗

Prostanoid-induced modulation of neuropeptide Y and noradrenaline release from the rat mesenteric bed.

1. A variety of prostanoids were examined for their ability to alter the periarterial nerve stimulation-induced release of noradrenaline (NA) and neuropeptide Y immunoreactive compounds (NPY-ir) from the perfused mesenteric arterial bed of the rat. 2. Periarterial nerve stimulation (16 Hz) increased the overflow of NA, NPY-ir and perfusion pressure. 3. The prostacyclin (PGI2) analogues, carbaPGI2 and cicaprost both produced a concentration-dependent attenuation of the nerve stimulation-induced increase in NA, NPY-ir overflow and perfusion pressure. 4. The prostaglandin (PG) analogue PGE2 attenuated the evoked increase in NPY-ir overflow as well as a modest decrease in NA. 5. PGE1, sulprostone and iloprost attenuated the nerve stimulation-induced increase in NA overflow but not NPY-ir. 6. Neither PGF2alpha nor the thromboxane A2 analogue U46619 altered the evoked increase in NA or NPY-ir overflow. 7. The results support the view that sympathetic co-transmitter release can be differentially modulated by paracrine/autocrine mediators at sympathetic neuroeffector junctions.

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

Distribution of muscarinic acetylcholine receptors and presynaptic nerve terminals in amphibian heart.

At many synapses, neurotransmitter receptor molecules in the postsynaptic membrane are selectively concentrated at a site directly opposite the presynaptic nerve terminal. In this paper, I examine acetylcholine (ACh) receptor distribution in cardiac muscle in relatin to the distribution of presynaptic axonal varicosities. The density of varicosities, stained with zinc iodide and osmium, ranges from 0.7/100 micrometer 2 in ventricle to 1.9/100 micrometer 2 in sinus venosus. It is estimated that < 3% of the muscle surface is apposed to presynaptic varicosities. ACh receptors, however, are randomly distributed on the muscle surface and not concentrated in patche. ACh receptor distribution was determined by iontophoretic application of ACh and mapping of ACh sensitivity and by [3H]QNB (quinuclidinyl benzilate) binding and autoradiography [3H]QNB binds with > 90% specificity to a single, saturable, high-affinity (Kd = 11.1 pM at 21 degrees C) class of binding sites. QNB binding sites are thought to correspond to ACh receptors, because muscarinic agonists compete for [3H]QNB binding and produce a hyperpolarization in the sinus venosus with the same order of potency. The concentrations of QNB binding sites in the sinus and atria are about twice those found in ventricle. The receptor density corresponds to the density of innervation measured by zinc iodide and osmium staining. Autoradiographic experiments show that [3H]QNB binding sites are distributed randomly over the entire surface of the muscle. This distribution of ACh receptors in cardiac muscle has important implications for the function of the cardiac neuroeffector junction.

Acetylcholine↗

Allicin-induced hypotension in rabbit eyes.

The intent of this work was to examine the actions of allicin on 1) intraocular pressure (IOP) in normal and unilaterally sympathectomized (SX) rabbits; 2) cAMP accumulation in the rabbit iris-ciliary body (ICB) and cultured nonpigmented epithelial (NPE) ciliary body cells; and 3) 3H-norepinephrine (NE) release by calculating fractional tritium overflow in response to electrical field stimulation (EFS, 5 Hz, 12 V/cm) in isolated, perfused rabbit ICBs. Allicin, one of the active compounds produced by garlic, was evaluated on IOP and it was determined that allicin (1, 2.5, or 10 micrograms), topically, but not the precursor, alliin (10 micrograms), lowered the IOP unilaterally in normal rabbits. Allicin (10 micrograms) reduced the IOP by 6 +/- 1 mmHg (n = 4) in normal rabbits at 2 hrs (maximum response) whereas no change occurred in sympathectomized rabbit eyes. Moreover, allicin (0.01, 0.1, or 1 microM) caused 40, 40, or 52% inhibition, respectively, of 3H-NE overflow in response to EFS. Isoproterenol (ISO, 1 microM) stimulated cAMP accumulation by 3.6 and 9 fold in isolated rabbit ICB and cultured NPE cells, respectively. Allicin (1 microM) had no effect on basal cAMP level while it inhibited ISO-stimulated cAMP accumulation by 40% and 23% in ICB and NPE cells, respectively. This study suggests that allicin lowered IOP, in part, by dual actions at the neuroeffector junction.

Animals↗

Thiopental potentiation of isolated rabbit pulmonary artery contractions with alpha receptor agonists.

The effects of thiopental sodium on the adrenergic neuroeffector junction were studied in isolated rabbit pulmonary arteries. Basal tension was not altered by thiopental (2 X 10(-5) and 10(-4) M) but was increased by high concentrations of thiopental (5 X 10(-4) M). Thiopental (10(-4) and 5 X 10(-4) M) potentiated contractions induced by transmural electrical stimulation. Contractile responses to exogenously applied low concentrations of norepinephrine (NE) were potentiated by thiopental (2 X 10(-5), 10(-4) and 5 X 10(-4) M), whereas those to high concentrations were not altered. In strips previously incubated in 1-[7,8-3H]-NE (10(-7) M), the release of [3H] induced by transmural stimulation (5 Hz) was not altered by thiopental (10(-4) and 5 X 10(-4) M). Potentiation by thiopental (10(-4) M) of the responses to transmural stimulation was not affected by prior application of cocaine or hydrocortisone. Contractions induced by alpha receptor agonists (phenylephrine and methoxamine) were potentiated by thiopental (10(-4) M), while those induced by acetylcholine were not altered. Contractile responses to potassium chloride were attenuated by thiopental (10(-4) M). Amobarbital sodium and pentobarbital sodium (10(-4) M, respectively) attenuated contractions induced by NE. It may be concluded that thiopental specifically increases the responsiveness of postsynaptic alpha receptors to NE.

Acetylcholine↗

Mechanism of the positive inotropic effect of ketamine in isolated ferret ventricular papillary muscle.

Ketamine is a cardiovascular stimulant through its sympathomimetic effects; however, its direct inotropic effect has been reported as positive in rat and negative in rabbit ventricular myocardium. This study reexamines the effect of ketamine on the contractile properties of mammalian ventricular myocardium. In isolated, electrically stimulated ferret right ventricular papillary muscles, the authors assessed the inotropic effect of ketamine (10(-6) M to 3 x 10(-4) M in 0.5 log M increments) alone and in various pharmacologic conditions designed to delineate ketamine's site(s) of action. Ketamine exerted a positive inotropic effect that was maximal at 10(-4) M. Bupranolol (10(-7) M) abolished this positive inotropic effect, whereas phentolamine (10(-6) M) did not. Depletion of norepinephrine stores by reserpine also eliminated ketamine's positive inotropic effect, indicating that ketamine caused indirect activation of the beta-adrenoceptor. Ketamine did not exert a positive inotropic effect in the presence of simultaneous inhibition of neuronal norepinephrine uptake with desmethylimipramine (DMI) (5 x 10(-6) M) and extraneuronal uptake with corticosterone (5 x 10(-5) M). It is likely that ketamine's action is to inhibit norepinephrine uptake at the neuroeffector junction rather than to augment norepinephrine release. In the presence of corticosterone, ketamine exerted a smaller positive inotropic effect than that seen with ketamine alone. Ketamine produced a small increase in force development in the presence of DMI, but this did not reach statistical significance. Inhibition of neuronal catecholamine uptake appears to be the predominant mechanism of ketamine's positive inotropic effect.

Animals↗

Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium.

BACKGROUND: Ketamine exerts both an indirect, positive inotropic effect and a direct, negative inotropic effect in isolated ferret ventricular myocardium. This negative inotropic effect becomes apparent after inactivation of the sympathetic neuroeffector junction. The aim of this study was to investigate the mechanisms of ketamine's intrinsic negative inotropic effect. METHODS: The authors analyzed the effects of ketamine after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca(++)-regulated photoprotein aequorin. Ketamine's effects were also evaluated in a preparation in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular myocardium in which the SR is poorly developed. RESULTS: Ketamine at concentrations > or = 3.3 x 10(-5) M decreased contractility and the amplitude of the intracellular Ca++ transient. After inactivation of sarcoplasmic reticulum Ca++ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, ketamine caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and ketamine's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Furthermore, > or = 10(-4) M ketamine decreased contractility in frog ventricular myocardium, a species that is almost entirely dependent on transsarcolemmal Ca++ influx for its myofibrillar activation. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of ketamine results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of ketamine's action is caused by inhibition of transsarcolemmal Ca++ influx.

Aequorin↗

Local modulation of adrenergic neurotransmission in blood vessels.

Norepinephrine, released from sympathetic nerve terminals, has a key role in adjusting continuously the performance of the cardiovascular system. Although the amount of transmitter released depends primarily on the degree of activation of postganglionic sympathetic fibers, local metabolites and circulating vasoactive substances, in addition to affecting smooth-muscle cells directly, alter the amount of norepinephrine released. Thus, metabolic acidosis, an increase in potassium ions and in osmolality reduce the output of norepinephrine in the face of a constant frequency of stimulation of the postganglionic fibers. Many receptors have been identified on the prejunctional nerves which, when activated, can increase or decrease transmitter release. Those agonists which decrease it include adenosine and the adenine nucleotides, and norepinephrine, acetylcholine, histamine, and serotonin, acting on purinergic, alpha 2-adrenoceptors, muscarinic, H2-histaminergic and S1-serotoninergic receptors, respectively. Those that increase transmitter release include epinephrine (acting on beta 2-adrenoceptors) and angiotensin II. Part of the action of certain drugs is due to their prejunctional effects. Thus, cardiac glycosides cause a release of norepinephrine, and the antidepressant drug amitriptyline causes inhibition of prejunctional alpha-adrenoceptors and muscarinic receptors. Local changes in temperature also have complex actions on the neuroeffector junction and the vascular smooth muscle, which are of prime importance for cutaneous vessels.

Acetylcholine↗

Plasma histamine and catecholamine levels during hypotension induced by morphine and compound 48/80.

Histamine receptors are present in adrenergic terminals, and histamine is reported to inhibit release of the neurotransmitter norepinephrine (NE) at certain neuroeffector junctions. However, a physiological role for histamine in modifying adrenergic neurotransmission has not been established. To examine the interaction of elevated plasma histamine and catecholamine release, two compounds that release histamine, morphine (3 mg/kg), and compound 48/80 (0.5 mg/kg), were administered intravenously (i.v.). Plasma norepinephrine (NE) levels were used to monitor sympathetic nervous system activity, and plasma epinephrine (Epi) levels were used to monitor adrenal activity. Both morphine and compound 48/80 caused an immediate and marked increase in plasma histamine. Simultaneous with this increase, a marked decrease in mean arterial pressure occurred. Plasma NE levels increased in animals administered compound 48/80, but in morphine-treated animals, plasma NE levels did not change from pretreatment values. Plasma Epi levels increased in both groups, but the magnitude and duration of the responses differed. The results indicate that elevated plasma catecholamines can increase in response to histamine-induced hypotension but this effect can be suppressed by the central actions of morphine.

Animals↗

Differential effects of central and peripheral desipramine on sympathoadrenal function and heart rate in conscious rabbits.

The effects of the tricyclic antidepressant, desipramine, on the baroreflex regulation of renal sympathetic nerve activity (SNA) and heart rate (HR), the nasopharyngeal reflex, plasma epinephrine and blood pressure (BP) were studied in conscious rabbits. Renal SNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) and during inhalation of cigarette smoke. Intracisternal (i.c.) and intravenous (i.v.) drug administration were compared, using doses which produced similar total central nervous system (CNS) concentrations. After a brief sympathoexcitation, i.c. desipramine inhibited renal SNA and MAP and increased plasma adrenaline and HR. The renal sympathetic baroreflex was substantially attenuated, with reflex range and gain reduced by 46 and 31%, respectively, but the cardiac baroreflex and nasopharyngeal reflex were affected minimally. Sixty-four percent of the desipramine remaining in the brain was concentrated in the medulla oblongata and spinalis; levels in cortex, thalamus, midbrain, lower spinal cord, and peripheral tissues were minimal. Treatment with i.v. desipramine decreased renal SNA and increased HR without altering MAP or epinephrine release. There was a slight attenuation of the nasopharyngeal reflex, a slight baroreceptor-independent reduction in renal SNA at most MAP levels, and an augmentation of the cardiac baroreflex. The drug was uniformly distributed throughout the CNS; only 20% of the centrally accumulated dose was in the medulla. Thus, i.c. desipramine produces a differentiated pattern of sympathoadrenal effects, probably by increasing norepinephrine (NE) concentrations at several sites within the medulla. The effects of i.v. desipramine were different, owing to poorer access to the medulla and the consequences of peripheral neuronal uptake blockade, which may include a modest inhibition at the sympathetic ganglia and an excitation at cardiac and vasoconstrictor neuroeffector junctions.

Adrenal Glands↗