The localization of sympathetic and vagal neurones innervating the carotid sinus in the rabbit

The distribution of neurones innervating the carotid sinus of the rabbit was determined by inserting chips of horseradish peroxidase (HRP) into the adventitial layer of the carotid sinus. Labelled neurones were found in the superior cervical ganglion, along the cervical sympathetic trunk and in the nodose ganglion (mean counts of 1876, 139 and 232, respectively). No labelled neurones were located in the middle cervical ganglion or the stellate ganglion. Within the superior cervical ganglion, the fraction of labelled neurones found in equal longitudinal quadrants of the ganglion were, from rostral to caudal, 2%, 12%, 42% and 44%. Thus the majority of neurones were located in the caudal region of the superior cervical ganglion. The primary pathway for sympathetic fibres innervating the carotid sinus was shown to be in branches of the external carotid nerve. The greatest number of labelled neurones in the nodose ganglion were located in the most rostral quadrants of the ganglion.     

Glucokinase is located in secretory granules of pancreatic D-cells

The effects of electrical stimulation, applied to the superior salivatory nucleus (SSN) or the cervical sympathetic nerve, on vascular permeability in nasal mucosa were studied in 16 cats. Plasma extravasation was quantified by using Evans blue. Vascular permeability in the cat nasal mucosa was increased by the electrical stimulation of SSN. Plasma extravasation induced by SSN stimulation was reduced by administration of nitric oxide synthase (NOS) antagonist, N(omega)-nitro-L-arginine methyl ester (L-NAME). Administration of atropine did not affect increased vascular permeability by SSN stimulation. We conclude that neurogenic plasma extravasation in cat nasal mucosa evoked by the parasympathetic nerve is not mediated by cholinergic fibers but rather by nitric oxide.     

Characterization of postsynaptic alpha-1 and alpha-2 adrenoceptors in the feline saphenous and femoral veins [corrected

Experiments were designed to characterize the effects mediated by alpha-1 and alpha-2 adrenoceptors in saphenous and femoral veins of the cat. Ring segments of saphenous and femoral veins were mounted for isometric tension recording in modified Krebs-bicarbonate solution, gassed with 95% O2-5% CO2 and maintained at 37 degrees C. Norepinephrine (a mixed alpha 1 and alpha 2 agonist), phenylephrine (a preferential alpha 1 agonist) and clonidine (a preferential alpha 2 agonist) caused dose (concentration)-dependent contractions in saphenous and femoral veins. The maximal contractions produced by clonidine were significantly less than those produced by norepinephrine or phenylephrine in both veins. However, threshold dose and EC50 values indicated that clonidine was more potent than norepinephrine and phenylephrine. Contractile responses to these agonists were attenuated when the veins were pretreated with alpha 1-or alpha 2-adrenoceptor antagonists, prazosin and yohimbine, respectively. The contractile responses to norepinephrine and tyramine were inhibited to a greater extent by yohimbine than by prazosin in both saphenous and femoral veins, suggesting that norepinephrine released from perivascular nerve terminals activates preferentially postsynaptic alpha 2-adrenoceptors. Further examination of alpha-adrenoceptor subtypes was achieved by comparing pA2 values of prazosin and yohimbine from Arunlakshana and Schild plots. Chronic sympathetic denervation by removing lumbar sympathetic chain significantly reduced the contractile responses evoked by tyramine. Denervation did not significantly affect the concentration-response curve to phenylephrine but significantly augmented the contractile responses evoked by clonidine in both veins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of some phenylethylamines in rhesus monkeys trained to discriminate (+)-amphetamine from saline

The distribution of intraepithelial nerve fibres and neuroendocrine cells within the surface and glandular epithelium of human nasal mucosa and larynx was examined using immunohistochemical techniques. Neuronal structures were immunostained for the general neuroendocrine marker protein gene-product (PGP) 9.5, and the two neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) using immunofluorescence and streptavidin-biotin-peroxidase complex (S-ABC) methods. Intraepithelial nerve fibres with free nerve endings contained PGP 9.5 and were found within the respiratory surface epithelium of the nasal mucosa and the squamous epithelium of the larynx. A subpopulation of these nerve fibres showed positive immunoreactivties with antibodies against SP and CGRP. Nerve fibres within the ductal epithelium of subepithelial excretory ducts passing the basal membrane and reaching the luminal part were detected. These nerve fibres showed CGRP-like immunoreactivity but not for SP. A dense network of nerve fibres within the squamous surface epithelium was detected in the subglottic and epiglottic region containing CGRP and SP in a small subpopulation of nerve fibres. Single intraepithelial taste buds in the epiglottic region and neuroendocrine cells within the subglottic epithelium expressed PGP 9.5.     

Effects of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death

A prominent innervation of the pineal gland of the European hamster with nerve fibres containing neuropeptide Y (NPY) and tyrosine hydroxylase (TH) was demonstrated by means of immunohistochemistry. Nearly all the TH- and NPY-immunoreactive nerve fibres in the superficial pineal gland disappeared after bilateral superior cervical ganglionectomy, showing that the majority of NPY- and TH-immunoreactive nerve fibres belonged to the sympathetic nervous system. Since, in the European hamster, preliminary studies of the NPY-fibre density in the pineal gland had indicated seasonal changes, the density of NPY-immunoreactive nerve fibre profiles was ascertained in the superficial pineal gland in a series of animals between the first part of November and late April. The highest density of NPY-immunoreactive nerve fibre profiles was observed during midwinter. On the other hand, during the same period of the year, the number of sympathetic TH-immunoreactive sympathetic nerve fibre profiles did not exhibit seasonal variation, nor did substitution of testosterone, during the sexually inactive period, affect the density of NPY-containing nerve fibres in the gland. Our results show the presence of a testosterone-independent annual variation in the content of NPY in the sympathetic nerve fibres innervating the pineal gland of the European hamster. This variation can be correlated with the changes in the daily pattern of melatonin production observed by others in the same species at this period of the year.     

Analysis and counter measure prevention and treatment of osteoporosis with traditional Chinese medicine]

The present study was devised to determine the effects of amphetamine on the sympathetic function of human nasal mucosa. A tissue bath method was employed on the vitro preparations of nasal turbinate mucosa from adult patients with nasal allergies or hypertrophic rhinitis. The effects of amphetamine on the contractile response of isolated human nasal mucosal blood vessels were investigated following electrical field stimulation and methoxamine. The results showed that amphetamine inhibited field stimulation and antagonized the effects on mucosal contraction induced by methoxamine. Likewise, the drug increased mucosal basal tension but had local drug toxicity when a 10(-4) M solution was used. Amphetamine could potentiate mucosal contraction induced by norepinephrine or epinephrine. The study indicated that amphetamine may increase sympathetic function by potentiating the effect of norepinephrine and that high concentration of amphetamine may actually antagonize alpha-adrenoceptors.     

Reinnervation of cross-regenerated gustatory nerve fibers into amiloride-sensitive and amiloride-insensitive taste receptor cells

Single nerve fiber responses to NaCl and their inhibition by amiloride were compared among the chorda tympani (CT) and glossopharyngeal (IXth), and their cross-regenerated nerves in the C57BL/KsJ mice. The CT nerve innervating the anterior part of the tongue contained approximately equal numbers of two types of NaCl-responsive neurons; one type showed strong suppression of NaCl responses by amiloride [amiloride-sensitive (AS) type], and the other type showed only weak or no suppression of NaCl responses by amiloride [amiloride-insensitive (AI) type]. In contrast, the IXth nerve innervating the posterior part of the tongue has almost exclusively the AI type. This relative abundance of the AS and AI types of fibers was not altered by cross-regeneration of the two gustatory nerves into the reverse tongue regions. This suggests that regenerated taste axons selectively recouple with the appropriate type of receptor cell whether they innervate the front or the back of the tongue. Such selective synapse reformation may help explain the stability of response profiles of taste neurons during continual receptor cell turnover.     

Electrical stimulation of the auditory nerve. I. Correlation of physiological responses with cochlear status

The purpose of the present study was to evaluate evoked potential and single fibre responses to biphasic current pulses in animals with varying degrees of cochlear pathology, and to correlate any differences in the physiological response with status of the auditory nerve. Six cats, whose cochleae ranged from normal to a severe neural loss (< 5% spiral ganglion survival), were used. Morphology of the electrically evoked auditory brainstem response (EABR) was similar across all animals, although electrophonic responses were only observed from the normal animal. In animals with extensive neural pathology, EABR thresholds were elevated and response amplitudes throughout the dynamic range were moderately reduced. Analysis of single VIIIth nerve fibre responses were based on 207 neurons. Spontaneous discharge rates among fibres depended on hearing status, with the majority of fibres recorded from deafened animals exhibiting little or no spontaneous activity. Electrical stimulation produced a monotonic increase in discharge rate, and a systematic reduction in response latency and temporal jitter as a function of stimulus intensity for all fibres examined. Short-duration current pulses elicited a highly synchronous response (latency < 0.7 ms), with a less well synchronized response sometimes present (0.7-1.1 ms). There were, however, a number of significant differences between responses from normal and deafened cochleae. Electrophonic activity was only present in recordings from the normal animal, while mean threshold, dynamic range and latency of the direct electrical response varied with cochlear pathology. Differences in the ability of fibres to follow high stimulation rates were also observed; while neurons from the normal cochlea were capable of 100% entrainment at high rates (600-800 pulses per second (pps)), fibres recorded from deafened animals were often not capable of such entrainment at rates above 400 pps. Finally, a number of fibres in deafened animals showed evidence of 'bursting', in which responses rapidly alternated between high entrainment and periods of complete inactivity. This bursting pattern was presumably associated with degenerating auditory nerve fibres, since it was not recorded from the normal animal. The present study has shown that the pathological response of the cochlea following a sensorineural hearing loss can lead to a number of significant changes in the patterns of neural activity evoked via electrical stimulation. Knowledge of the extent of these changes have important implications for the clinical application of cochlear implants.     

Functional properties of spinal interneurons activated by muscular free nerve endings and their potential contributions to the clasp-knife reflex

1. The goal of this study was to characterize the functional properties of spinal interneurons that are excited by muscular free nerve endings and to assess their contributions to the clasp-knife reflex. 2. The patterns of activity of 82 spinal interneurons that were excited by squeezing the Achilles tendon or manipulation of the muscle surfaces, preferential stimuli for muscular free nerve endings, were extracellularly recorded in lamina V-VII of the L5-S1 spinal cord in decerebrated and spinalized cats. 3. Interneurons were uniformly excited by increases in muscular length and force. Responses to muscle stretch exhibited gradual decay during maintained stretch, afterdischarge after stretch release, and adaptation to repeated stretch. Responses to isometric contraction induced by electrical stimulation of motor axons was also prolonged after contraction, but did not decay during maintained contraction. For similar increases in force, stretch evoked greater excitation than contraction, indicating that both stretch and contraction contributed to interneuronal activity. Overall, the time course and magnitude of the interneuronal responses to stretch and contraction paralleled the time course and magnitude of the clasp-knife reflex. 4. Interneurons were powerfully excited by muscular free nerve endings, which mediate the clasp-knife reflex, and by cutaneous receptors. Only occasionally were they excited by primary spindle or Golgi tendon organ afferents, which suggests that activation of muscular free nerve endings mediated the interneuronal responses to stretch and contraction. 5. Simultaneous recordings of interneuronal activity and the clasp-knife reflex revealed a broad correlation between interneuronal activity and clasp-knife inhibition. 6. Because the patterns of activity of free nerve ending-responsive interneurons during stretch and contraction were similar to the clasp-knife reflex, were closely correlated with clasp-knife inhibition during simultaneous interneuronal and reflex recordings, and were powerfully excited by muscular free nerve endings, it is likely that the interneurons described above contributed to the clasp-knife reflex. 7. In contrast, a small number (n = 16) of interneurons were recorded that were only weakly excited by muscular free nerve endings but strongly excited by group I afferents, exhibited less spontaneous and evoked activity, and had significantly different responses to stretch and contraction. These interneurons are less likely to have contributed to the clasp-knife reflex.     

Electrophysiologic study of propagation of excitation in the cat pterygopalatine ganglion

Action potentials were studied in nerves of the cat pterygopalatine ganglion evoked by stimuli applied to other nerves of the ganglion (in situ). It is established that most fibres passing through the ganglion are continuous sympathetic postganglionic fibres (not less than 3 groups). Most parasympathetic preganglionic fibres are synaptical on the ganglionic neurons and are represented by a group of fibres with the same threshold of excitation. Intracellular recording from single neurons of the pterygopalatine ganglion showed that stimulation of the Vidian nerve caused orthodromic spikes with short latency in one group of neurons and spikes with long latency in other neurons (2.5-6 ms and 10-40 ms respectively). Only fast fibres appear to terminate on most neurons of the ganglion, and only slow fibres do on some other neurons. Tonic activity was not observed when was performed from intact nerves of the pterygopalatine ganglion. The interacellular recording from single neurons of the ganglion showed that frequency of spike potentials either is low (1-3 per second) in some neurons or the potentials are absent in general in other neurons.     

Prejunctionally mediated inhibition of neurotransmission by isoprenaline in rat vas deferens

Effects of isoprenaline on monophasic contractions evoked by electric field stimulation were studied in rat isolated prostatic vas deferens. Isoprenaline reduced electrically evoked contractions (EC50: 0.27 +/- 0.05 microM), and propranolol concentration-dependently antagonized the effect of isoprenaline. In contrast, isoprenaline (0.3-3 microM) did not affect the contractile response induced by exogenous noradrenaline or ATP, while forskolin (100 nM) attenuated agonist-induced contraction. In some tissues, adrenergic and purinergic components of the electrically evoked contraction were isolated by exposure to alpha,beta-methylene ATP (3 microM) and prazosin (3 microM), respectively. Isoprenaline induced a greater inhibition of purinergic than adrenergic component of the electrically evoked contraction. Iberiotoxin (50 nM), glibenclamide (3 microM), 4-aminopyridine (0.3 mM) and tetraethylammonium ions (1 mM) attenuated the effect of isoprenaline. These results indicate that isoprenaline-induced inhibition of the electrically evoked (both purinergic and adrenergic) contraction was mediated primarily through activation of prejunctional beta-adrenoceptors, which probably inhibited release of contractile transmitters from sympathetic nerves supplying vas deferens. Lack of effect of isoprenaline on agonist-induced contraction does not favour a functional role of beta-adrenoceptors in vas smooth muscle.     

Pressure-independent inhibition of sympathetic activity by noradrenaline: role of baroreceptor C fibres

The effect of i.v. infusion of noradrenaline on activity in the renal sympathetic nerve was studied in rabbits anesthetized with chloralose and urethane. Noradrenaline (3--8 microgram/kg-min) initially increased mean arterial pressure 20--40 mmHg and consequently reduced renal nerve activity. However, studies over a wide range of pressures--obtained by changing the blood volume, revealed that noradrenaline after a few minutes had induced a pressure-independent reduction of sympathetic discharge. The effect disappeared with baroreceptor denervation. An unchanged relationship between arterial pressure and integrated activity in the whole left aortic nerve (which is largely a measure of activity in A fibres) suggested that the sympathetic depression was due to excitation of aortic nerve C fibres. This conclusion was supported by studies of sympathetic responses to selective stimulation of aortic nerve A and C fibres at equal pressures before and during infusion of noradrenaline. Compared to the reflex activity from A fibres, C fibre stimulation was invariably less effective in suppressing renal nerve activity during the infusion. Our studies indicate that noradrenaline may effect a negative feedback control of sympathetic discharge through activation of baroreceptor C fibres.     

Immunohistochemical distribution of S-100 protein and type IV collagen in human embryonic and fetal sympathetic neuroblasts

The expression and distribution of S-100 protein and type IV collagen was studied immunohistochemically in sympathetic neuroblasts from the paravertebral region to the adrenal glands in human embryos and fetuses ranging from 7 to 12 weeks gestational age. From 7 weeks gestational age, S-100 protein was detected in round or oval cells mingling with sympathetic neuroblasts, and in spindle-shaped cells forming a continuous layer around them. The latter S-100 protein-positive cells were found in contact with the Schwann cells of nerve fibres entering the groups of sympathetic neuroblasts. Staining for type IV collagen showed that all groups of sympathetic neuroblasts were surrounded by a continuous basement membrane. By examining serial sections stained for type IV collagen and S-100 protein, a continuous basement membrane was found along the distribution pattern of the peripheral S-100 protein-positive spindle cells. The morphology of these cells, and their relationships with Schwann cells and with the basement membrane of the sympathetic neuroblasts, indicated that they were Schwann-like cells probably capable of synthesizing a continuous basement membrane separating the neuroblasts from the adjacent tissues. In contrast, the round or oval S-100 protein-positive cells, in contact with the sympathetic neuroblasts and not associated with nerve fibres, were considered as sustentacular or sustentacular precursor cells. At week 7 gestational age, the peri-adrenal sympathetic neuroblasts and their sustentacular and Schwann-like cells started to invade the adrenal glands and mingled with the adrenal cortical cells. These findings suggest the extra-adrenal origin of the sustentacular cells in embryonic and fetal adrenal glands.     

Effects of acetylcholine and sodium cyanide on cat carotid baroreceptors

1 The effects of intracarotid (i.a.) injections of acetylcholine (ACh) and sodium cyanide (NaCN) on baroreceptor activity recorded from the sinus nerve have been investigated in cats anaesthetized with pentobarbitone.2 Two types of baroreceptor unit were recorded. The predominant type discharged at least 3 to 4 spikes per pulse wave at normal BP; they are referred to as ;polyspike' units and may have been associated with A fibres. The other type discharged a maximum of 1 to 3 spikes per pulse wave, even at high BP; they are referred to as ;few-spike' units and may have been from C fibres.3 NaCN had no direct effect on either type of baroreceptor unit, even when injected in high doses (2.04 to 5.1 mumol i.a.) which cause maximal chemoreceptor stimulation, and it is concluded that as far as the cat's carotid baroreceptors and chemoreceptors are concerned, NaCN is a specific chemoreceptor stimulant.4 ACh had no direct effect on polyspike baroreceptor units unless very high doses (1.83 mumol i.a.) were injected, when there was occasionally a transient slight increase in discharge. This effect appeared to be secondary to muscle contraction caused by ACh since it was not seen when an adequate neuromuscular-blocking dose of gallamine had been administered.5 ACh stimulated the few-spike type of baroreceptor unit, an effect which was dose-related and lasted for up to 3 s; the threshold dose for baroreceptor stimulation was higher than that needed to excite chemoreceptor units. The increased discharge also occurred during experiments in which gallamine had been administered. Only five of these units were recorded during the investigation, despite an intensive search for them.6 There was a delayed increase in baroreceptor sensitivity following the administration of ACh in doses (37 to 366 nmol i.a.) which had no immediate direct effect on polyspike baroreceptor discharge. The effect was evidently not secondary to changes in sympathetic nerve activity to the sinus region since it was observed during an experiment in which the ganglioglomerular nerves had been cut. Whether the increased sensitivity resulted from direct or indirect actions of ACh remains to be determined.7 It is concluded that low doses of ACh or other drugs with nicotinic properties are unlikely to evoke baroreceptor reflexes on intracarotid injection, although they may cause delayed changes in baroreceptor sensitivity. Higher doses of ACh do not directly affect baroreceptor polyspike (A fibre) units, but transient baroreflex changes might result from stimulation of baroreceptor few-spike (C fibre) units. It is most unlikely that NaCN has any direct effect on baroreceptor reflex activity when injected into the carotid artery in doses used to elicit chemoreceptor reflexes.     

Tumor necrosis factor alpha inhibits contractions to sympathetic nerve stimulation by a nitric oxide-dependent mechanism

Gram-negative sepsis and administration of tumor necrosis factor alpha (TNF alpha) are associated with hypotension and peripheral neuropathies suggestive of impaired sympathetic neurotransmission. We examined the effect of TNF alpha on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracted to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequency-dependent manner. The contractions of the BPA to SNS were mediated by norepinephrine and activation of postsynaptic alpha 1-adrenoceptors, since they were attenuated by prazosin. Maximum contraction of the BPA to SNS was significantly enhanced (148 +/- 37% increase, n = 6) after inhibition of nitric oxide synthase with L-NG-monomethylarginine (LNMMA, 500 microM), an effect abrogated by L-arginine (1 mM). TNF alpha (0.0042, 0.042, and 0.42 micrograms/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exogenous norepinephrine. In BPA incubated with LNMMA (5-500 microM), TNF alpha facilitated rather than inhibited SNS. TNF alpha increased the formation of amperiometrically measured free nitric oxide in bovine adrenal chromaffin cells in primary culture. The data show that in the absence of LNMMA, TNF alpha releases free nitric oxide from a sympathetic neuron and selectively inhibits the contractions of the BPA to SNS. In BPA in which nitric oxide synthase I is inhibited by LNMMA, TNF alpha amplifies the contractions to SNS, even in the absence of endothelium. Thus, TNF alpha can modify vascular smooth muscle tone by affecting SNS. TNF alpha inhibits SNS at the level of the neuron by a mechanism involving the L-arginine-nitric oxide pathway. TNF alpha-induced suppression of SNS and neurotransmission may contribute to the hypotension and peripheral neuropathy of sepsis.     

Beta-adrenoceptor mediated facilitation of noradrenaline and adenosine 5'-triphosphate release from sympathetic nerves supplying the rat tail artery

1. The effects of prejunctional beta-adrenoceptor activation on electrically evoked noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were studied by use of continuous amperometry and conventional intracellular recording techniques. Excitatory junction potentials (e.j.ps) were used as a measure of ATP release, and NA-induced slow depolarizations and oxidation currents as measures of NA release, from postganglionic sympathetic nerves innervating the rat tail artery in vitro. 2. Isoprenaline (0.1 microM) increased the amplitude of e.j.ps, slow depolarizations and oxidation currents evoked by short trains of stimuli at 1 to 4 Hz. The facilitatory effect of isoprenaline on e.j.ps and oxidation currents was most pronounced on responses evoked by the first stimulus in a train. 3. Isoprenaline (0.1 microM) did not detectably alter the amplitude-frequency distribution of spontaneous e.j.ps. 4. The facilitatory effect of isoprenaline on e.j.ps, slow depolarizations and oxidation currents was abolished by the beta-adrenoceptor antagonist, propranolol (0.1 microM). Propranolol alone had no effect on e.j.ps, slow depolarizations or oxidation currents. 5. Thus, activation of prejunctional beta-adrenoceptors increases the release of both NA and ATP from postganglionic sympathetic nerves. The findings are consistent with the hypothesis that NA and ATP are released from the same population of nerve terminals and presumably from the same vesicles.     

Distribution of SP- and CGRP-immunoreactivity in the cat's larynx

The distribution of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive (ir) fibres in the cat's larynx was investigated utilizing immunohistochemistry. Many SP- and CGRP-ir fibres with varicosities were found within and below the epithelium and along the basement membrane of the mucosa of all different regions except in the membranous portion of the vocal fold. In the subepithelium, some SP- and CGRP-ir nerve bundles and nerve fibres were recognized around the vessels and glands. In the mucosa, the pattern of distribution and the density of SR-ir fibres were similar to those of CGRP-ir fibres. These reactive fibres were denser in the supraglottic region than in the subglottic region. In the taste bud-like structures, only SP-ir fibres appeared, whereas in the motor endplates, CGRP-reaction was found exclusively. The present findings suggest that the regional distribution of SP- and CGRP-immunoreactivity might be related with sensory and autonomic innervation in the larynx.     

Prolonged increase in micturition threshold volume by anogenital afferent stimulation in the rat

Neuroendocrine components exist in the human nasal mucosa. However, the pathophysiological and neuroimmunological roles of the regulatory peptides in allergic rhinitis (AR) require further investigation. To analyse the functional morphology and quantify the tissue concentration of regulatory peptides in the nasal mucosa of AR subjects, human inferior turbinate mucosa specimens from 25 patients with AR, 20 patients with non-allergic rhinitis and 10 patients without any nasal diseases were investigated. Using immunohistochemistry and radioimmunoassays, we detected the presence, distribution and concentrations of various neuropeptides [vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P (SP) and calcitonin gene-related peptide (CGRP)] and general neuroendocrine markers (neuron-specific enolase and chromogranin A). Quantitative analysis of the stained fibres and cells was performed using a graphic AutoCAD program. The presence and distribution of NPY, CGRP and SP nerve fibres and neuroendocrine cells were similar among the three subject groups. AR subjects had significantly higher tissue concentrations of VIP and SP. AR subjects had increased numbers of VIP fibres which predominantly innervated vessels. Thus, VIP and SP play important neuroimmunological roles in the pathogenesis of AR.     

Renal immunocytochemical distribution and pharmacological properties of the dual angiotensin II/AVP receptor

There is evidence that sympathetic nerve activity leads to endothelium-derived nitric oxide release, which in turn attenuates neurogenic vasoconstriction. Here we tested in vivo (1) whether the magnitude of the vasoconstriction induced by N(G)-nitro-L-arginine methyl ester given systemically is altered when ongoing sympathetic activity is abolished by sectioning the lumbar sympathetic trunk, and (2) whether hindlimb sympathetic vasoconstriction elicited by electrical stimulation of the lumbar sympathetic trunk is enhanced after inhibition of nitric oxide synthesis. Blood flow in the microvascular beds of hairless skin and skeletal muscle of the rat hindlimb was measured with laser Doppler flowmetry. Sectioning the lumbar sympathetic trunk resulted in an increase of blood flow in both tissues, indicating that tonic neurogenic vasoconstriction was abolished. Inhibition of nitric oxide synthesis resulted in vasoconstriction in both vascular beds. This vasoconstriction was more pronounced after abolition of sympathetic activity than with intact sympathetic supply in skin but was smaller in skeletal muscle. The vasoconstriction elicited by graded electrical stimulation of the centrally sectioned lumbar sympathetic trunk with frequencies less than 5 Hz was significantly enhanced after blockade of nitric oxide in skeletal muscle but not in skin microvasculature. These findings suggest that under physiological conditions, sympathetic nerve impulses directly promote the release of nitric oxide in skeletal muscle but not in cutaneous blood vessels. Therefore, basal nitric oxide release is probably in part dependent on sympathetic activity in skeletal muscle, whereas it appears to be mainly due to flow-dependent shear stress in hairless skin microvasculature.     

Pharmacodynamics of 2-(4-benzyl-piperidino)-1-(4-hydroxyphenyl)-1-propanol (Ifenprodil). (3) Effects on the autonomic, peripheral and central nervous systems

Effects of ifenprodil tartrate, a potent vasodilator, on the autonomic, peripheral and central nerve system were studied in experimental animals. In isolated vas deferens of guinea pigs, the contraction in response to noradrenaline and sympathetic nerve stimulation was competetively antagonized by ifenprodil 10(-7)--10(-5) M (pA2: 7.69 against noradrenaline). Ifenprodil (50 approximately 1,000 mug/kg i.v.) inhibited the contraction of cat nictitating membrane and dog urinary bladder induced by sympathetic nerve stimulation. Ifenprodil (250 approximately 1,000 mug/kg i.v.) lowered adrenaline-induced lethality (ED50: 360 mug/kg). The drug produced a hypermotility of guinea pig uterus, and showed a transient hypertonus of dog gut which was abolished by atropine. Ifenprodil (10 approximately 20 mg/kg i.v.) inhibited the propulsion of charcoal meal in mice. In Shay rats, more than 10 mg/kg i.m. of the drug inhibited the secretion of acid gastric juice and the ulceration. Ifenprodil showed a potent local anesthetic action in the guinea pig cornea and skin. The spontaneous EEG of rabbits showed a resting pattern (0.25 approximately 2 mg/kg i.v.) followed by an arousal pattern (5 approximately 10 mg/kg). Ifenprodil (20 approximately 100 mg/kg p.o.) potentiated a hypnosis induced by barbital, and potentiated pentylenetetrazol, strychnine and picrotoxin induced convulsion. The drug (20 and 100 mg/kg p.o.) lowered the body temperature of rats. From these results it is concluded that ifenprodil produces a blocking action of alpha-adrenoceptors in various smooth muscle preparations and a direct relaxation of the smooth muscle itself without affecting the motor and central nerve systems.