Excitatory amino acid receptors in the paraventricular hypothalamic nucleus mediate pressor response induced by carotid body chemoreceptor stimulation in rats

In urethane-anesthetized rats with spinal transection, antagonists of excitatory amino acid receptors, P2 purinoceptors and adrenoceptors were microinjected into the paraventricular hypothalamic nucleus (PVN) and their effects on the pressor response evoked by carotid body chemoreceptor stimulation were examined. Microinjections of the non-selective excitatory amino acid antagonist kynurenate, the non-NMDA receptor antagonist CNQX and the NMDA antagonist 2-amino-5-phosphonovalerate (AP5) into the PVN inhibited the chemoreceptor reflex-induced pressor response. The excitatory amino acid agonist L-glutamate injected into the PVN produced an increase in blood pressure. The P2 purinoceptor antagonist suramin did not affect the pressor response and ATP did not affect basal blood pressure. The alpha adrenoceptor antagonist phentolamine, prazosin and yohimbine also inhibited the chemoreceptor-induced pressor response, while the beta antagonist propranolol did not affect it. These findings indicate that excitatory amino acid receptors and alpha adrenoceptors in the PVN are involved in mediating the pressor response induced by carotid body chemoreceptor stimulation in rats.     

Effects of low pH and nicotine on carotid body chemoreceptor activity in the rabbit

Ixodes scapularis ticks acquired spirochetes while cofeeding with Borrelia burgdorferi-infected nymphs (donors) on uninfected naive gerbils. Overall, 19% (67 of 345) of the recipient nymphs randomly exposed to gerbils with donor nymphs acquired spirochetes by fluorescent antibody (FA) tests, 18% (62 of 345) by the polymerase chain reaction. In a second experiment, donor nymphs were placed on the left ears, recipient nymphs were placed on the left and right ears, and xenodiagnostic larvae were placed on the gerbils' backs. Only recipient nymphs and larvae removed from the left ears were infected with B. burgdorferi. Infection rates were 47% (9 of 19), 87% (13 of 15) and 88% (14 of 16) in recipient nymphs placed on gerbils 0, 3, or 5 days after the donor nymphs, respectively, and 48% (12 of 25) in the larvae by FA analysis. Spirochetes appear to be acquired by cofeeding ticks from a localized infection near the feeding site rather than from a disseminated infection in the skin or blood.     

ATP activates phospholipase C in the cat carotid body in vitro

In this study we investigated the hypothesis that ATP could play a role in the transduction of the hypoxic stimulus in the carotid body (CB) by being a regulator of the phosphatidylinositol-4,5-bisphosphate (PIP2)-specific phospholipase C (PLC). We addressed this question by comparing the PLC activity in the absence and presence of ATP in homogenates of CBs dissected from anesthetized cats that were preexposed in vivo to the contrasting conditions of normoxia (PaO2 approximately 90 mmHg) and hypoxia (PaO2 approximately 20 mmHg). The tissue of a nearby superior cervical ganglion (SCG) was used as a reference. The homogenate was the source of PLC. PLC activity was assayed by measuring the formation of radioactive inositol 1,4,5-trisphosphate from [3H]PIP2, used as an exogenous substrate. ATP was added to the assay mixture at the concentrations of 0.25 mM and 1 mM, chosen on the basis of test trials on ATP dependence of PLC changes. We found that ATP increased appreciably the PLC activity over its basal (absence of ATP) level in the normoxic carotid body. The stimulatory effect of ATP was augmented in the hypoxic carotid body, the lower ATP concentration having a stronger effect. Such PLC changes were absent in the SCG. These findings suggest a regulatory role for ATP in the PLC-linked hypoxic signal transduction in the carotid body.     

Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN

This multicentre, double-blind, randomised, crossover study compared the efficacy, safety and tolerability of subcutaneous sumatriptan (6 mg and 12 mg) with placebo in 134 in-patients with cluster headache. Headache improvement to mild or no pain at 5, 10 and 15 min after treatment was recorded. At 10 min, headache relief was reported by 25% (placebo), 49% (6 mg) and 63% (12 mg) of patients and at 15 min the results were 35% (placebo), 75% (6 mg) and 80% (12 mg) (p < 0.001 for all comparisons with placebo). The 12 mg dose was not significantly better than the 6 mg dose and was associated with more adverse events. The 6 mg dose is therefore recommended for the acute treatment of cluster headache.     

Evidence for two different types of P2 receptors stimulating insulin secretion from pancreatic B cell

Escherichia coli heat-labile enterotoxin (LT) consists of an A subunit and five B subunits. These subunits oligomerize into an assembled holotoxin within the periplasm. Structural analysis of LT has revealed that the A subunit interacts with the B subunit through its carboxy terminus. This indicates that the carboxy-terminal portion of the protein is required for assembly of holotoxin in the periplasm. However, it is not known whether other regions of the A subunit contribute to the assembly. The A subunit constituting the holotoxin contains a disulfide bond between Cys-187 and Cys-199. It has been observed in many proteins that the intramolecular disulfide bond is deeply involved in the function and tertiary structure of the protein. We speculated that the disulfide bond of the A subunit contributes to the assembly in the periplasm, although the bond is not a structural element of the carboxy-terminal portion of the A subunit. We replaced these cysteine residues of the A subunit by oligonucleotide-directed site-specific mutagenesis and analyzed the LTs produced by cells containing the mutant LT genes. The amount of the mutant holotoxin produced was small compared with that of the wild-type strain, indicating that the disulfide bond of the A subunit contributes to the structure which functions as the site of nucleation in the assembly. A reconstitution experiment in vitro supported the notion. Subsequently, we found that the mutant A subunit constituting holotoxin is easily degraded by trypsin and that in cells incubated with mutant LTs, the lag until the intracellular cyclic AMP begins to accumulate is longer than in cells incubated with native LTs. These results might be useful for the analysis of the interaction of LT with target cells at the molecular level.     

Opposite effects of lanthanum on different types of nicotinic acetylcholine receptors

The effects of lanthanum (La3+) were studied on muscle and neuronal nicotinic acetylcholine receptors (AChRs) expressed in Xenopus oocytes. La3+ exerts a dose-dependent positive modulation on alpha1 beta1 gamma8 muscle AChRs, whereas it modulates negatively either alpha2 beta2, alpha2 beta4 or alpha3 beta4 neuronal AChRs. Moreover, La3+ appears to accelerate the desensitization of neuronal receptors. In both muscle and neuronal AChRs, the respective potentiating or inhibiting effects of La3+ on the ACh-currents are voltage-independent, suggesting that La3+ is acting at a site located in the external domain of the receptor.     

Atrial receptors in the cat

Action potentials were recorded from slips of the cervical vagi in anaesthetized cats. Single functional units with atrial patterns of discharge (type A, B and Intermediate) were first obtained and then attempts were made to alter (i.e. convert) their patterns of discharge. Finally the points of origin of their action potentials were located. The investigations were done in five stages. 2. In the first series, thirty unselected units were investigated in thirty cats. Twenty-five of these were located in the endocardium of vein-atrial system and consisted of two type A, fifteen type B and eight Intermediate type units. The remaining five units were located elsewhere in the chest Conversion of the pattern of discharge was achieved in sixteen of the twenty-five atrial units. Both atrial type A units were converted. 3. In the second series, eight type A units were selectively studied in twelve cats. Five were located in the atrial endocardium and all were converted. Of the other three units which were located at other sites in the chest, one could not be converted. 4. In the third series, four type A units which could not be converted were selectively studied in twenty cats. All were located outside the atria. 5. In the fourth series, three type B units which could not be converted were selectively studied in six cats. These units were located in the pulmonary veins and in the lateral walls of the atria. 6. In the fifth series, fifty-five units were investigated in three anaesthetized spontaneously breathing cats. The proportion of the types of units were similar to that obtained in the artificially respired cats (first series). 7. The present study has shown that atrial receptors with a type A pattern of discharge are relatively rare in the cat and that conversion of the patterns of discharge is a common phenomenon. Evidence is presented which suggests that there is one basic type of atrial receptor whose pattern of discharge is determined by their precise location in the vein-atrial system.     

Innervation of the carotid body, types of nerve endings and their possible significance

The nerve endings in the carotid body of normal cats are investigated by means of serial sections. Two types of endings not described previously are especially studied: the non-synaptic bouton and the meniscus with prolongations. The first is a small nerve ending with abundant mitochondria and glycogen which is devoid of synaptic vesicles. The second is a normal meniscus which presents prolongations containing the same cytological elements of the nonsynaptic boutons. It is proposed that some menisci are lateral endings of an afferent fiber. Relating these results with well-known functional characteristics of the carotid body, the existence of axonal reflexes is suggested. These views can explain apparently contradictory facts.     

NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

N-methyl-D-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (VE) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (VT) decreased while frequency increased, resulting in a modest reduction in VE. Inspiratory time (TI) decreased, whereas expiratory time remained unchanged. The VE responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (VT/TI) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas VT was unaffected. Sodium cyanide doses associated with significant VE increases were 5 and 50 microg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reduced VE during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.     

Tumor of the carotid body

Clinical and X-ray examinations for hip dysplasias in 500 babies in one ward showed 40% wrongly positive and 5.6% wrongly negativ (silent or masked) results, control of which necessiates roentgenograms in the second or third month or coltrolled spreading immediately after birth.     

Rapid synaptic transmission in the avian ciliary ganglion is mediated by two distinct classes of nicotinic receptors

We analyzed the kinetics and pharmacology of EPSCs in two kinds of neurons in the embryonic avian ciliary ganglion. Whole-cell voltage-clamp recordings revealed that the singly innervated ciliary neurons had large-amplitude (1.5-8.0 nA) EPSCs that could be classified according to the kinetics of their falling phases. Most of the neurons responded with an EPSC the falling phase of which followed a double exponential time course with time constants of approximately 1 and 10 msec. The EPSCs of the remaining ciliary neurons followed a single time constant ( approximately 8 msec). Multiple innervated choroid neurons had smaller-amplitude responses (0.2-1.5 nA when all inputs were activated) that appeared to contain only a slowly decaying component (tau = 12 msec). The fast and slow components of EPSC decay seen in most ciliary neurons could be pharmacologically isolated with two toxins against nicotinic acetylcholine receptors (AChRs). The fast component was blocked by 50 nM alpha-bungarotoxin (alpha-BuTx), which binds alpha7-subunit-containing AChRs. The slow component was selectively blocked by 50 nM alpha-conotoxin MII (alpha-CTx-MII), which blocks mammalian AChRs containing an alpha3/beta2 subunit interface. A combination of both alpha-BuTx and alpha-CTx-MII abolished nearly all evoked current. Similar pharmacological results were found for ciliary neurons with monoexponentially decaying EPSCs and for choroid neurons. These results suggest that nerve-evoked transmitter acts on at least two different populations of AChRs on autonomic motor neurons in the ciliary ganglion.     

Effects of different natural stimulants on the activity of the rabbits' carotid chemoreceptor

The effects of different natural stimulants on the afferent unit discharge of rabbit carotid chemoreceptors were studied in the in vitro carotid body- sinus nerve preparation. A total of 32 chemoreceptive units were recorded. The results were as follows: (1) Of the 32 units, 10 (31%) showed chemosensory responses only to PO2 decrease; 9 (28%) to all stimulants (PO2 decrease, PCO2 increase and pH decrease); 9 (28%) to PO2 decrease and PCO2 increase; 3 (9%) to PO2 decrease and pH decrease; only one to pH decrease. (2) The potency of the three natural stimulants in eliciting the changes in intensity of discharge showed a decreasing order as follows: PO2 decrease > PCO2 increase > pH decrease. The above results suggest that the carotid body may contain only one or a combination of 2 or 3 kinds of chemoreceptors respectively sensitive to decrease PO2 to increase PCO2 or decrease pH.     

Evidence for two differentially regulated populations of peripheral beta-endorphin-releasing cells in humans

In the current study we tested the hypothesis that human plasma beta-endorphin (beta E) is derived from at least two subpopulations of beta E-releasing cells: one sensitive to glucocorticoids as well as to dopamine (DA; regulated analogously to the corticotrophs of the rat pituitary), and one insensitive to glucocorticoids but sensitive to DA (regulated analogously to the melanotrophs of the rat pituitary). To test this hypothesis, human plasma levels of ACTH, cortisol, and beta E-like immunoreactivity were measured at baseline and after haloperidol treatment (0.05 mg/kg, i.v.) in two experimental groups, one pretreated with dexamethasone (1.5 mg) and one pretreated with placebo. Plasma PRL levels were also measured in both groups as an indicator of DA receptor blockade. Dexamethasone partially suppressed both baseline and haloperidol-stimulated levels of human plasma beta E-like immunoreactivity, whereas it completely suppressed both basal and haloperidol-stimulated levels of ACTH and cortisol and had no statistically significant effect on either basal or haloperidol-stimulated PRL levels. These data support a negative feedback effect of glucocorticoids on one DA-sensitive cell population that releases both ACTH and beta E (corticotroph like), but not on a second cell population that releases beta E but not ACTH.     

Evidence for two types of spatial representations: Hemispheric specialization for categorical and coordinate relations.

Analyses of human object recognition abilities led to the hypothesis that 2 kinds of spatial relation representations are used in human vision. Evidence for the distinction between abstract categorical spatial relation representations and specific coordinate spatial relation representations was provided in 4 experiments. These results indicate that Ss make categorical judgments—on/off, left/right, and above/below—faster when stimuli are initially presented to the left cerebral hemisphere, whereas they make evaluations of distance—in relation to 2 mm, 3 mm, or 1 in. (2.54 cm)—faster when stimuli are initially presented to the right cerebral hemisphere. In addition, there was evidence that categorical representations developed with practice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrus- and ovariectomy-induced body weight changes: Evidence for two estrogenic mechanisms.

Estrogenic modulation of body weight in female rats is usually thought to result indirectly from estrogenic modulation of food intake. However, present data from 5 experiments with 79 female albino rats suggest that estrogens influence body weight by at least 2 mechanisms, 1 of which is independent of changes in food intake. When Ss were ovariectomized (Ovx) and food intake was limited to preoperative levels, Ovx Ss nonetheless gained large amounts of body weight. Although Ovx Ss gained more weight than controls on the same amount of food, during 33 hrs of food deprivation Ovx and control Ss lost weight at the same rate, indicating that the prefasting metabolic rates of the 2 groups were similar. During the 1st 40 days after surgery, the ano-nasal lengths of Ovx Ss increased twice as fast as that of intact Ss, which suggests a mechanism for the gradual increase in weight induced by Ovx. The weights of intact Ss followed a regular 4-day cycle during ad lib feeding, but when the estrus-associated decrease in food intake was prevented, the cyclic weight changes were altered. Thus estrogens appear to regulate body weight by modulation of food intake and modulation of ano-nasal growth or other metabolic processes. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species

The effects of the carbamate physostigmine and of the organophosphates (OPs) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were examined on different subtypes of neuronal nicotinic acetylcholine receptors (nAChR). Stimulation with 1 mM ACh induced transient nicotinic inward currents in mouse N1E-115 and human SH-SY5Y neuroblastoma and in locust thoracic ganglion cells. All four acetylcholinesterase (AChE) inhibitors reduced the nicotinic currents in a concentration-dependent manner. Parathion is about 50 times more potent in blocking nAChR, compared to its active AChE inhibiting metabolite paraoxon. The relative blocking potency of the different AChE inhibitors was the same in all cell types, and followed the order parathion > physostigmine > PSP > paraoxon. In N1E-115 cells the IC50 values of block amounted to 2 microM, 30 microM, 39 microM and 96 microM for parathion, physostigmine, PSP and paraoxon, respectively. In all cell types, the nicotinic currents were equally blocked by parathion. Human nAChR in SH-SY5Y cells appeared more sensitive to block by physostigmine, PSP and paraoxon, while these AChE inhibitors similarly inhibited nicotinic currents in insect cells and in mouse neuroblastoma cells. The observation that the concentration-dependence of block is different from that of AChE inhibition, indicates a distinct interaction of AChE inhibitors with nAChR. Only in locust cells physostigmine induced a non-desensitizing inward current, that appeared to originate from nAChR activation. Occasionally, the OPs were able to activate slow ionic currents in mouse, but not in human and locust cells. As the OP-induced agonistic activity in mouse cells was not associated with the blocking action, the target site appeared to be distinct from nAChR. These results show that AChE inhibitors block nAChR with different potencies, dependent on the compound and the receptor subtype, and may activate distinct ion currents in neuronal cells of different species origin.