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Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors. Norepinephrine (NE) signaling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release. However, there is also evidence for NE inhibition of CRH neurons (possibly via beta receptors), an effect that may occur at higher levels of stimulation, suggesting that NE effects on the HPA axis may be context-dependent. Lesions of ascending NE inputs to the paraventricular nucleus attenuate stress-induced ACTH but not corticosterone release after chronic stress, indicating reduction in central HPA drive and increased adrenal sensitivity. Non-catecholaminergic NTS glucagon-like peptide 1/glutamate neurons play a broader role in stress regulation, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress. Overall, the data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Mammalian aortic bodies (ABs) are putative peripheral arterial chemoreceptors whose function remains controversial, partly because information on their cellular physiology is lacking. In this study, we used ratiometric Ca2+ imaging to investigate for the first time chemosensitivity in short-term cultures of dissociated cells of juvenile rat ABs, located near the junction of the left vagus and recurrent laryngeal nerves. Among the surviving cell population were glomus or type I cell clusters, endogenous local neurons and glia-like cells. A variety of chemostimuli, including hypoxia, isohydric or acidic hypercapnia, and isocapnic acidosis, caused a rise in intracellular [Ca2+] in AB type I cells. The [Ca2+]i responses were indistinguishable from those in carotid body (CB) type I cells grown in parallel cultures from the same animals, and responses to acidic hypercapnia were prevented by the non-specific voltage-gated Ca2+ channel antagonist, 2mM Ni2+. Furthermore, we identified a subpopulation (∼40%) of glia-like cells in AB cultures that resembled CB type II cells based on their approximately equal sensitivity to ATP and UTP, consistent with the expression of purinergic P2Y2 receptors. Finally, we showed that some local neurons, known to be uniquely associated with these AB paraganglia in situ, generated robust [Ca2+]i responses to these chemostimuli. Thus, these AB type I cells and associated putative type II cells resemble those from the well-studied CB. Unlike the CB, however, they also associate with a special group of endogenous neurons which we propose may subserve a sensory function in local cardiovascular reflexes.

Vagal paraganglia resemble the carotid body and are chemosensitive to reduction in the partial pressure of oxygen (P O2) (O'Leary et al., 2004). We hypothesised that they may also mediate communication between the immune system and the central nervous system and more specifically respond to the pro-inflammatory cytokines: interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). We recorded axonal firing rate of isolated superfused rat glomus cells - located at the bifurcation of the superior laryngeal nerve - to IL-1 beta or TNF-alpha at concentrations of 0.5 ng/ml, 5 ng/ml and 50 ng/ml. Twenty-three successful single fibre recordings were obtained from 10 animals. IL-1 beta and TNF-alpha had no statistically significant effect on the frequency of action potentials observed (p=0.39 and 0.42, respectively, repeated measures ANOVA). The activity of both cytokines was tested by observing translocation of P65-NF kappaB from cytoplasm to nucleus in cultured HELA cells. In conclusion, an immune role for SLN paraganglia has not been established., ((c) 2010 Elsevier B.V. All rights reserved.)

Rationale: Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated., Objectives: The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect., Methods: We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique., Measurements and Main Results: Nociceptin (3 mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current., Conclusion: These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.

To test the hypothesis that vagal afferent (VA) stimulation modulates the first cervical dorsal horn (C(1)) neuron activity, which is projected by tooth pulp (TP) afferent inputs through the activation of a local GABAergic mechanism via 5-hydroxytryptamine(3) (5-HT(3)) receptors, we used the technique of microiontophoretic application of drugs. In pentobarbital-anesthetized rats, we recorded C(1) spinal neuron activity responding to TP stimulation. The TP stimulation-evoked C(1) spinal neuron excitation was inhibited by VA stimulation, and this inhibition was significantly attenuated by iontophoretic application of the 5-HT(3) receptor antagonist ICS 205-930 (3-tropanyl-indole-3-carboxylate hydrochloride [endo-8-methyl-8-azabicyclo [3.2.1] oct-3-ol indol-3-yl-carboxylate hydrochloride]) (40 nA) or the GABA(A) receptor antagonist bicuculline (40 nA). In another series of experiments, we determined that 60 nA iontophoretic application of glutamate produced a maximal increase in the C(1) spinal neuron activity at a minimal current. In 53 of 65 neurons (81.5%), VA conditioning stimulation (1.0 mA x 0.1 ms, 50 Hz for 30 s) caused a significant inhibition (35.1%) of the glutamate (60 nA) application-evoked C(1) spinal neuron excitation. Iontophoretic application of ICS 205-930 (40 nA) or bicuculline (40 nA) significantly attenuated the VA stimulation-induced inhibition of glutamate iontophoretic application (60 nA)-evoked C(1) spinal neuron excitation. These results suggest that VA stimulation-induced suppression of C(1) spinal neuron activity, responding to TP stimulation, involve 5-HT(3) receptor activation, possibly originating in the descending serotonergic inhibitory system, and postsynaptic modulation of inhibitory GABAergic neurons.

It has been shown that peripheral chemoreceptor sensitivity is enhanced in both clinical and experimental heart failure (HF) and that impairment of nitric oxide (NO) production contributes to this enhancement. In order to understand the cellular mechanisms associated with the alterations of chemoreceptor function and the actions of NO in the carotid body (CB), we compared the outward K+ currents (IK) of glomus cells in sham rabbits with that in HF rabbits and monitored the effects of NO on these currents. Ik was measured in glomus cells using conventional and perforated whole-cell configurations. IK was attenuated in glomus cells of HF rabbits, and their resting membrane potentials (-34.7 +/- 1.0 mV) were depolarized as compared with those in sham rabbits (-47.2 +/- 1.9 mV). The selective Ca(2+)-dependent K+ channel (KCa) blocker iberiotoxin (IbTx, 100 nm) reduced IK in glomus cells from sham rabbits, but had no effect on IK from HF rabbits. In perforated whole-cell mode, the NO donor SNAP (100 microm) increased IK in glomus cells from HF rabbits to a greater extent than that in sham rabbits (P < 0.01), and IbTx inhibited the effects of SNAP. However, in conventional whole-cell mode, SNAP had no effect. N omega-nitro-L-arginine (L-NNA, NO synthase inhibitor) decreased Ik in sham rabbits but not in HF rabbits. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) inhibited the effect of SNAP on Ik. These results demonstrate that IK is reduced in CB glomus cells from HF rabbits. This effect is due mainly to the suppression of KCa channel activity caused by decreased availability of NO. In addition, intracellular cGMP is necessary for the KCa channel modulation by NO.

Bromocriptine, a dopamine agonist, is known to lower cardiovascular mortality in L-dopa-treated patients with Parkinson's disease, probably by reducing the cardiac sympathetic activity. We aimed at unmasking the central effects of bromocriptine on the heart by power spectrum analysis. Ten healthy subjects (aged 31+/-2 years) in supine and sitting positions were evaluated after the administration of bromocriptine (2.5 mg) alone and after pharmacological peripheral D(2)-like blockade by domperidone (20 mg). We calculated (autoregressive method) the following: the low-frequency (LF) component (an index of cardiac sympathetic tone), the high-frequency (HF) component (an index of cardiac vagal tone), and the LF/HF ratio (an index of cardiac sympathovagal balance). With subjects in the supine position, bromocriptine alone induced a significant increase in the LF component and the LF/HF ratio, together with a reduction in norepinephrine plasma levels and blood pressure values. These conflicting effects can be explained as the combined result of direct and indirect (reflex-mediated) actions of bromocriptine in vivo. No changes in cardiac autonomic drive were observed with subjects in the sitting position. After domperidone pretreatment, bromocriptine induced a reduction in the LF component and in the LF/HF ratio. The sitting position caused an increase in heart rate and in the LF/HF ratio. We demonstrated both peripheral and central effects of bromocriptine. In particular, pretreatment with a peripheral antagonist (domperidone) allowed us to unmask the central effect of bromocriptine on cardiac sympathetic drive.

Background: Incidence of sudden cardiac death peaks during the early morning hours when there is a rapid withdrawal of vagal and an increase of sympathetic tone. The rate of autonomic change could be of prognostic importance., Patients and Methods: A total of 65 patients with angina pectoris, free from other diseases and drug free, were Holter monitored for 24 h. A total of 30 patients were also monitored on isosorbide-5-mononitrate (IS-5-MN) and on metoprolol respectively. A total of 33 age-matched healthy subjects served as controls. Spectral components of heart rate variability (HRV) were analysed hourly, with special reference to the rapid changes of autonomic tone during the night and early morning hours. Circadian variation was assessed in two ways: (1) Mean HRV day (8 a.m.-8 p.m.) and night (0-5 a.m.) were compared. (2) For the morning/night hours (0-10 a.m.), individual hourly values for max. and min. HRV, the difference max.-min. (gradient), the rate of change per hour between max. and min. (velocity) and the largest difference between two consecutive hours (max. velocity) were recorded and the mean value for the group calculated., Results: During the night/morning hours, healthy controls demonstrated faster HF max. velocity (P=0.002) and higher HF gradient (P=0.011) than angina patients. Metoprolol and IS-5-MN increased the HF gradient (P=0.008 and P=0.003, respectively), and metoprolol tended to increase the max. velocity (P=0.02). Metoprolol substantially decreased the LF/HF gradient (P=0.001), velocity (P=0.008) and max. velocity (P=0.0001)., Conclusion: Rapid vagal withdrawal seemed to be a sign of a healthy autonomic nervous system in the control group but was significantly slower in angina patients. IS-5-MN and metoprolol tended to normalise vagal withdrawal and metoprolol slowed down the rapid increase in sympathetic predominance in the morning in patients.

Studies in vitro suggest that cephalosporin antibiotics release the gut hormone cholecystokinin. Cholecystokinin is known to inhibit gastric emptying. Here we examine the effects of cefaclor on gastric emptying and intestinal motility. Male Sprague-Dawley rats were fitted with gastric cannulas. Following a 3-week recovery, the rate of gastric emptying of saline, peptone (4.5%) or cefaclor was determined after instillation into the gastric cannula, while intestinal transit was measured by using the propagation of arabic gum + charcoal mixture given intraduodenally. Gastric emptying of saline was significantly delayed by the addition of cefaclor (3, 10, 30 or 100 mM). The CCK-A antagonist SR-27897B (1 mg kg(-1), i.p.) reversed the delay induced by 10 mM cefaclor, whereas the CCK-B antagonist CI-988 (1 mg kg(-1), i.p.) had no significant effect. In capsaicin-treated rats, 10 mM cefaclor emptied more rapidly than in vehicle-treated animals. Thirty-minute intestinal transit was increased at 30 and 100 mM of cefaclor, while the gastric acid secretion following cefaclor instillation was no different than the group which received saline. The cephalosporin antibiotic cefaclor appears to be a potent stimulant of CCK release from gut endocrine cells, resembling the effects of peptone. Cefaclor delays gastric emptying via capsaicin-sensitive afferent pathways, which involve CCK-A receptor interaction.

The role of nitric oxide (NO) in the vagal modulation of heart rate (HR) is controversial. We tested the hypothesis that NO acts via a pre-synaptic, guanylyl cyclase (GC) dependent pathway. The effects of inhibiting NO synthase (NOS) and GC were evaluated in isolated atrial/right vagal nerve preparations from adult (550-750 g) and young (150-250 g) female guinea pigs. Levels of NOS protein were quantified in right atria using Western blotting and densitometry. The non-specific NOS inhibitor N- omega -nitro- L -arginine (L -NA, 100 microM, n=5) significantly reduced the negative chronotropic response to vagal nerve stimulation (VNS) at 3 and 5 Hz in the adult guinea pig. This effect was reversed with 1 m ML -arginine. Similar results were observed with the specific neuronal NOS inhibitor vinyl-N5-(1-imino-3-butenyl)- L -ornithine (L -VNIO, 100 microM, n=7). Inhibition of GC with 1H-(1,2,4)-oxadiazolo-(4, 3-a)-quinoxalin-1-one (ODQ, 10 microM, n=7) also significantly reduced the negative chronotropic response to VNS at 3 and 5 Hz in adult guinea pigs. Neither L -NA (n=6), L -VNIO (n=5) nor ODQ (n=6) changed the HR response to cumulative doses of carbamylcholine in adult guinea pig atria suggesting that the action of NO is pre-synaptic. The HR response to VNS was unaffected by L -NA (n=7) or ODQ (n=7) in young guinea pigs and Western blot analysis showed significantly lower levels of nNOS protein in right atria from young animals. These results suggest a pre-synaptic NO-cGMP pathway modulates cardiac cholinergic transmission, although this may depend on the developmental stage of the guinea pig., (Copyright 2000 Academic Press.)

It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in Sprague-Dawley rats was recorded. Intravenous infusion of CCK-8 (0.1-1 nmol) suppressed the efferent activity. The effect of CCK-8 was significantly reduced in animals with total subdiaphragmatic vagotomy in comparison to those with partial vagotomy. Intravenous infusion of CCK(A) receptor antagonist L-364,718 (1-100x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8, but the CCK(B) receptor antagonist L-365,260 (1-100x10(-6) g) did not in the conditions of either partial or total vagotomy. Intracisternal infusion of L-364,718 (1x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8 i.v. Infusion of exogenous CCK-8 did not affect the activity of supradiaphragmatic vagal afferents. The results suggest that the effect of systemically administered CCK-8 on vagal efferent activity is mediated by both peripherally (subdiaphragmatically) and centrally localized CCK(A) receptors.

Background: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling., Methods and Results: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF., Conclusions: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

1. The reflex changes in the inotropic state of the left ventricle, measured as the dP/dt max (maximum rate of change of pressure), occurring in response to selective stimulation of the carotid and aortic body chemoreceptors by sodium cyanide, were studied in the cat anaesthetized with a mixture of chloralose and urethane. 2. The animals were artificially ventilated with an open pneumothorax. The heart rate and mean arterial blood pressure were maintained constant. 3. With on-going central respiratory activity, stimulation of the carotid bodies caused an increase in respiratory movements. Variable changes in left ventricular dP/dt max occurred, the predominant response being an increase. The mean change was 8.3 +/- 2.9 % from a control value of 6850 +/- 450 mmHg s-1. Stimulation of the aortic bodies resulted in a smaller increase in respiration or no effect, but a significant increase occurred in left ventricular dP/dt max of 19.6 +/- 2.9 % from a control value of 6136 +/- 228 mmHg s-1. No significant changes in left ventricular end-diastolic pressure occurred in response to stimulation of either group of chemoreceptors. 4. Tests of chemoreceptor stimulations were repeated during temporary suppression of the secondary respiratory mechanisms: the central respiratory drive was suppressed reflexly by electrical stimulation of the central cut ends of both superior laryngeal nerves and lung stretch afferent activity was minimized by stopping artificial respiration. Carotid body stimulation again evoked variable responses, the predominant now being a reduction in left ventricular dP/dt max of 3.1 % from a control value of 5720 +/- 320 mmHg s-1, which was significantly different to that occurring during on-going spontaneous respiration. Aortic body stimulation caused an increase in left ventricular dP/dt max similar to the response during on-going spontaneous respiration. 5. The positive inotropic responses were mediated via the sympathetic nervous system, as indicated by their abolition as a result of intravenous injections of the beta-adrenoceptor blocking agent, propranolol. 6. It is concluded that the carotid bodies exert a small variable effect on left ventricular dP/dt max, the predominant positive inotropic response being due to the concomitant neurogenic effects of the increase in respiration. In contrast, the positive inotropic response to excitation of the aortic chemoreceptors is not respiratory modulated.

Respiratory sinus arrhythmia (RSA) is often quantified by computing the spectra of heart period (HP) or of its reciprocal heart rate (HR) at the respiratory frequency. This study was undertaken to describe the effect of an acute beta-blockade achieved with bisoprolol on RSA, obtained during a calibrated breathing (breathing frequency 0.25 Hz, tidal volume VT 500 or 700 mL) in 15 normal volunteers, using a double-blind, placebo-controlled, cross-over method. The two heart signals were computed and the RSA values were compared to the individual estimates of vagal tone obtained using an additional atropine injection. The difference between the HP (or HR) value obtained after beta-blockade and the HP (or HR) value observed following the double blockade (bisoprolol plus atropine) was taken as an index of cardiac vagal tone. Bisoprolol administration resulted in a significant reduction in HR reaching 60.3 +/- 1.4 bpm at VT of 500 mL (compared to 70.5 +/- 1.8 bpm with placebo, P < 0.001). Changes in HP were also significant with an increase in HP reaching 1004.5 +/- 22.2 msec at this controlled VT (compared to 860.3 +/- 21.5 msec with placebo, P < 0.001). Similar changes were observed at a VT of 700 mL. The relationship between RSA in bpm and vagal tone was not significant for HR while a significant positive relationship was observed between RSA in msec and vagal tone for the two respiratory patterns (r = 0.65 for a tidal volume of 500 mL, P < 0.01, and r = 0.62 for 700 mL, P < 0.05). This demonstrates that the detection of the variability effect highly depends upon the unit. The parallelism between vagal tone and RSA supports the view that the HF component of HRV in msec quantifies the vagal tone. The increased RSA during beta-blockade could well reflect this vagotonic effect of this class of drugs.

1. The reflex changes in the dromotropic state of the heart (P-R interval or atrioventricular conduction time) in response to selective stimulation of the carotid and aortic bodies by sodium cyanide were studied in the anaesthetized cat. The heart was paced and the arterial blood pressure was kept constant to minimize secondary effects of changes in arterial baroreceptor activity. 2. Stimulation of the carotid and aortic bodies caused an increase in the atrioventricular conduction time. 3. Evidence is presented to suggest that this negative dromotropic response was due predominantly to a vagal cholinergic mechanism. There is a small sympathetic component but only in so far as the carotid body reflex is concerned. 4. The negative dromotropic responses were enhanced during reflex suppression of the central inspiratory neuronal drive combined with minimal activity of the slowly adapting pulmonary stretch afferents indicating that they are respiratory modulated. 5. The clinical implications of these results are discussed.

Previous studies have shown that injection of galanin (GAL: 6.2 nmol/kg) causes prolonged inhibition of cardiac vagal action in anaesthetised cats. Stimulation of the cardiac sympathetic nerve (16 Hz for 5 min) also produces inhibition of cardiac vagal action, an effect which has been proposed to be due to the release of endogenous GAL from sympathetic nerves. In a previous study we tested galantide (M15) and in this study we compared galantide with two other GAL antagonists for their GAL antagonist activity in our experimental model. Each of these incorporate the N-terminal fragment GAL 1-13 and a C-terminal portion of another bioactive peptide and all are C-terminally amidated. GAL 1-13 Substance P 5-11 amide (galantide: M15: 62 nmol/kg and 156 nmol/kg), GAL 1-13 Spantide amide (C7: 156 nmol/kg) and GAL 1-13 NPY 24-36 amide (M32a: 62 nmol/kg) all significantly reduced the cardiac vagal inhibitory effect of exogenous GAL and also reduced the effect of sympathetic stimulation on subsequent cardiac vagal slowing, giving strong support to our hypothesis that GAL is involved in this phenomenon. No antagonist reduced the depressor effect of GAL. This study demonstrates the GAL antagonist properties of these agents on autonomic neuroeffector functions making them useful tools in elucidating further functions of endogenous GAL.

Adenosine, which is released during hypoxia, increases carotid chemoreceptor discharge. It is not known if adenosine also may stimulate the aortic chemoreceptors. The purpose of this study was to investigate if adenosine also can stimulate aortic chemoreceptors. The effect of adenosine (0.01, 0.1 and 1.0 mumol/kg) on aortic chemoreceptor discharge was studied in seven anesthetized, paralyzed and artificially ventilated adult cats. Intra-aortic injections of adenosine produced an increase in chemoreceptor discharge, which reached its peak between 10 and 20 s. The chemoreceptor augmentation increased with higher doses of adenosine. Adenosine also caused a fall in blood pressure. The increase of chemoreceptor discharge was not related to fall in arterial blood pressure. Since adenosine is released during hypoxia, it is suggested that part of the cardiovascular changes induced by hypoxia is due to stimulation of aortic chemoreceptors by adenosine.

In anesthetized dogs, almitrine (0.5-3 mg/kg i.v.) induced a dose-dependent increase in respiratory rate and ventilation. The aortic and carotid chemoreceptors were involved in the effects of almitrine. Section of both carotid sinus nerves and vagus nerves abolished the effects of the drug on respiration. The respiratory response did not occur in dogs with bilateral lesions of the nucleus of the solitary tract. The electrical activity of chemoreceptor fibres was increased. Perfusion of almitrine into the carotid artery stimulated respiration. Inhalation of pure oxygen shifted the dose-response curve of the respiratory effect towards the right. Almitrine slightly stimulated ventilation in dogs with bilateral section of carotid sinus nerves and aortic nerves and this disappeared when both vagus nerves were cut indicating that this effect was mediated through some chemoreceptor fibres present in the vagus nerves or through afferent vagal fibres.

Sixteen cats were studied to test the hypothesis that oxygen chemoreception in the cat aortic body is dependent on the beta-adrenergic mechanism. The chemoreceptor activity was measured from a few aortic chemoreceptor afferents in each cat, anesthetized with alpha-chloralose (60 mg X kg-1). Three types of experiments were conducted. Aortic chemoreceptor responses to steady-state hypoxia (PaO2 range, 100-30 Torr) were measured (a) before and during intravenous infusion of the beta-receptor agonist, isoproterenol (0.5 micrograms X kg-1) in nine spontaneously breathing cats, and (b) before and after intravenous injection of the beta-receptor antagonist, propranolol (1 mg X kg-1) in seven cats which were paralyzed and artificially ventilated. In the third category (c) the stimulatory effect of hypotension on aortic chemoreceptor activity was measured in six of the seven cats in group (b) before and after propranolol injection. Isoproterenol infusion only moderately stimulated aortic chemoreceptor activity. This stimulation was blocked by propranolol. However, propranolol did not attenuate aortic chemoreceptor responses to hypoxia or to hypotension. We conclude that the beta-receptor adrenergic mechanism does not mediate oxygen chemoreception in the cat aortic body.

Transversal and longitudinal aortic bulb strips show isometric contractions in response to the vasotocin action. The extreme sensitivity of the preparations correspond to a final hormone concentration of 8.25 X 10(-16) M.

Aortic chemoreceptor activity, from single- or few-fiber afferent nerve preparations, was measured in response to dopamine and a dopaminergic blocker, haloperidol, in 18 anesthetized cats. In six of these cats the effect of dopamine was assessed before and after inhibiting monoamine oxidase (MAO) by pargyline. Intravenous dopamine infusion (7-14 microgram X kg-1 X min-1) had a generally inhibitory effect on aortic chemoreceptor activity, but the magnitude of this effect varied with arterial partial pressure of O2 (Pao2) levels. The inhibitory effect of dopamine increased as Pao2 levels fell, and at severely hypoxic Pao2 levels (below 30 Torr) exogenous dopamine had no significant effect. The inhibitory effect of dopamine also increased during hyperoxic hypercapnia. Blockade of dopamine receptors in the aortic body by haloperidol-stimulated chemoreceptor activity significantly during hypoxia, suggesting an O2-dependent release of dopamine from the aortic body as Pao2 falls. Inhibition of MAO by pargyline had no significant effect on the control rate of activity at any level of Pao2 but augmented the inhibitory effect of exogenously administered dopamine. These data indicate that MAO is not significantly involved in the degradation of endogenous dopamine at the aortic receptor sites, but may participate in the degradation of exogenous dopamine.

The participation of afferences from carotid and aortic bodies to the hyperventilation caused by cytotoxic hypoxia was assessed in pentobarbitone-anesthetized cats. Dose-response curves for the ventilatory effects induced by i.v. injections of NaCN were obtained before and after successive denervations of peripheral chemoreceptors, in different sequences. Bilateral aortic neurotomy (BAN) or unilateral carotid neurotomy (UCN) did not affect significantly the minimal sensitivity to the drug, although maximal reactivity was reduced in some cats. After bilateral carotid neurotomy (BCN), with preservation of aortic nerves, sensitivity was reduced, but hyperventilation was still provoked by large doses of cyanide. BAN + BCN abolished the ventilatory responses to the drug. In cats with BAN + UCN, ventilatory responses had a high degree of correlation with increases of carotid chemosensory discharges in the range between ca 200% of control and the gasping threshold. It is concluded that the aortic bodies of the cat play a significant role in the hyperventilation produced by cytotoxic hypoxia, although it is less marked than that induced through the carotid bodies.

Young male and female New Zealand white rabbits were given a daily subcutaneous injection of reserpine (Serpasil, Ciba; 3 mg/kg) for two days and were sacrificed 24 hours after the last injection. The subclavian glomera (aortic bodies) were processed for electron microscopy to determine the effects of this biogenic amine depleting agent on the electron-opaque cytoplasmic granules of the parenchymal type I cells. Observations of glutaraldehyde-osmium tetroxide fixed glomera from reserpinized animals showed a slight decrease in granule density of the type I cells. Glomera fixed in glutaraldehyde and incubated in potassium dichromate (pH 4.1) demonstrated a reduction in granule opacity following reserpine treatment. Control glomera incubated in potassium dichromate displayed electron-opaque granules. These results indicate that reserpine does deplete the amines without granule disappearance or changes in granule population. The positive reaction of the control tissue granules to potassium dichromate incubation suggests that the predominant biogenic amines in the electron-opaque granules are unsubstituted monoamines. Persistence of the opaque granules following reserpinization and glutaraldehyde-osmium tetroxide double fixation, may be due to amine-binding protein within the granules. The mode of granule depletion could not be ascertained with certainty.

The aortic nerve was used to study the blocking action of procaine and bupivacaine on natural spike activity. In anesthetized cats, a segment of the aortic nerve was placed in a perfusion chamber and exposed to increasing drug concentrations, varying pH, while temperature remained constant. Total nerve activity was recorded continuously, and its change was related to drug concentration. The half-time of recovery following drug wash-out was also determined. At pH 7.4, the minimal blocking concentration was 0.5 X 10(-3) mol/l for procaine and 0.05 X 10(-3) mol/l for bupivacaine, the half-times of recovery 1.4 and 3.0 min, respectively. Procaine and bupivacaine reversibly blocked natural spike activity at the same concentrations as they blocked electrically evoked activity. The aortic nerve, whose physiologic spike traffic can be followed continuously for hours, may be used to advantage for studying the long-term effects of local anesthetics in vivo.