scholarly journals Cardiovascular responses to microinjections of urocortins into the NTS: role of inotropic glutamate receptors

2009 ◽  
Vol 296 (6) ◽  
pp. H2022-H2029 ◽  
Author(s):  
Takeshi Nakamura ◽  
Hreday N. Sapru
Keyword(s):  
Glutamate Receptors ◽  
Nucleus Tractus Solitarius ◽  
Cardiovascular Responses ◽  
New Members ◽  
Corticotrophin Releasing Factor ◽  
Affinity Ligand ◽  
Medial Nucleus ◽  
Peptide Family ◽  
Male Wistar Rats ◽  
Afferent Terminals

Urocortin 1 (Ucn1) and urocortin 3 (Ucn3) are new members of the corticotrophin-releasing factor (CRF) peptide family. Ucn1 is a ligand for both the CRF type 1 receptors (CRF1Rs) and the CRF type 2 receptors (CRF2Rs), whereas Ucn3 is a high-affinity ligand for the CRF2Rs. Recently, we reported that Ucn3 microinjections into the medial nucleus tractus solitarius (mNTS) elicit decreases in mean arterial pressure (MAP) and heart rate (HR) (Nakamura T, Kawabe K, Sapru HN. Am J Physiol Heart Circ Physiol 296: H325–H332, 2009). The presence of CRF2Rs on afferent terminals has been reported in the mNTS of the rat. It was hypothesized that activation of CRF2Rs on afferent terminals in the mNTS may release glutamate, which, in turn, may elicit decreases in MAP and HR via activation of ionotropic glutamate receptors (iGLURs). This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of Ucn1 (0.12 mM) into the mNTS elicited decreases in MAP and HR. The responses were partially blocked by microinjections of iGLUR antagonists into the mNTS. On the other hand, the decreases in MAP and HR elicited by microinjections of Ucn3 (0.06 mM) into the mNTS were completely blocked by microinjections of iGLUR antagonists into the mNTS. These results indicate that activation of CRF2Rs in the mNTS, by Ucn1 and Ucn3, releases glutamate, which, in turn, elicits decreases in MAP and HR via activation of iGLURs.

scholarly journals Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat

2011 ◽  
Vol 300 (1) ◽  
pp. H230-H240 ◽  
Author(s):  
Vineet C. Chitravanshi ◽  
Hreday N. Sapru
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Cardiovascular Effects ◽  
Cardiovascular Responses ◽  
Splanchnic Nerve ◽  
Vagus Nerves ◽  
Medial Nucleus ◽  
Male Wistar Rats ◽  
Bilateral Vagotomy ◽  
Prior Application ◽  
Greater Splanchnic Nerve

Cardiovascular effects of angiotensin-(1–12) [ANG-(1–12)] were studied in the medial nucleus of the tractus solitarius (mNTS) in anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of ANG-(1–12) (0.06 mM) into the mNTS elicited maximum decreases in mean arterial pressure (MAP; 34 ± 5.8 mmHg) and heart rate (HR; 39 ± 3.7 beats/min). Bilateral vagotomy abolished ANG-(1–12)-induced bradycardia. Efferent greater splanchnic nerve activity was decreased by microinjections of ANG-(1–12) into the mNTS. Blockade of ANG type 1 receptors (AT1Rs; using ZD-7155 or L-158,809), but not ANG type 2 receptors (AT2Rs; using PD-123319), significantly attenuated ANG-(1–12)-induced cardiovascular responses. Simultaneous inhibition of both angiotensin-converting enzyme (ACE; using captopril) and chymase (using chymostatin) completely blocked the effects of ANG-(1–12). Microinjections of A-779 [ANG-(1–7) antagonist] did not attenuate ANG-(1–12)-induced responses. Pressure ejection of ANG-(1–12) (0.06 mM, 2 nl) caused excitation of barosensitive mNTS neurons, which was blocked by prior application of the AT1R antagonist. ANG-(1–12)-induced excitation of mNTS neurons was also blocked by prior sequential applications of captopril and chymostatin. These results indicate that 1) microinjections of ANG-(1–12) into the mNTS elicited depressor and bradycardic responses by exciting barosensitive mNTS neurons; 2) the decreases in MAP and HR were mediated via sympathetic and vagus nerves, respectively; 3) AT1Rs, but not AT2Rs, mediated these actions of ANG-(1–12); 4) the responses were mediated via the conversion of ANG-(1–12) to ANG II and both ACE and chymase were involved in this conversion; and 5) ANG-(1–7) was not one of the metabolites of ANG-(1–12) in the mNTS.

scholarly journals Cardiovascular responses to microinjections of urocortin 3 into the nucleus tractus solitarius of the rat

2009 ◽  
Vol 296 (2) ◽  
pp. H325-H332 ◽  
Author(s):  
Takeshi Nakamura ◽  
Kazumi Kawabe ◽  
Hreday N. Sapru
Keyword(s):  
Nucleus Tractus Solitarius ◽  
Cardiovascular Responses ◽  
Splanchnic Nerve ◽  
Artificial Cerebrospinal Fluid ◽  
Peptide Family ◽  
Male Wistar Rats ◽  
Bilateral Vagotomy ◽  
Urocortin 3 ◽  
Greater Splanchnic Nerve

Urocortin 3 (Ucn3) is a new member of the corticotropin-releasing factor (CRF) peptide family and is considered to be a specific and endogenous ligand for CRF type 2 receptors (CRF2Rs). The presence of CRF2Rs has been reported in the nucleus tractus solitarius (NTS) of the rat. It was hypothesized that the activation of CRF2Rs in the medial NTS (mNTS) may play a role in cardiovascular regulation. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of Ucn3 (0.03, 0.06, 0.12, and 0.25 mM) into the mNTS of anesthetized rats elicited decreases in mean arterial pressure (MAP: 5.0 ± 1.0, 21.6 ± 2.6, 20.0 ± 2.8, and 12.7 ± 3.4 mmHg, respectively) and heart rate (HR: 7.8 ± 2.6, 46.2 ± 9.3, 34.5 ± 8.4, and 16.6 ± 4.9 beats/min, respectively). Microinjections of artificial cerebrospinal fluid (100 nl) into the mNTS did not elicit cardiovascular responses. Maximum decreases in MAP and HR were elicited by 0.06 mM concentration of Ucn3. Cardiovascular responses to Ucn3 were similar in unanesthetized midcollicular decerebrate rats. A bilateral vagotomy completely abolished Ucn3-induced bradycardia. The decreases in MAP and HR elicited by Ucn3 (0.06 mM) were completely blocked by astressin (1 mM; nonselective CRFR antagonist) and K41498 (5 mM; selective CRF2R antagonist). Microinjections of Ucn3 (0.06 mM) into the mNTS decreased the efferent greater splanchnic nerve activity. After the blockade of CRF2Rs in the mNTS, a Ucn3-induced decrease in the efferent sympathetic nerve discharge was abolished. These results indicate that Ucn3 microinjections into the mNTS exerted excitatory effects on the mNTS neurons via CRF2Rs, leading to depressor and bradycardic responses.

Cardiovascular regulation and expressions of NO synthase-tyrosine hydroxylase in nucleus tractus solitarius of ovine fetus

2003 ◽  
Vol 284 (4) ◽  
pp. H1057-H1063 ◽  
Author(s):  
Sheng-Xing Ma ◽  
Qun Fang ◽  
Brian Morgan ◽  
Michael G. Ross ◽  
Conrad R. Chao
Keyword(s):  
Blood Pressure ◽  
Tyrosine Hydroxylase ◽  
Arterial Blood Pressure ◽  
Nucleus Tractus Solitarius ◽  
Cardiovascular Responses ◽  
No Synthase ◽  
No Donor ◽  
Fetal Sheep ◽  
Medial Nucleus ◽  
Arterial Blood

The purpose of this study was to examine cardiovascular responses to fourth cerebral ventricle (4V) administration of nitroglycerin (NTG) or an inhibitor of nitric oxide (NO) synthase (NOS) in the near-term ovine and to determine whether, during birth, neuronal NOS (nNOS) is induced in noradrenergic A1 neurons in the medial nucleus tractus solitarius (mNTS). In chronically instrumented fetal sheep, 4V injection of NTG (1.2 nmol), an NO donor, produced an arterial blood depressor and a moderate decrease in heart rate. Arterial blood pressure is increased by 4V administration of N G-nitro-l-arginine methyl ester (10 nmnol), an inhibitor of NOS, in fetuses. Sections of the medulla from fetuses and newborn lambs were examined by using immunolabeling with tyrosine hydroxylase (TH) antibody combined with NADPH diaphorase (NADPHd) histochemistry, a marker of nNOS activity. The NADPHd-positive cells and TH-positive cells containing NADPHd reactivity were significantly increased in the mNTS of newborns compared with the fetuses. The results suggest that during birth, there is upregulation of NADPHd/nNOS in the noradrenergic neurons of mNTS resulting in a centrally mediated reduction of fetal arterial blood pressure.

scholarly journals Identification and biological activity of ovine and caprine calcitonin receptor-stimulating peptides 1 and 2

2008 ◽  
Vol 198 (2) ◽  
pp. 429-437 ◽  
Author(s):  
Christopher J Charles ◽  
Takeshi Katafuchi ◽  
Timothy G Yandle ◽  
Naoto Minamino
Keyword(s):  
Plasma Renin ◽  
New Members ◽  
Amino Terminal ◽  
Peptide Family ◽  
Plasma Camp ◽  
Receptor Activity Modifying Proteins ◽  
Conscious Sheep ◽  
Dose Dependent

We have recently reported the isolation of three new members of the calcitonin (CT) gene-related peptide family of peptides, the CT receptor (CT-R)-stimulating peptides (CRSPs). We now report the sequencing and characterization of ovine/caprine CRSP-1 and caprine CRSP-2. Mature ovine and caprine CRSP-1 are identical and have strong structural homology to CRSP-1s identified to date from other species. As with other CRSP-1s, ovine/caprine CRSP-1 binds to and activates the CT-R but not the CT-like receptor (CL-R) in combination with the receptor activity-modifying proteins (RAMPs). By contrast, caprine CRSP-2 does not activate any of these receptor-RAMP complexes. Intravenous infusions of ovine CRSP-1 to normal conscious sheep induced dose-dependent reduction in plasma total Ca levels (P=0.02) and corrected Ca levels (P=0.017) associated with increases in plasma cAMP (P=0.002). CRSP-1 reduced both plasma amino-terminal pro-C-type natriuretic peptide levels (P=0.006) and plasma renin activity (P=0.028). There were no significant effects observed on hemodynamic or renal indices measured. In conclusion, we have sequenced ovine/caprine CRSP-1 and caprine CRSP-2 precursors. This newly identified CRSP-1 has been shown to share the structural and biological features of CRSP-1s known to date. In vivo studies confirm that ovine CRSP-1 reduces plasma Ca levels in sheep, presumably via a cAMP-mediated mechanism. By contrast, caprine CRSP-2 did not stimulate any combination of CT-R, CL-R, and RAMPs. Accession numbers of cDNA determined in this study are caprine CRSP-1, AB364646; caprine CRSP-2, AB364647; and ovine CRSP-1, AB364648.

Afferent synaptic drive of rat medial nucleus tractus solitarius neurons: dynamic simulation of graded vesicular mobilization, release, and non-NMDA receptor kinetics

1995 ◽  
Vol 74 (4) ◽  
pp. 1529-1548 ◽  
Author(s):  
J. H. Schild ◽  
J. W. Clark ◽  
C. C. Canavier ◽  
D. L. Kunze ◽  
M. C. Andresen
Keyword(s):  
Nmda Receptor ◽  
Frequency Response ◽  
Nucleus Tractus Solitarius ◽  
Membrane Model ◽  
Dependent Manner ◽  
Receptor Kinetics ◽  
Medial Nucleus ◽  
Presynaptic Mechanisms ◽  
Wide Range ◽  
Synaptic Drive

1. We have developed a comprehensive mathematical model of an afferent synaptic connection to the soma of a medial nucleus tractus solitarius (mNTS) neuron. Model development is based on numerical fits to quantitative data recorded in our laboratory. This work is part of a continuing collaborative effort aimed at identifying and characterizing the mechanisms responsible for the non-linear integrative properties of this first synapse in the baroreceptor reflex. 2. The complete model consists of three major parts: 1) a Hodgkin-Huxley (HH)-type membrane model of the prejunctional sensory terminal bouton; 2) a multistage model describing vesicular storage, adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-dependent mobilization, release and recycling; and 3) a HH-type membrane model of the postjunctional mNTS cell that includes descriptions for a desensitizing non-N-methyl-D-aspartate (NMDA) ionic current that is responsible for the fast excitatory postsynaptic potentials (EPSPs) observed in mNTS cells. The membrane models for both the terminal bouton and the mNTS neuron are coupled to separate lumped fluid compartment models describing intracellular Ca2+ ion concentration dynamics. 3. Our modeling strategy is twofold. The first is to validate model performance by reproducing a wide variety of experimental data both from our laboratory and from the literature. The second is to explore the functional aspects of the model in order to gain a greater appreciation for the balance between presynaptic mechanisms (e.g., terminal membrane properties and vesicular dynamics) and postsynaptic mechanisms (e.g., non-NMDA receptor kinetics and neuronal dynamics) that underlie the afferent synaptic drive of mNTS neurons. 4. The model accurately reproduces EPSP dynamics recorded with the use of a wide range of stimulus protocols. The model can also mirror the unique pattern of graded frequency- and use-dependent reduction in peak EPSP magnitude observed experimentally through 60 s of constant, suprathreshold synaptic activation. We demonstrate how vesicular mobilization, recycling, and receptor kinetics can function synergistically in establishing synaptic transfer. Furthermore, we show that by allowing the aggregate rate of vesicle mobilization to respond in a use-dependent manner, it is possible to compensate for the attenuating affects of desensitization at elevated rates of stimulation. 5. Our simulations indicate that the low-frequency characteristics of this synapse are dominated by vesicular dynamics, whereas the high-frequency properties arise from a combination of Ca(2+)-dependent vesicular mobilization and the kinetics of the non-NMDA receptor. Desensitization can influence the peak magnitude and decay time of the EPSP, thereby affecting synaptic throughput. However, we demonstrate that, as the time course of neurotransmitter in the synaptic cleft decreases, the influence of desensitization should be somewhat diminished. As a result, the effective bandwidth of the synapse increases and becomes limited by the gating characteristics of the non-NMDA channel. 6. The model also includes a neuromodulatory aspect in that the frequency response of the synapse can be modulated by an adenylate cyclase-mediated regulatory mechanism. Although our simulations indicate the behavior of a limited number of possible neuromodulatory agents, the results demonstrate the pivotal role such agents could play in modifying synaptic transfer characteristics presynaptically. 7. Both continuous and burst-mode tract stimulation evoke patterns of action potentials in spontaneously active mNTS neurons that are mimicked very well by our model. Our simulations demonstrate that, as the rate of stimulation increases beyond approximately 20-30 Hz, the inherent low-pass frequency-response characteristics of the synapse limit the overall dynamic range of the mNTS neuron, causing the postsynaptic cell to “entrain” at frequencies within its normal operating range.

Dynamics of sensory afferent synaptic transmission in aortic baroreceptor regions on nucleus tractus solitarius

1995 ◽  
Vol 74 (4) ◽  
pp. 1518-1528 ◽  
Author(s):  
M. C. Andresen ◽  
M. Yang
Keyword(s):  
Action Potential ◽  
Synaptic Transmission ◽  
Frequency Response ◽  
Action Potentials ◽  
Nucleus Tractus Solitarius ◽  
Reversal Potential ◽  
Constant Frequency ◽  
Epsp Amplitude ◽  
Postsynaptic Potentials ◽  
Medial Nucleus

1. Synaptic responses of medial nucleus tractus solitarius (mNTS) neurons to solitary tract (ST) activation were studied in a horizontal brain slice preparation of the rat medulla. Slices included sections of ST sufficiently long that the ST could be electrically activated several millimeters from the recording site of cell bodies in mNTS. 2. Three types of synaptic events were evoked in response to ST stimulation: simple excitatory postsynaptic potentials (EPSPs), simple inhibitory postsynaptic potentials (IPSPs), and complex EPSP-IPSP sequences. Simple EPSPs had substantially shorter latencies than IPSPs (3.39 +/- 0.65 ms, mean +/- SE, n = 42, vs. 5.86 +/- 0.71 ms, n = 6, respectively). 3. EPSP amplitude increased linearly with increasing hyperpolarization, with an extrapolated reversal potential near 0 mV. 4. EPSPs were maximal at < 0.5 Hz of sustained, constant-frequency ST stimulation (n = 14). EPSP amplitude declined to an average of 57.5% of control at 10 Hz after 2 s of sustained stimulation. With 1 min of sustained, 100-Hz stimulation, EPSP amplitude declined to near zero. 5. With stimuli intermittently delivered as 100-ms bursts every 300 ms, generally comparable average EPSPs were evoked during constant and burst patterns of ST stimulation. The amplitude of the initial EPSP in each burst was very well maintained even at intraburst stimulation rates of 100 Hz. 6. At resting membrane potentials, low constant frequencies of ST stimulation (< 5 Hz) reliably elicited action potentials and suppressed spontaneous spiking, but higher frequencies led to spike failures (> 85% at 100 Hz). Between 5 and 10 Hz, this periodic stimulation-suppression cycle clearly entrained action potential activity to the ST stimuli. Similar patterns of current pulses (5 ms) reliably evoked action potentials with each pulse to higher frequencies (50 Hz) without failures, and entrainment was similar to ST stimulation. 7. In a subset of nucleus tractus solitarius (NTS) neurons (3 of 9 studied), bursts of ST stimuli were as much as 50% more effective at transmitting high frequencies (> 10 Hz) of ST stimulation than the equivalent constant frequencies (P < 0.0001). 8. The long-latency simple IPSPs with no preceding EPSPs reversed to become depolarizing at potentials more negative than -62.9 +/- 7.0 mV (n = 5) and were blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (n = 3). The ST stimulation frequency-response relation of these IPSPs was similar to that for the short-latency EPSP response excited by ST synapses. Thus these IPSPs appear to be activated polysynaptically via a glutamatergic-GABAergic sequence in response to ST activation. 9. The results suggest that sensory afferent synapses in mNTS have limited transmission of high-frequency inputs. Both synaptic transmission and the characteristics of the postsynaptic neuron importantly contribute to the action potential transmission from afferent to NTS neuron and beyond. This overall frequency response limitation may contribute to the accommodation of reflex responses from sensory afferent inputs such as arterial baroreceptors within their physiological discharge frequency range.

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