Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

2003 ◽  
Vol 285 (5) ◽  
pp. H2001-H2012 ◽  
Author(s):  
Martin Farias ◽  
Keith Jackson ◽  
Michael Johnson ◽  
James L. Caffrey
Keyword(s):  
Heart Rate ◽  
Phosphodiesterase Inhibitor ◽  
Endogenous Opioids ◽  
Muscarinic Agonist ◽  
No Donor ◽  
Parasympathetic Nerve ◽  
Sa Node ◽  
Vagal Control ◽  
Nos Inhibitors ◽  
Vagal Bradycardia

Endogenous opioids and nitric oxide (NO) are recognized modulators of cardiac function. Enkephalins and inhibitors of NO synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that NO systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cGMP pathway. Microdialysis probes were inserted into the SA node, and they were perfused with nonselective ( Nω-nitro-l-arginine methyl ester) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate l-arginine. Introduction of MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of l-arginine and not by d-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor S-nitroso- N-acetyl-penicillamine, the protein kinase G activator 8-bromo-cGMP, or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals.

Intrinsic cardiac enkephalins inhibit vagal bradycardia in the dog

1995 ◽  
Vol 268 (2) ◽  
pp. H848-H855 ◽  
Author(s):  
J. L. Caffrey ◽  
Z. Mateo ◽  
L. D. Napier ◽  
J. F. Gaugl ◽  
B. A. Barron
Keyword(s):  
Heart Rate ◽  
Heart Tissue ◽  
Muscarinic Agonist ◽  
Maximal Effect ◽  
Canine Heart ◽  
Vagal Control ◽  
Vagal Bradycardia ◽  
The Right ◽  
Direct Acting ◽  
A Site

Met-enkephalin-Arg-Phe (MEAP) has been identified in acid extracts of canine heart tissue. The effects of synthetic MEAP on the vagal control of heart rate were investigated in anesthetized dogs. The arterial infusion of MEAP (3 nmol.min-1.kg-1) inhibited the bradycardia observed during electrical stimulation of the right vagus nerve by 72%. After the infusion was stopped, the responsiveness to vagal stimulation returned to normal, with a half-time between 2 and 3 min. The inhibition by MEAP was reversed by the high-affinity opiate antagonist diprenorphine (100 micrograms/kg). MEAP did not alter the negative chronotropic effect of the direct-acting muscarinic agonist methacholine. This observation suggested that MEAP exerted its effect at a site in the efferent vagal tract proximal to nodal muscarinic receptors. Increasing MEAP infusions (0.09-3.00 nmol.min-1.kg-1) produced a graded suppression of vagal bradycardia, with a half-maximal effect near 0.3 nmol.min-1.kg-1. Met-enkephalin (ME) produced responses very similar to those obtained with MEAP. The effects of ME were also blocked by prior administration of diprenorphine. Dose responses to ME were shifted to the right of those for MEAP, and half-maximal responses for ME were obtained at two to four times the dose required for MEAP. The data suggest that the intrinsic cardiac enkephalin MEAP can regulate vagal control of heart rate at physiologically achievable concentrations and may serve as a local regulator of the parasympathetic-myocardial interface.

Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice

2001 ◽  
Vol 281 (6) ◽  
pp. H2310-H2317 ◽  
Author(s):  
J. K. Choate ◽  
E. J. F. Danson ◽  
J. F. Morris ◽  
D. J. Paterson
Keyword(s):  
Heart Rate ◽  
No Synthase ◽  
Wild Type ◽  
No Donor ◽  
Vagal Control ◽  
Cholinergic Regulation ◽  
Intracellular Pathways ◽  
Rate Of Decline

The role of nitric oxide (NO) in the vagal control of heart rate (HR) is controversial. We investigated the cholinergic regulation of HR in isolated atrial preparations with an intact right vagus nerve from wild-type (nNOS+/+, n = 81) and neuronal NO synthase (nNOS) knockout (nNOS−/−, n = 43) mice. nNOS was immunofluorescently colocalized within choline-acetyltransferase-positive neurons in nNOS+/+ atria. The rate of decline in HR during vagal nerve stimulation (VNS, 3 and 5 Hz) was slower in nNOS−/− compared with nNOS+/+ atria in vitro ( P < 0.01). There was no difference between the HR responses to carbamylcholine in nNOS+/+ and nNOS−/− atria. Selective nNOS inhibitors, vinyl-l-niohydrochloride or 1–2-trifluoromethylphenyl imidazole, or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly ( P < 0.05) attenuated the decrease in HR with VNS at 3 Hz in nNOS+/+ atria. NOS inhibition had no effect in nNOS−/− atria during VNS. In all atria, the NO donor sodium nitroprusside significantly enhanced the magnitude of the vagal-induced bradycardia, showing the downstream intracellular pathways activated by NO were intact. These results suggest that neuronal NO facilitates vagally induced bradycardia via a presynaptic modulation of neurotransmission.

Presynaptic modulation of acetylcholine release from cardiac parasympathetic neurons

1985 ◽  
Vol 248 (1) ◽  
pp. H33-H39 ◽  
Author(s):  
G. T. Wetzel ◽  
J. H. Brown
Keyword(s):  
Receptor Antagonist ◽  
Adrenergic Receptor ◽  
Acetylcholine Release ◽  
Electrical Field Stimulation ◽  
Inhibitory Effect ◽  
Muscarinic Agonist ◽  
Parasympathetic Nerve ◽  
Presynaptic Modulation ◽  
Rat Atria ◽  
Alpha Adrenergic Receptors

Acetylcholine can be released from parasympathetic nerve endings in rat atria by 57 mM K+ depolarization or by electrical field stimulation. We have studied the presynaptic modulation of [3H]acetylcholine release from superfused rat atria prelabeled with [3H]choline. Exogenous acetylcholine and the specific muscarinic agonist oxotremorine inhibit the stimulation-induced overflow of [3H]acetylcholine into the superfusion medium. The half-maximal inhibitory concentration (IC50) of oxotremorine is 0.3 microM. The cholinesterase inhibitor neostigmine also decreases K+-stimulated [3H]acetylcholine overflow, whereas the muscarinic antagonist atropine enhances the overflow of [3H]acetylcholine. These data suggest that acetylcholine release in atria is modulated through negative feedback by the endogenous transmitter. The sympathetic adrenergic neurotransmitter norepinephrine and the neurohormone epinephrine also inhibit the overflow of [3H]acetylcholine by approximately 60%. The IC50 values for the inhibitory effects of these catecholamines are 6.3 and 2.2 microM, respectively. The inhibitory effect of norepinephrine is blocked by the alpha-adrenergic receptor antagonist yohimbine but not by the beta-adrenergic receptor antagonist propranolol. We suggest that presynaptic muscarinic and alpha-adrenergic receptors participate in the physiological and pharmacological control of cardiac parasympathetic activity.

Assessment of parasympathetic control of heart rate by a noninvasive method

1984 ◽  
Vol 246 (6) ◽  
pp. H838-H842 ◽  
Author(s):  
F. M. Fouad ◽  
R. C. Tarazi ◽  
C. M. Ferrario ◽  
S. Fighaly ◽  
C. Alicandri
Keyword(s):  
Heart Rate ◽  
Respiratory Sinus Arrhythmia ◽  
Separate Group ◽  
Noninvasive Method ◽  
Sinus Arrhythmia ◽  
Beta Adrenergic ◽  
Normal Volunteers ◽  
Vagal Control ◽  
Parasympathetic Control ◽  
The Relationship

The degree of parasympathetic control of heart rate was assessed by the abolition of respiratory sinus arrhythmia with atropine. Peak-to-peak variations in heart periods (VHP) before atropine injection correlated significantly (r = 0.90, P less than 0.001) with parasympathetic control, indicating that VHP alone may be used as a noninvasive indicator of the parasympathetic control of heart rate. Pharmacologic blockade of beta-adrenergic supply in a separate group of normal volunteers did not alter the relationship between VHP and parasympathetic control, indicating that the condition of the experiment (complete rest in a quiet atmosphere) allows the use of VHP alone without pharmacologic interventions to characterize the vagal control of heart rate in humans.

scholarly journals Heart rate responses to a muscarinic agonist in rats with experimentally induced acute and subacute chagasic myocarditis

2000 ◽  
Vol 42 (4) ◽  
pp. 219-224 ◽  
Author(s):  
Argenis TORRES ◽  
Diego F. DÁVILA ◽  
Carlos F. GOTTBERG ◽  
Jose H. DONIS ◽  
Gabriela ARATA DE BELLABARBA ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinus Node ◽  
Regression Line ◽  
Acute Stage ◽  
Baseline Heart Rate ◽  
Muscarinic Agonist ◽  
Parasympathetic Innervation ◽  
Subacute Stage ◽  
Old Rats ◽  
Experimentally Induced

We administered arecoline to rats, with experimentally induced chagasic myocarditis, in order to study the sinus node sensitivity to a muscarinic agonist. Sixteen month old rats were inoculated with 200,000 T. cruzi parasites ("Y" strain). Between days 18 and 21 (acute stage), 8 infected rats and 8 age-matched controls received intravenous arecoline as a bolus injection at the following doses: 5.0, 10.0, 20.0, 40.0, and 80.0 mug/kg. Heart rate was recorded before, during and after each dose of arecoline. The remaining 8 infected animals and 8 controls were subjected to the same experimental procedure during the subacute stage, i.e., days 60 to 70 after inoculation. The baseline heart rate, of the animals studied during the acute stage (349 ± 68 bpm, mean ± SD), was higher than that of the controls (250 ± 50 bpm, p < 0.005). The heart rate changes were expressed as percentage changes over baseline values. A dose-response curve was constructed for each group of animals. Log scales were used to plot the systematically doubled doses of arecoline and the induced-heart rate changes. The slope of the regression line for the acutely infected animals (r = - 0.99, b =1.78) was not different from that for the control animals (r = - 0.97, b = 1.61). The infected animals studied during the subacute stage (r = - 0.99, b = 1.81) were also not different from the age-matched controls (r = - 0.99, b = 1.26, NS). Consequently, our results show no pharmacological evidence of postjunctional hypersensitivity to the muscarinic agonist arecoline. Therefore, these results indirectly suggest that the postganglionic parasympathetic innervation, of the sinus node of rats with autopsy proved chagasic myocarditis, is not irreversibly damaged by Trypanosoma cruzi.

scholarly journals The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

1995 ◽  
Vol 15 (5) ◽  
pp. 774-778 ◽  
Author(s):  
Qiong Wang ◽  
Dale A. Pelligrino ◽  
Verna L. Baughman ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Inhibitory Action ◽  
Neuronal Nitric Oxide Synthase ◽  
Muscarinic Agonist ◽  
Doppler Flowmetry ◽  
Nos Inhibitors ◽  
Oxide Synthase

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg−1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19–27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood–brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

scholarly journals Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+signaling

2014 ◽  
Vol 306 (10) ◽  
pp. H1385-H1397 ◽  
Author(s):  
Jie Liu ◽  
Syevda Sirenko ◽  
Magdalena Juhaszova ◽  
Steven J. Sollott ◽  
Shweta Shukla ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cell Function ◽  
Ryanodine Receptors ◽  
Phosphodiesterase Inhibitor ◽  
Receptor Activation ◽  
Functional Changes ◽  
Adult Mice ◽  
Size Number ◽  
Pathway Activation ◽  
Beating Rate

A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca2+clock, and the electrogenic-sarcolemmal membrane clock. Ca2+-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca2+signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na+/Ca2+exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca2+load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SR Ca2+-ATPase pump, ryanodine receptors, and Na+/Ca2+exchanger. Thus a deterioration in intrinsic Ca2+clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca2+cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.

Heart Rate Variability During Early Mobilization in Patients with Acute Ischemic Stroke

2018 ◽  
Vol 80 (1-2) ◽  
pp. 50-54 ◽  
Author(s):  
Masafumi Nozoe ◽  
Miho Yamamoto ◽  
Miki Kobayashi ◽  
Masashi Kanai ◽  
Hiroki Kubo ◽  
...  
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Nervous Activity ◽  
Early Mobilization ◽  
Sympathetic Nervous Activity ◽  
Parasympathetic Nerve ◽  
Significant Difference ◽  
Sympathetic Nervous

Autonomic dysfunction is one of the predictors of poor outcome in patients with acute ischemic stroke. We compared the heart rate variability (HRV) during early mobilization in patients with or without neurological deterioration (ND). We enrolled 7 acute ischemic patients with ND and 14 without ND and measured their HRV in the rest and mobilization by electrocardiography. There was a significant difference in sympathetic nervous activity during mobilization between the 2 groups. However, no significant differences in blood pressure, heart rate, and parasympathetic nerve activity were observed. In patients with acute ischemic stroke, it is likely that the increase in sympathetic nervous activity during mobilization is associated with ND.

Abstract P161: Tai Chi Movements Bring On Parasympathetic Nerve Output As Indicated By Audible Bowel Sounds

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Desuo Wang
Keyword(s):  
Heart Rate ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Tai Chi ◽  
Parasympathetic Nervous System ◽  
Autonomic Nerve ◽  
Parasympathetic Nerve ◽  
Bowel Sounds ◽  
Sympathetic Nervous ◽  
Tai Chi Exercise

Tai Chi movements are unique exercise that can improve cognition, strength somatomotor coordination, and enhance autonomic nerve regulation on internal organ function. The mild increase in heart rate and/or slight sweat during and after practicing Tai Chi indicates the activation of the sympathetic nervous system. There is lack of evidence to show that Tai Chi exercise enhances the activity of parasympathetic nervous system though it has been claimed that practicing Tai Chi could do so. The author tested the hypothesis that Tai Chi exercise brings on an increase in parasympathetic nerve outputs (PNO). The PNO is evaluated by recording the bowel sounds using an audio recorder (Sony digital voice recorder ICD-PX Series) and the data analyses were done using NCH software (WavePad audio editor). The heart rate was simultaneously recorded using a fingertip pulse oximeter (Zacurate Pro Series 500DL) during Tai Chi exercise. All the data was repeatedly collected from a Tai Chi Master in a study period of 6 months. A total of 30 recordings were used to carry out the analysis. The audible bowel sounds occurred when the performer started to do the Ready-Movement of Yang-style Tai Chi. These Tai Chi induced-bowel sounds lasted from the beginning to the end of a set of movements (3-5 min for 24-moves style). The frequency of bowel sounds was in a range of 0.2 to 3.5 Hz. The average number of bowel sounds was approximately 2.5 sounds per Tai Chi Move. The intensity and frequency of the bowel sounds are not related to the change of the performer’s heart rate. In comparison, meditation or deep squat exercise performed by the Tai Chi master did not cause any changes in the bowel sounds. According to the autonomic innervation of the GI tract, increase of bowel movements is mediated by PNO. In conclusion, Tai Chi movements can simultaneously exercise skeletal muscles, sympathetic nervous system and parasympathetic nervous system. The enhancement of parasympathetic nervous system output by Tai Chi exercise is a valuable modality of physical exercise for wellness.

Nitric oxide modulates cardiac performance in the heart of Anguilla anguilla

2001 ◽  
Vol 204 (10) ◽  
pp. 1719-1727 ◽  
Author(s):  
S. Imbrogno ◽  
L. De Iuri ◽  
R. Mazza ◽  
B. Tota
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Cardiac Output ◽  
Anguilla Anguilla ◽  
Cardiac Performance ◽  
Stroke Work ◽  
Nos Inhibitors ◽  
Cgmp Pathway ◽  
Triton X ◽  
Endocardial Endothelium

Nothing is known about the effects of nitric oxide (NO) on cardiac performance in fish. Using an in vitro working heart preparation that generates physiological values of output pressure, cardiac output and ventricular work and power, we assessed the effects of NO on the cardiac performance of the eel Anguilla anguilla. We examined basal cardiac performance (at constant preload, afterload and heart rate), the effects of cholinergic stimulation and the Frank-Starling response (preload-induced increases in cardiac output at constant afterload and heart rate). The NO synthase (NOS) inhibitors N(G)-monomethyl-l-arginine (l-NMMA) and l-N(5)(1-iminoethyl)ornithine (l-NIO), the guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ) and Triton X-100, a detergent that damages the endocardial endothelium, all increased stroke volume (V(S)) and stroke work (W(S)). In contrast, the endogenous NOS substrate l-arginine, tested before and after treatment with haemoglobin, the NO donor 3-morpholinosydnonimine, tested with and without the superoxide scavenger superoxide dismutase, and the stable cGMP analogue 8-bromoguanosine 3′,5′-cyclic monophosphate (8-Br-cGMP) decreased V(S) and W(S). Acetylcholine chloride produced a biphasic effect. At nanomolar concentrations, in 34 % of the preparations, it induced a NO-cGMP-dependent positive inotropism that required the integrity of the endocardial endothelium. Pretreatment with Triton X-100 or with NO-cGMP pathway inhibitors (l-NMMA, l-NIO, N(G)-nitro-l-arginine methyl ester, Methylene Blue and ODQ) abolished the positive effect of acetylcholine. In contrast, at micromolar concentrations, acetylcholine produced a negative effect that involved neither the endocardial endothelium nor the NO-cGMP pathway. Pre-treatment with l-arginine (10(−)(6)mol l(−)(1)) was without effect, whereas l-NIO (10(−)(5)mol l(−)(1)) significantly reduced the Frank-Starling response. Taken together, these three experimental approaches provide evidence that NO modulates cardiac performance in the eel heart.

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