Search

Several device-based approaches to autonomic nervous system modulation are under investigation for the treatment of resistant hypertension and heart failure (Table 1).1 This line of research has evolved from the recognition that these diseases originate or are worsened by excess sympathetic activity and loss of parasympathetic tone.9–13 Drug therapies, including β-blockers, α-blockers, and centrally acting antihypertensive drugs, can modulate these neurohormonal systems, but they are often insufficient to control blood pressure (BP) or are limited by side effects or nonadherence. Technological innovations have produced devices that modulate the autonomic nervous system, including renal denervation, carotid baroreceptor stimulation, vagal nerve stimulation, and spinal cord stimulation. View this table: Table 1. Select Completed and Ongoing Clinical Trials of Autonomic Modulation Therapies in Hypertension and Heart Failure In Europe, several autonomic modulation therapy devices have received the Conformite Europeenne mark.14 US Food and Drug Administration evaluation of these devices is ongoing. The need for adequately powered, randomized, controlled studies with longer follow-up to capture definitive evidence of safety and effectiveness has been noted.14–17 The 9th and 10th Global Cardiovascular Clinical Trialists Forum (Paris, France, December 2012 and December 2013) convened a panel of primary investigators of ongoing trials, along with biostatisticians, National Institutes of Health scientists, European, and United States regulators, and medical device and pharmaceutical industry scientists to discuss the strengths and limitations of current clinical trials, optimal designs for future trials, approvability of new devices, and considerations for integrating these technologies into practice. This article summarizes the key discussion points and identifies knowledge gaps in this field that need to be addressed by additional research. The mechanisms of autonomic modulation are complex, and a comprehensive review of these mechanisms is outside the scope of this article. Briefly, all existing strategies aim to decrease central sympathetic outflow. Renal …

International audience; Previous studies have shown that serotonin3 receptor activation in the nucleus tractus solitarius (NTS) increased mean arterial pressure (MAP) and inhibited the cardiac component of the baroreceptor reflex [9]. We have examined the effects of such stimulation upon spontaneous and evoked sympathetic nerve activity. Microinjection of serotonin (10 nmol) into the NTS of halothane-anaesthetized, paralyzed and artificially ventilated rats produced an increase in MAP and lumbar sympathetic nerve discharge which could be completely prevented by prior local microinjection of zacopride, a potent serotonin3 antagonist (200 pmol). In addition, 1-(m-chlorophenyl)-biguanide, a selective serotonin3 receptor agonist, mimicked the sympathoexcitatory effect of serotonin. Since the gain of the sympathetic component of the baroreflex was unaltered after intra-NTS microinjection of serotonin, it could be concluded that serotonin3 receptors activation in the NTS induces a sympathetic activation which is not mediated through an inhibition of the sympathetic baroreceptor reflex arc.

International audience; The modulation by 5-HT2 receptors in the nucleus tractus solitarius of the reflex bradycardia evoked by stimulation of peripheral baroreceptors and cardiopulmonary chemoreceptors, and their possible functional interactions with local NMDA receptors, were investigated in pentobarbital- and urethane-anaesthetized rats, respectively. Microinjection of the 5-HT2 receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (0.1-0.5 pmol), into the nucleus tractus solitarius elicited a dose-dependent hypotension and bradycardia. Bilateral microinjections at the same site of a subthreshold dose of 2,5-dimethoxy-4-iodoamphetamine (0.05 pmol) significantly enhanced the aforementioned reflex-evoked bradycardiac responses. In contrast, local bilateral microinjections of the NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid (500 and 1000 pmol), reduced, in a dose-dependent manner, both reflex-evoked responses. The facilitatory effect of 2,5-dimethoxy-4-iodoamphetamine upon these reflex-evoked bradycardiac responses was prevented by prior local microinjection of low doses of either the selective 5-HT2 receptor antagonist, ketanserin (10 pmol), or 2-amino-5-phosphonopentanoic acid (100 pmol), which, on their own, did not affect the reflex-associated bradycardia. These data suggest that 5-HT2 receptors within the nucleus tractus solitarius participate in a facilitatory modulation of the reflex control of heart rate, probably through functional interactions with local NMDA receptors.

International audience; Intra-atrial administration of phenylbiguanide has been shown to trigger, through the stimulation of vagal afferent C-fibers, reflex bradycardia, hypotension, and sympathoinhibition classically known as the Bezold-Jarisch (B-J) reflex (O. Krayer. Naunyn-Schmiedeberg's Arch. Exp. Pathol. Pharmacol. 240: 361-368, 1961). The effects of microinjections, into the nucleus tractus solitarius (NTS), of serotonin (5-HT) and 1-(m-chlorophenyl)-biguanide (CPBG), a potent 5-HT3 receptor agonist, on these reflex responses were studied in urethananesthetized rats. 5-HT (600 and 900 pmol) and CPBG (10-150 pmol) produced a dose-dependent inhibition of the atropine-sensitive bradycardiac component of the B-J reflex. The effect of both agonists was reversed by prior local microinjection of the 5-HT3 receptor antagonists zacopride (100 pmol) and ondansetron (100 pmol), but not by that of the 5-HT2 receptor antagonist ketanserin (10 pmol) or the mixed 5-HT1/5-HT2 receptor antagonist methysergide (100 pmol). In contrast, CPBG (150 pmol) did not affect the B-J reflex inhibition of lumbar sympathetic nerve discharge. These results show that stimulation of NTS 5-HT3 receptors produced an inhibition of the cardiovagal component of the B-J reflex without affecting its sympathetic component. Because the stimulation of these receptors also inhibits the cardiac component of the baroreflex, the present data suggest the participation of NTS 5-HT3 receptors in the mechanisms that modulate cardiac reflex responses elicited by messages from different vagal afferents.

International audience; In the present study, we examined the possibility of the presence of the Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (NPFF) system in the rat heart as well as the effects of drugs affecting noradrenergic transmission upon the cardiovascular responses elicited by peripheral administration of NPFF. The presence of NPFF receptors on heart sections and of NPFF-immunoreactivity in heart tissue was demonstrated with autoradiographic and radioimmunoassay procedures, respectively. Intravenous administration of NPFF (100-300 micrograms/kg) produced a dose-dependent increase in blood pressure and heart rate without affecting plasma noradrenaline and adrenaline levels. These effects of NPFF were also observed, although attenuated, in catecholamine-depleted rats and in rats pretreated with a ganglionic blocking agent, hexamethonium (10 mg/kg, i.v.). Prazosin (100 micrograms/kg, i.v.), an alpha1 adrenergic receptor antagonist, reduced the NPFF-induced blood pressure response by 50%. In contrast, propranolol (2 mg/kg, i.v.) and metroprolol (0.5 mg/kg, i.v.), beta- and beta1 adrenergic receptor antagonists, respectively, reduced the NPFF-induced heart rate response by 50%. Surprisingly, the alpha2 adrenergic receptor antagonists, idazoxan (2 mg/kg, i.v.) and yohimbine (2 mg/kg, i.v.), both produced a drastic increase in the NPFF-induced heart rate response. These data, which demonstrate the presence of the NPFF system in the rat heart, suggest that the cardiovascular responses of peripheral administration of NPFF are mediated by the stimulation of peripheral NPFF receptors. In addition, the present data show that the aforementioned NPFF-induced responses are also mediated by catecholamine-dependent mechanisms and suggest a functional interaction between adrenergic and NPFF systems.

International audience; The role of the nucleus tractus solitarius (NTS) serotonergic afferents in cardiovascular (CV) regulation is yet to be established. However, several findings suggest that in this nucleus the serotonergic endings coming from the nodose ganglia (NG) are involved in the control of blood pressure (BP). The purpose of the present study was to identify the CV effects of the destruction of this NG-NTS serotonergic pathway. For that, the BP, BP variability (BPV) and heart rate (HR) effects of the local microinjection of 5,7-dihydroxytryptamine (5,7-DHT), into the NG and NTS were investigated in awake freely moving rats. The local degeneration of serotonergic elements was associated with a significant decrease in the 5-HT and 5-hydroxyindole acetic acid levels within the NG and NTS in 5,7-DHT treated rats. In addition, the microinjection of the neurotoxin in both structures produced a transient and significant increase in BP. This effect was of greater amplitude and associated with an increase in BPV in NG lesioned rats. These results may indicate that the NG-NTS serotonergic pathway participates in the transfer of the messages arising from the aortic baroreceptors. However, the vagal component of the baroreflex assessed with the phenylephrine test was not significantly modified in NG lesioned animals as compared to controls. Consequently, if the present data suggest that the NG-NTS serotonergic pathway plays a depressor role in BP regulation, its involvement in the reflex CV responses triggered by the stimulation of the aortic baroreceptors has yet to be established.

International audience; In halothane-anesthetized, paralyzed, and artificially ventilated rats, the putative 5-hydroxytryptamine1A receptor agonist 8-OHDPAT (13.1 micrograms/kg iv) produced hypotension (-14.6 +/- 1.3 mmHg, n = 35), reduced lumbar sympathetic nerve discharge (SND, -17.8%, n = 35), and slowed the discharge rate of sympathoexcitatory neurons recorded in the rostroventrolateral medulla (RVLM, -17.6%, n = 20). The gain of the baroreflex was unaffected by the drug, but SND and RVLM unit discharges were silenced at significantly reduced levels of mean arterial pressure (MAP; 153 vs. 171 mmHg for SND, 155 vs. 172 mmHg for RVLM cells). Subsequent intravenous administration of the alpha 2-adrenergic receptor agonist clonidine (5.3 micrograms/kg) produced an additional decrease in MAP (-21.2 +/- 1.9 mmHg, n = 24) and SND (-24%, n = 24), Bilateral microinjections of 8-OHDPAT into the RVLM (1 nmol/side, n = 9) or into the raphe pallidus-obscurus (2 injections of 1 nmol each, n = 7) also produced hypotension (-22.9 +/- 3.2 and -14.4 +/- 2.8 mmHg, respectively) and sympathoinhibition (-39.1 and -24.6%, respectively). Bilateral microinjection into RVLM of the alpha 2-adrenergic antagonists idazoxan (16 nmol/side, n = 6) or rauwolscine (2 nmol/side, n = 6) attenuated the sympatholytic effect of both 8-OHDPAT (13.1 micrograms/kg, iv) and clonidine (5.3 micrograms/kg iv). These results suggest that 8-OHDPAT may exert a portion of its central sympatholytic effect by activating alpha 2-adrenergic receptors in the rostroventral medulla.

International audience; The presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol >> CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)