In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n ¼ 68) or placebo (n ¼ 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean AE standard error [SE] difference, -8.1 AE 3.24; p ¼ 0.012). Reductions in WOMAC physical function subscale (-4.9 AE 2.48; p ¼ 0.048) and Brief Pain Inventory worst pain (-0.5 AE 0.28; p ¼ 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared 1383with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.
A single bout of exercise can lead to a postexercise decrease in blood pressure in hypertensive individuals, called postexercise hypotension. Compelling evidence suggests that the central baroreflex pathway plays a crucial role in the development of postexercise hypotension. This review focuses on the exercise-induced changes in brainstem nuclei involved in blood pressure regulation.
Presynaptic metabotropic glutamate receptors (mGluRs) serve as autoreceptors throughout the CNS to inhibit glutamate release and depress glutamatergic transmission. Both presynaptic and postsynaptic mGluRs have been implicated in shaping autonomic signal transmission in the nucleus tractus solitarius (NTS). We sought to test the hypothesis that activation of presynaptic mGluRs depresses neurotransmission between primary autonomic afferent fibres and second‐order NTS neurones. In second‐order NTS neurones, excitatory postsynaptic currents (EPSCs) synaptically evoked by stimulation of primary sensory afferent fibres in the tractus solitarius (ts) and currents postsynaptically evoked by α‐amino‐3‐hydroxy‐4‐isoxazoleproprionic acid (AMPA) were studied in the presence and absence of mGluR agonists and antagonists. Real‐time quantitative RT‐PCR (reverse transcription‐polymerase chain reaction) was used to determine whether the genes for the mGluR subtypes were expressed in the cell bodies of the primary autonomic afferent fibres. Agonist activation of Group II and III but not Group I mGluRs reduced the peak amplitude of synaptically (ts) evoked EPSCs in a concentration‐dependent manner while having no effect on postsynaptically (AMPA) evoked currents recorded in the same neurones. At the highest concentrations, the Group II agonist, (2S,3S,4S)‐CCG/(2S,1′S,2′S)‐2‐carboxycyclopropyl (l‐CCG‐I), decreased the amplitude of the ts‐evoked EPSCs by 39 % with an EC50 of 21 μm, and the Group III agonist, l(+)‐2‐amino‐4‐phosphonobutyric acid (l‐AP4), decreased the evoked EPSCs by 71 % with an EC50 of 1 mm. mRNA for all eight mGluR subtypes was detected in the autonomic afferent fibre cell bodies in the nodose and jugular ganglia. Group II and III antagonists ((2S,3S,4S)‐2‐methyl‐2‐(carboxycyclopropyl)glycine (MCCG) and (RS)‐α‐methylserine‐O‐phosphate (MSOP)), at concentrations that blocked the respective agonist‐induced synaptic depression, attenuated the frequency‐dependent synaptic depression associated with increasing frequencies of ts stimulation by 13–34 % and 13–19 %, respectively (P < 0.05, for each). We conclude that Group II and III mGluRs (synthesized in the cell bodies of the primary autonomic afferent fibres and transported to the central terminals in the NTS) contribute to the depression of autonomic signal transmission by attenuating presynaptic release of glutamate.
The nucleus tractus solitarii (NTS) is essential for coordinating arterial baroreflex control of blood pressure. The primary baroreceptor afferent fibres make their first excitatory synaptic contact at second-order NTS neurones with glutamate as the major neurotransmitter. Glutamate regulates its own release by activating presynaptic metabotropic glutamate autoreceptors (mGluRs) on the baroreceptor central terminals to suppress its further release in frequency-dependent manner. γ-Aminobutyric acid (GABA) interneurones provide the major inhibitory synaptic input. It is the integration of excitatory and inhibitory inputs that shapes the NTS output of baroreceptor signals. We hypothesized that glutamate released from the primary central afferent terminals can spill over to presynaptic mGluRs on GABA interneurones to suppress GABA release at the second-order baroreceptor neurones. We assessed GABA transmission in second-order baroreceptor neurones identified by attached aortic depressor nerve (ADN) boutons. The medial NTS was stimulated to evoke GABA inhibitory postsynaptic currents (eIPSCs). Glutamate spillover, generated by brief 2 s, 25 Hz trains of stimuli applied to the tractus solitarius (TS), induced a small (10%) but significant reduction in the eIPSC amplitudes. The depression was enhanced to a 25% decrease by increasing glutamate in the cleft with a glutamate-uptake inhibitor (M-trans-pyrrolidine-2,4-dicarboxylic acid, 1 µM), blocked by a Group II mGluR antagonist (LY341495, 200 nM) and mimicked by a Group II agonist ((2S,3S,4S)-CCG/(2S,1 S,2 S)-2-carboxycyclopropyl; L-CCG-I). A presynaptic mGluR locus was established by the mGluR agonist-mediated increase in the paired-pulse ratio of two consecutive eIPSCs in conjunction with the decrease in the first eIPSC, and a decrease in the frequency (39-46% reduction at EC 50 concentration), but not amplitude, of spontaneous and miniature GABA IPSCs. The data indicate that endogenous glutamate activation of Group II presynaptic mGluRs can decrease GABA release at the first central synapses, suggesting a heterosynaptic role for the Group II mGluRs in shaping baroreceptor signal transmission.
With increasing frequencies of autonomic afferent input to the nucleus tractus solitarii (NTS), postsynaptic responses are depressed. To test the hypothesis that a presynaptic mechanism contributes to this frequency-dependent depression, we used whole cell, voltage-clamp recordings in an NTS slice. First, we determined whether solitary tract stimulation (0.4-24 Hz) resulted in frequency-dependent depression of excitatory postsynaptic currents (EPSCs) in second-order neurons. Second, because decreases in presynaptic glutamate release result in a parallel depression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor-mediated components of EPSCs, we determined whether the magnitude, time course, and recovery from the depression were the same in both EPSC components. Third, to determine whether AMPA receptor desensitization contributed, we examined the depression during cyclothiazide. EPSCs decreased in a frequency-dependent manner by up to 76% in second- and 92% in higher-order neurons. AMPA and NMDA EPSC components were depressed with the same magnitude (by 83% and 83%) and time constant (113 and 103 ms). The time constant for the recovery was also not different (1.2 and 0.8 s). Cyclothiazide did not affect synaptic depression at >/=3 Hz. The data suggest that presynaptic mechanism(s) at the first NTS synapse mediate frequency-dependent synaptic depression.
We sought to determine whether metabotropic glutamate receptors contribute to frequency-dependent depression of vagal and aortic baroreceptor signal transmission in the nucleus of the solitary tract (NTS) in vivo. In α-chloralose-anesthetized rabbits, we determined the number of extracellular action potentials synaptically evoked by low (1 Hz)- or high-frequency vagal (3–20 Hz) or aortic depressor nerve (ADN) (6–80 Hz) stimulation and postsynaptically evoked by the ionotropic glutamate receptor agonist α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The metabotropic glutamate receptor agonist (2 S,1′ S,2′ S)-2-(carboxycyclopropyl)glycine (L-CCG-I) attenuated NTS responses monosynaptically evoked by 1-Hz vagus stimulation by 34% ( n = 25; P = 0.011), while augmenting AMPA-evoked responses by 64% ( n = 17; P = 0.026). The metabotropic glutamate receptor antagonist α-methyl-4-phosphonophenylglycine (MPPG) did not affect NTS responses to low-frequency vagal stimulation ( n = 11) or AMPA ( n = 10) but augmented responses to high-frequency stimulation by 50% ( n= 25; P = 0.0001). MPPG also augmented NTS responses to high-frequency ADN stimulation by 35% ( n = 9; P = 0.048) but did not affect responses to low-frequency stimulation ( n = 9) or AMPA ( n = 7). The results suggest that metabotropic glutamate receptors, presumably at presynaptic sites, contribute to frequency-dependent depression of vagal and aortic baroreceptor signal transmission in NTS.
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