New Findings r What is the central question of this study?This study was designed to investigate whether the Phox2b-expressing neurons in the retrotrapezoid nucleus are important to breathing and chemoreflexes in conscious rats. r What is the main finding and its importance?The high rate of destruction of a defined cell population (Phox2b + TH − ) of the retrotrapezoid nucleus by the toxin suggests that the specialized connectivity of retrotrapezoid nucleus neurons, their glutamatergic nature and their relatively high sensitivity to CO 2 are determinant factors in explaining their large contribution to the central and peripheral chemoreflexes.Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO 2 /H + . A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b + TH − ) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP-SAP) into the RTN destroyed Phox2b + TH − neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP-SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO 2 ) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b + TH − neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b + TH − neurons is a plausible cause of the respiratory deficits observed after injection of SSP-SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.

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Michelini LC. Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity. Am J Physiol Regul Integr Comp Physiol 301: R958 -R966, 2011. First published July 27, 2011 doi:10.1152/ajpregu.00104.2011.-We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate traininginduced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630 -640; 1103-1113). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (Ϫ8%) in both groups, with a fall in blood pressure (Ϫ10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9-and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control. sinoaortic denervation; exercise training; hypothalamus; paraventricular nucleus; supraoptic nucleus; oxytocin; spontaneous hypertension ACCUMULATING EXPERIMENTAL evidence from our and other laboratories has shown that aerobic training promotes several beneficial cardiovascular effects in normotensive and hypertensive individuals. Training causes remodeling of the heart with a simultaneous stroke volume increase and heart rate (HR) decrease (5, 34, 40), outward eutrophic remodeling of arterioles, capillary angiogenesis, and venule neoformation in the exercised muscles (1-3, 10, 24). Exercise training is also accompanied by a predominance of relaxation over contractile endothelium-derived factors (15, 44). These adaptive mechanisms by improving blood flow and tissue conductance, by reducing vascular resistance, and restoring normal endothelial function favor the amelioration of impaired functions in cardiovascular disease.Training reduces both the activity of the renin-angiotensin system and oxidative stress (13,22,38) and effectively induces neuronal pla...

ADAM17 is a metalloprotease and disintegrin that lodges in the plasmatic membrane of several cell types and is able to cleave a wide variety of cell surface proteins. It is somatically expressed in mammalian organisms and its proteolytic action influences several physiological and pathological processes. This review focuses on the structure of ADAM17, its signaling in the cardiovascular system and its participation in certain disorders involving the heart, blood vessels, and neural regulation of autonomic and cardiovascular modulation.

Despite the well established sympathoexcitation evoked by chemoreflex activation, the specific sub-regions of the central nervous system underlying such sympathetic responses remain to be fully characterized. In the present study we examined the effects of intermittent chemoreflex activation in awake rats on Fos-immunoreactivity (Fos-ir) in various subnuclei of the paraventricular nucleus of the hypothalamus (PVN), as well as in identified neurosecretory preautonomic PVN neurons. In response to intermittent chemoreflex activation, a significant increase in the number of Fos-ir cells was found in autonomic-related PVN subnuclei, including the posterior parvocellular, ventromedial parvocellular and dorsal-cap, but not in the neurosecretory magnocellular-containing lateral magnocellular subnucleus. No changes in Fos-ir following chemoreflex activation were observed in the anterior PVN subnucleus. Experiments combining Fos immunohistochemistry and neuronal tract tracing techniques showed a significant increase in Fos-ir in rostral ventrolateral medulla (RVLM)-projecting (PVN-RVLM), but not in nucleus of solitarii tract (NTS)-projecting PVN neurons. In summary, our results support the involvement of the PVN in the central neuronal circuitry activated in response to chemoreflex activation, and indicate that PVN-RVLM neurons constitute a neuronal substrate contributing to the sympathoexcitatory component of the chemoreflex.