Chronic intermittent hypoxia (CIH) in rats produces changes in the central regulation of cardiovascular and respiratory systems by unknown mechanisms. We hypothesized that CIH (6% O 2 for 40 s, every 9 min, 8 h day −1 ) for 10 days alters the central respiratory modulation of sympathetic activity. After CIH, awake rats (n = 14) exhibited higher levels of mean arterial pressure than controls (101 ± 3 versus 89 ± 3 mmHg, n = 15, P < 0.01). Recordings of phrenic, thoracic sympathetic, cervical vagus and abdominal nerves were performed in the in situ working heart-brainstem preparations of control and CIH juvenile rats. The data obtained in CIH rats revealed that: (i) abdominal (Abd) nerves exhibited an additional burst discharge in late expiration; (ii) thoracic sympathetic nerve activity (tSNA) was greater during late expiration than in controls (52 ± 5 versus 40 ± 3%; n = 11, P < 0.05; values expressed according to the maximal activity observed during inspiration and the noise level recorded at the end of each experiment), which was not dependent on peripheral chemoreceptors; (iii) the additional late expiratory activity in the Abd nerve correlated with the increased tSNA; (iv) the enhanced late expiratory activity in the Abd nerve unique to CIH rats was accompanied by reduced post-inspiratory activity in cervical vagus nerve compared to controls. The data indicate that CIH rats present an altered pattern of central sympathetic-respiratory coupling, with increased tSNA that correlates with enhanced late expiratory discharge in the Abd nerve. Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model.
The respiratory pattern generator modulates the sympathetic outflow, the strength of which is enhanced by challenges produced by hypoxia. This coupling is due to the respiratory-modulated presympathetic neurons in the rostral ventrolateral medulla (RVLM), but the underlining electrophysiological mechanisms remain unclear. For a better understanding of the neural substrates responsible for generation of this respiratory-sympathetic coupling, we combined immunofluorescence, single cell qRT-pCR, and electrophysiological recordings of the RVLM presympathetic neurons in in situ preparations from normal rats and rats submitted to a metabolic challenge produced by chronic intermittent hypoxia (CIH). Our results show that the spinally projected cathecholaminergic C1 and non-C1 respiratory-modulated RVLM presympathetic neurons constitute a heterogeneous neuronal population regarding the intrinsic electrophysiological properties, respiratory synaptic inputs, and expression of ionic currents, albeit all neurons presented persistent sodium current-dependent intrinsic pacemaker properties after synaptic blockade. A specific subpopulation of non-C1 respiratory-modulated RVLM presympathetic neurons presented enhanced excitatory synaptic inputs from the respiratory network after CIH. This phenomenon may contribute to the increased sympathetic activity observed in CIH rats. We conclude that the different respiratory-modulated RVLM presympathetic neurons contribute to the central generation of respiratory-sympathetic coupling as part of a complex neuronal network, which in response to the challenges produced by CIH contribute to respiratory-related increase in the sympathetic activity.
Molkov YI, Zoccal DB, Moraes DJ, Paton JF, Machado BH, Rybak IA. Intermittent hypoxia-induced sensitization of central chemoreceptors contributes to sympathetic nerve activity during late expiration in rats. J Neurophysiol 105: 3080 -3091, 2011. First published April 6, 2011 doi:10.1152/jn.00070.2011.-Hypertension elicited by chronic intermittent hypoxia (CIH) is associated with elevated activity of the thoracic sympathetic nerve (tSN) that exhibits an enhanced respiratory modulation reflecting a strengthened interaction between respiratory and sympathetic networks within the brain stem. Expiration is a passive process except for special metabolic conditions such as hypercapnia, when it becomes active through phasic excitation of abdominal motor nerves (AbN) in late expiration. An increase in CO 2 evokes late-expiratory (late-E) discharges phase-locked to phrenic bursts with the frequency increasing quantally as hypercapnia increases. In rats exposed to CIH, the late-E discharges synchronized in AbN and tSN emerge in normocapnia. To elucidate the possible neural mechanisms underlying these phenomena, we extended our computational model of the brain stem respiratory network by incorporating a population of presympathetic neurons in the rostral ventrolateral medulla that received inputs from the pons, medullary respiratory compartments, and retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). Our simulations proposed that CIH conditioning increases the CO 2 sensitivity of RTN/pFRG neurons, causing a reduction in both the CO 2 threshold for emerging the late-E activity in AbN and tSN and the hypocapnic threshold for apnea. Using the in situ rat preparation, we have confirmed that CIHconditioned rats under normal conditions exhibit synchronized late-E discharges in AbN and tSN similar to those observed in control rats during hypercapnia. Moreover, the hypocapnic threshold for apnea was significantly lowered in CIH-conditioned rats relative to that in control rats. We conclude that CIH may sensitize central chemoreception and that this significantly contributes to the neural impetus for generation of sympathetic activity and hypertension.
Given the proportion of individuals with resistance to, and poor compliance or tolerance of, antihypertensive medication new drugs to treat this syndrome are required urgently. We show that peripheral chemoreceptors generate aberrant signalling contributing to high blood pressure in hypertension and thus reveal a novel target. We discovered that P2x3 receptor mRNA expression was up regulated substantially in chemoreceptive petrosal sensory neurones in hypertensive rats. These neurones generated both tonic drive and hyperreflexia in hypertensive (but not normotensive rats), and both phenomena were normalised by blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduced arterial pressure and basal sympathetic activity and normalised carotid body hyperreflexia in conscious hypertensive rats; no effect was observed in normotensive rats. These preclinical data support the P2X3 receptor as a putative novel target for controlling human
Long-term exposure to intermittent hypoxia may lead to important cardiovascular dysfunctions, such as hypertension. Rodent models of chronic intermittent hypoxia (CIH) have been used to study the mechanisms underlying the increase in mean arterial pressure (MAP) observed after exposure to CIH. Several studies suggest that the hypertension of rats submitted to CIH is associated with an increase in sympathetic activity. However, there are no studies documenting the direct measurement of sympathetic activity in conscious freely moving rats exposed to CIH. Therefore, the present study aimed to evaluate whether or not the increase of MAP in rats exposed to CIH is associated with an increase in sympathetic activity. To reach this goal, we analysed the effect of ganglionic blockade on baseline MAP as well as the plasma levels of catecholamines. Rats submitted to CIH (fractional inspired O 2 of 6%, for 40 s in every 9 min, 8 h day −1 ) for 35 days (n = 31) exhibited a significant increase in MAP compared with control rats (n = 28) maintained under normoxia (112 ± 2 versus 103 ± 1 mmHg, P = 0.0003). The injection of the ganglionic blocker hexamethonium resulted in a similar fall in MAP in CIH and control groups (−46 ± 2 versus −41 ± 3 mmHg). However, hexamethonium after previous antagonism of the angiotensin II type 1 (AT 1 ) receptors with losartan produced a larger decrease in MAP in the CIH than in the control group (−58 ± 2 versus −50 ± 2 mmHg, P = 0.0165). The injection of losartan itself produced no major changes in the baseline MAP in both groups. The measurement of plasma catecholamines showed an increase in plasma noradrenaline (10.12 ± 0.90 versus 4.74 ± 0.32 ng ml −1 , P = 0.0042) in rats exposed to CIH compared with control rats. These data provide strong evidence to support the concept that rats submitted to CIH exhibit an increase in sympathetic activity, which seems to be determinant in the maintenance of hypertension in this experimental model.
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