| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Themed Issue Papers |
1 Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, GZ 405, 330 Brookline Avenue, Boston, MA 02215, USA
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
(Received 19 September 2006;
accepted after revision 15 November 2006; first published online 23 November 2006)
Corresponding author J. W. Weiss: Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, GZ 405, 330 Brookline Avenue, Boston, MA 02215, USA. Email: jweiss{at}bidmc.harvard.edu
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
Evidence connecting sleep apnoea to hypertension
Of the different possible consequences of CIH in sleep apnoea patients, the best documented is diurnal systemic hypertension. Possibly the most convincing evidence to support a causal role for OSA in the development of hypertension has come from recent epidemiological data collected in community-dwelling populations. The Wisconsin Sleep Cohort Study examined the prevalence of sleep apnoea in a cohort of Wisconsin state employees, using attended full polysomnography, and related sleep-disordered breathing to daytime blood pressure. Using standard cuff inflation, as well as 24 h non-invasive monitoring, subjects in this study with an apnoea index greater than 5 events h–1 of sleep had a significantly higher arterial pressure than did those individuals with snoring but without apnoea or individuals with no snoring (Peppard et al. 2000). All analyses were controlled for obvious confounding variables, such as age, body mass index, cigarette smoking, alcohol intake and gender. Additional support for a causal connection between OSA and hypertension comes from data from the Sleep Heart Health Study, a multicentre study of cardiovascular risk from OSA. These data suggest that the risk of prevalent hypertension is increased significantly by an apnoea/hypopnoea index (AHI, apnoeas + hypopnoeas per hour of sleep) greater than 30 (Nieto et al. 2004).
In addition to these human data that suggest a direct connection between sleep apnoea and diurnal hypertension, there are now two animal models that support a causal link between sleep-disordered breathing and elevated arterial pressure. The first model represents an attempt to mimic the nocturnal fluctuations in oxygen saturation experienced by sleep apnoea patients. In this model, rats are exposed to intermittent hypocapnic hypoxia for 8 h each day induced by alterations in inspired oxygen concentration (Fletcher et al. 1992). The second model more closely mimics the upper airway changes of obstructive sleep apnoea. In this model, which uses a chronic dog preparation, a computer is used to activate a solenoid valve that occludes a tracheotomy tube whenever the animal sleeps. The occlusion is released when the animal awakens, mimicking human sleep apnoea. Significantly, animals subjected to this protocol for 2 months developed sustained daytime elevations of arterial pressure that resolved when the airway occlusions were halted (Brooks et al. 1997b).
Sympathoexcitation links sleep apnoea to hypertension
These physiological studies provide strong evidence to support a causal relationship between OSA and hypertension. While the mechanism or mechanisms by which nocturnal upper airway obstructions lead to daytime hypertension are not well established, several lines of evidence suggest that nocturnal hypoxaemia may be important. First, the rats described above that were exposed to intermittent hypoxia did not develop significant hypertension when the carotid bodies were removed (Bao et al. 1997). Second, our own data show that normal human volunteers exposed to 8 h of cyclic hypoxia overnight for 28 days develop increased arterial pressure that persists after the exposure is terminated (unpublished observations, Gilmartin G, Tamisier R, Lynch M, Weiss JW). Third, administration of 100% oxygen decreased both muscle sympathetic nerve activity (MSNA) and arterial pressure in patients with OSA but not in nonapnoeic control subjects (Narkiewicz et al. 1998). Finally, in a study that strongly implicates cyclic hypoxia rather than sleep disruption in the circulatory consequences of airway obstruction during sleep, the same dogs that developed hypertension after airway occlusion developed nocturnal oscillations in pressure but no daytime hypertension when exposed to sleep disruption caused by acoustic tones (Brooks et al. 1997a). These studies suggest that cyclic intermittent hypoxaemia mediates the hypertension that occurs as a consequence of OSA.
A likely mechanism by which nocturnal hypoxaemia could contribute to increased arterial pressure is through sustained sympathoexcitation. Carlson and colleagues were the first to use peroneal microneurography to assess sympathetic activity in OSA patients (Carlson et al. 1993). These investigators reported marked elevations of MSNA in OSA patients while awake compared with non-apnoeic control subjects, a finding now confirmed by others. Further supporting the connection between sleep apnoea and sympathetic hyperactivity is the evidence that effective sleep apnoea treatment with nasal continuous positive airway pressure (CPAP) results in a decrease in resting sympathetic tone, again assessed with peroneal microneurography (Waradeker et al. 1996). Although long-term control of arterial pressure has been thought to be regulated through hormonal and renal regulation of intravascular volume, recent animal studies suggest that sympathoexcitation contributes to sustained hypertension in several models, including the spontaneously hypertensive rat (SHR) and several models of renal insufficiency-induced hypertension (Osborn et al. 1997). It is believed that augmented renal sympathetic nerve activity alters body fluid regulation in these models, thereby contributing to increased arterial pressure. Significantly, in the model of CIH-induced hypertension in rats, the renal sympathetic nervous system is necessary for the change in blood pressure, since section of the renal nerves before the exposure to CIH prevents the rise in arterial pressure (Bao et al. 1997).
Causes of sympathoexcitation in sleep apnoea
This evidence that sustained sympathoexcitation links exposure to cyclic intermittent hypoxia and systemic hypertension makes understanding the causes of heightened sympathetic activity key to understanding this important cardiovascular consequence of obstructive sleep apnoea. Efferent sympathetic outflow is influenced by peripheral reflex activity (chemoreflex, baroreflex and metaboreflex) and also by central sympathetic activity. Considerable research suggests that peripheral chemoreflex sensitivity is augmented by exposure to CIH. Peng and colleagues have reported an increase in carotid sinus nerve activity during both normoxia and rechallenge to hypoxia in rats exposed for 14 days to cyclic hypoxia (20 s every 5 min, 8 h day–1; Peng et al. 2003; Peng & Prabhakar, 2004). Our own studies also found increased firing of the carotid sinus nerve (CSN) in rats exposed to 5 weeks of CIH (5% nadir of SaO2, 30 s of each minute, 8 h day–1). Data regarding the effect of cyclic hypoxia on the gain of the sympathetic response to hypoxia also suggest that cyclic hypoxia is capable of increasing the gain of the chemoreflex. Greenburg and colleagues exposed rats to cyclic hypoxia for 8 h a day for 30 consecutive days and then measured the response of nerves in the cervical sympathetic ganglion to acute hypoxic exposure (Greenberg et al. 1999). In this model, intermittent hypoxia apparently increased the slope and intercept of the SNA response to acute hypoxia during anaesthesia, consistent with an increase in chemosensitivity. Data supporting increased chemoreceptor gain in patients with sleep apnoea are consistent with an effect of the disease on hypoxic chemosensitivity. Supporting the hypothesis that untreated OSA may increase chemoreflex gain are two manuscripts: one manuscript reported that OSA patients treated with nasal CPAP for 3 months demonstrate a decrease in the ventilatory response to progressive hypoxia relative to their untreated baseline that is consistent with deacclimatization (Tun et al. 2000); and a second manuscript showed that hyperoxia decreased MSNA in OSA patients but not in non-apnoeic control subjects (Narkiewicz et al. 1998).
If cyclic hypoxia and obstructive sleep apnoea do result in increased chemoresponsiveness, what is the mechanism? Although no studies have directly examined this question, recent research into the mechanism of hypoxic acclimatization may be pertinent. Recently, evidence has emerged suggesting a role for an enhancer of chemoreceptor activity, endothelin, as a mediator of acclimatization (Chen et al. 2001). Endothelin (ET) is a 21-amino acid peptide that is found in endothelium and in type 1 cells (glomus cells) in the carotid bodies (Prabhakar & Jacono, 2005). Endothelin acts at two receptors, the endothelin A (ETA) receptor and the endothelin B (ETB) receptor. Functional studies with ETA receptor antagonists suggest that ET causes chemoexcitation at the ETA receptor (Chen et al. 2000). Chen and colleagues have now presented evidence, based on reverse transcriptase-polymerase chain reaction, that continuous hypoxia (14 days of hypobaric hypoxia, fractional inspired O2
0.1) increases expression of the ETA receptor and of preproendothelin, the precursor of endothelin, in the carotid body. Furthermore, these investigators showed that analysis of chemoreceptor activity using carotid sinus nerve recordings and a selective ETA antagonist suggested that the increases in chemoreceptor activity paralleled the increases in ET and ETA expression. Another enhancer of chemoreceptor activity, angiotensin II, has received less attention as a mediator of acclimatization (Lam & Leung, 2002; Lam et al. 2004). Substantial evidence supports a role for angiotensin II as a neuromodulator, particularly of sympathetic activity in the central nervous system (Zucker, 2002). Recent evidence now indicates that the carotid body is an organ that has a local angiotensin II generating system. Carotid sinus nerve activity is increased by angiotensin II in the in vitro carotid body preparation, indicating that the effect of angiotensin II on chemoreceptor activity is not a consequence of altered arterial pressure or blood flow (Lam & Leung, 2002). Angiotensin II is formed from its precursor, angiotensinogen, after cleavage by angiotensin II-converting enzyme, and angiotensinogen protein and mRNA have been localized in glomus cells. Leung and colleagues have now demonstrated that chronic hypoxia upregulates the transcriptional and post-transcriptional expression of AT1 receptors in the carotid body (Lam et al. 2004).
Although this evidence suggests complementary roles for ET and angiotensin II in hypoxic acclimatization, nitric oxide, a gas with an inhibitory effect on chemosensitivity, has not yet been implicated in the increased peripheral chemosensitivity after hypoxic exposure. Nitric oxide synthase (NOS) is present in the human body in two constitutive forms and in an inducible form. Like endothelin, constitutive nitric oxide synthase is present in the carotid body in endothelium (eNOS) as well as in nerve terminals (nNOS; Prabhakar, 1999). Recent evidence suggests that both eNOS and nNOS modulate carotid chemoreceptor activity, although the greater amount of eNOS may contribute proportionally to chemoreceptor regulation (Iturriaga et al. 2000). Altered regulation of NOS, the enzyme responsible for nitric oxide production, has been shown by Sun and colleagues to account, in large part, for increased chemoreceptor sensitivity in a pacing model of congestive heart failure (Sun et al. 1999). Bisgard discounted NO as mediating increased chemoreceptor activity in prolonged altitude exposure because studies have shown NOS is upregulated in carotid body tissue after a 14 day exposure of rats to hypobaric hypoxia, suggesting enhanced inhibition (Bisgard, 2000). More recently, however, Kusakabe has demonstrated that a 90 day exposure of rats to hypobaric hypoxia decreases NOS expression in carotid body tissue (Kusakabe et al. 1998). Significantly, new research has shown that cyclic intermittent hypoxia for 35 days in a model previously shown to induce arterial hypertension is also associated with downregulation of NOS in neuronal tissue in the right atrium (Mohan et al. 2001). Our own data indicate that nNOS mRNA is also downregulated in carotid bodies of rats exposed to CIH. Thus, the duration and possibly the pattern of the hypoxic exposure may influence whether NOS is upregulated or downregulated in carotid body tissue. We know of no studies that have investigated NO availability after different patterns of hypoxic exposure.
These data indicate how alterations in angiotensin II, endothelin and nitric oxide may influence sympathetic activity by modulating peripheral chemoreflex sensitivity after exposure to CIH. There are even more compelling data suggesting that these systems may serve as neuromodulators in central sites of sympathoregulation. Investigators are just beginning to explore how changes in central sympathoregulation might contribute to hypertension in patients with sleep apnoea. Fortunately, considerable evidence exists from other models of hypertension to guide our search.
Outflow from postganglionic renal sympathetic nerves is modulated by input from preganglionic neurones in the spinal cord which, in turn, receive input from sympathetic premotor neurones in a number of locations in the central nervous system, including the rostral ventral lateral medulla (RVLM), the medullary raphe, the A5 area of the pons and the paraventricular nucleus of the hypothalamus (PVN). In addition, these premotor neurones receive input from a wide variety of CNS locations, including neurones within the circumventricular organs (CVO) in the lamina terminalis (Dampney, 2004; Dampney et al. 2005). Although all these regions may be involved in states of pathological sympathoexcitation, considerable attention has been focused recently on the role of the PVN in several animal models of sustained hypertension (SHR and Dahl-sensitive rats) and in the heightened sympathetic activity that is associated with congestive heart failure (CHF; Zucker et al. 2004). While modulation of sympathetic activity within the PVN is complex, a number of studies suggest that sustained sympathoexcitation can occur as a consequence of downregulation of nNOS in neurones in the PVN because such neurones are sympathoinhibitory (Zhang et al. 1997). Also contributing to sympathoexcitation in these conditions is overexpression of AT1 receptors in the PVN (Zucker, 2002; Zucker et al. 2004). Angiotensin II-containing neurones are sympathoexcitatory in the PVN, RVLM and CVO. Our preliminary data indicate that in rats exposed to cyclic hypoxia, nNOS expression in the PVN is decreased and in the CVO AT1 expression is increased.
The greatest evidence exists for the connection between the brain renin–angiotensin II system (RAS) and hypertension, much of which has been covered in recent reviews (Romero & Reckelhoff, 1999; Veerasingham & Raizada, 2003). The brain expresses genes that code all components of the renin–angiotensin II system, including genes for angiotensinogen, the precursor to angiotensin II, and for the angiotensin II receptors, AT1 and AT2. Initially, there was controversy over whether renin was produced locally in the brain or was only produced in the kidney. This has now been resolved; the renin transcript produced locally in the CNS, however, encodes a truncated renin isoform that probably acts intracellularly because it lacks the prefragment that targets the secretory pathway (Veerasingham & Raizada, 2003). Although both AT1 and AT2 receptors are expressed in the brain, nearly all central actions on arterial pressure regulation occur through the AT1 receptors, which are expressed in high density in the CVO, particularly the subfornical organ, the median preoptic nucleus, the PVN and the nucleus tractus solitarii (NTS; Dampney et al. 2005). Pharmacological studies indicate that increased brain angiotensin II activity mediates sympathoexcitation and hypertension. Infusion of losartan into the lateral ventricle (I.C.V.) of SHR rats decreases systemic pressure but has no haemodynamic effect in control animals (Ye et al. 2002). This effect on arterial pressure appears to be mediated through a reduction in renal sympathetic nerve activity. Additional evidence for a role of the brain RAS in hypertension has been provided by I.C.V. administration of antisense oligonucleotides to angiotensinogen or to the AT1 receptor (Kagiyama et al. 2001). Interestingly, antisense inhibition of angiotensinogen mRNA in the PVN does not alter arterial pressure in SHR, suggesting that angiotensin II in the PVN does not contribute to hypertension in SHR rats, although other studies suggest that angiotensin II-containing neurones in this location may contribute to salt-induced hypertension (Gyurko et al. 1993).
The signalling pathways by which angiotensin II induces sympathoexcitation have been partly worked out, although not all steps have been demonstrated in neuronal tissues. Substantial evidence supports a role for reactive oxygen species in central angiotensin II-mediated sympathetic activation. In endothelium, angiotensin II infusion increases superoxide generation by increasing Protein Kinase C (PKC) activity, which increases expression of nox1, gp91phox and p22phox, all components of NAD(P)H oxidase (Zalba et al. 2001). In RVLM, Chan and colleagues demonstrated that the NAD(P)H oxidase-derived superoxide anion mediates sympathetic activation by phosphorylating p38 mitogen activated protein K (MAPK) and extracellular signal regulated (ERK1/2), but not stress-activated protein kinase/Jun N-terminal kinase. Finally, p38 MAPK and ERK1/2 augment sympathetic activation by enhancing presynaptic glutamate release (Chan et al. 2005). This sequence may not completely account for all actions of angiotensin II, however, since Veerasingham has additionally demonstrated a role for the p85 
-subunit of phosphoinositide 3-kinase (PI3K) in presympathetic areas of the spontaneously hypertensive rat (Veerasingham et al. 2005), and PI3K inhibitors influence activity of neurones from spontaneously hypertensive rats (Sun et al. 2003).
Although angiotensin II appears to have its major effect on arterial pressure and sympathetic activity at the subfornical organ, angiotensinergic neurones project to the PVN, another site of central sympathoregulation (Dampney et al. 2005). In PVN, however, substantial evidence indicates that nitric oxide plays a major role in arterial pressure control. Nitric oxide is sympathoinhibitory in the PVN, since microinjection of the NO donor sodium nitroprusside (SNP) into the region produces a decrease in sympathetic activity that is eliminated by additional injection of the GABA antagonist bicuculline (Zhang & Patel, 1998). Downregulation of nNOS will thus contribute to sympathoexcitation. As noted above regarding nNOS expression in the carotid body, the mechanism by which hypoxia alters nNOS expression is incompletely worked out, and contradictory findings have been reported, with hypoxic exposure both increasing and decreasing nNOS mRNA and protein expression. Evidence for eNOS in endothelial cells suggests a biphasic effect of hypoxia on NOS expression with enhancement followed by both transcriptional and post-transcriptional reductions in eNOS activity (McQuillan et al. 1994). No such data exist for nNOS. There are considerable data, however, indicating that angiotensin II reduces nNOS expression in the PVN as one of its mechanisms regulating central sympathetic activity (Campese & Zhong, 2002).
Evidence connecting endothelin-1 (ET-1) to central sympathetic control is much less than for either angiotensin II or NO, but several lines of investigation suggest that ET-1 plays a similar role to angiotensin II. First, ETA receptors are widely distributed within the central nervous system, and are found in the subfornical organ, the PVN and the RVLM (Rossi et al. 1997). In addition, injection of ET-1 intracerebroventricularly causes hypertension in rats, and this hypertensive response is prevented by lesioning the PVN. Finally, the hypertensive response to I.C.V. ET-1 is mediated through the sympathetic nervous system rather than through vasopressin release (Rossi et al. 2000; Rossi & Chen, 2001). Interestingly, the work of Phillips and co-workers suggests that patients with obstructive sleep apnoea have elevated levels of endothelin circulating in the blood, and these levels decline with effective therapy (Phillips et al. 1999). There are no studies of endothelin levels in cerebrospinal fluid of OSA patients.
Conclusion
This brief review has summarized the connection between obstructive sleep apnoea and hypertension. We have speculated here about mechanisms by which nocturnal CIH might contribute to sustained sympathoexcitation, i.e. sympathetic hyperactivity that outlasts the hypoxic stimulus. We are just beginning to explore these mechanisms. Hopefully, greater understanding will allow us to develop additional interventions for patients with this common disorder.
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Brooks D, Horner RL, Kimoff RJ, Kozar LF, Render-Texeira CL & Phillipson EA (1997a). Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Resp Crit Care Med 155, 1609–1617.[Abstract]
Brooks D, Horner RL, Kozar LF, Render-Teixeira CL & Phillipson EA (1997b). Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 99, 106–109.[Medline]
Campese VM, Ye S & Zhong H (2002). Downregulation of neuronal nitric oxide synthase and interleukin-1ß mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 39, 519–524.
Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J & Wallin BG (1993). Augmented resting sympathetic nerve activity in awake patients with obstructive sleep apnea. Chest 103, 1763–1768.[CrossRef][Medline]
Chan SHH, Hsu K-S, Huang C-C, Wag L-L, Ou C-C & Chan JYH (2005). NAD(P)H oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ Res 97, 772–780.
Chen J, He L, Dinger B & Fidone S (2000). Cellular mechanisms involved in rabbit carotid body excitation elicited by endothelin peptides. Resp Physiol 121, 13–23.[CrossRef][Medline]
Chen J, He L, Dinger B, Stensaas LJ & Fidone S (2001). Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 282, L1314–L1323.
Dampney R (2004). Medullary pathways regulating sympathetic outflow: the need for more lateral thinking. Am J Physiol Regul Integr Comp Physiol 286, R446–R448.
Dampney RAL, Horiuchi J, Killinger S, Sherrif MJ, Tan PSP & McDowall LM (2005). Long-term regulation of arterial pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol 32, 419–425.[CrossRef][Medline]
Fletcher EC, Lesske J, Qian W, Miller CCI & Unger T (1992). Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19, 555–561.
Greenberg HE, Sica AL, Batson D & Scharf SM (1999). Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 86, 298–305.
Gyurko R, Wielbo D & Phillips MI (1993). Antisense inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. Regul Pept 49, 167–174.[CrossRef][Medline]
Iturriaga R, Villanueva S & Mosqueira M (2000). Dual effects of nitric oxide on cat carotid body chemoreception. J Appl Physiol 89, 1005–1012.
Kagiyama S, Varela A, Phillips MI & Galli SM (2001). Antisense inhibition of brain renin-angiotensin II system decreased blood pressure in chronic 2-kidney, 1 clip hypertensive rats. Hypertension 37, 371–375.
Kusakabe T, Matsuda H, Harada Y, Hayashida Y, Gono Y, Kawakami T & Takenaka T (1998). Changes in the distribution of nitric oxide synthase immunoreactive nerve fibers in the chronically hypoxic rat carotid body. Brain Res 795, 292–296.[CrossRef][Medline]
Lam SY, Fung ML & Leung PS (2004). Regulation of the angiotensin II-converting enzyme activity by a time-course hypoxia in the carotid body. J Appl Physiol 96, 809–813.
Lam SY & Leung PS (2002). A locally generated angiotensin II system in rat carotid body. Regul Pept 107, 97–103.[CrossRef][Medline]
McQuillan LP, Leung GK, Marsden PA, Kostyk SK & Kourembanas S (1994). Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol Heart Circ Physiol 267, H1921–H1927.
Mohan RM, Golding S & Paterson DJ (2001). Intermittent hypoxia modulates nNOS expression and heart rate response to sympathetic nerve stimulation. Am J Physiol Heart Circ Physiol 281, H132–H138.
Narkiewicz K, Borne JPVD, Montano N, Dyken ME, Phillips BG & Somers VK (1998). Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 97, 943–945.
Nieto FJ, Herrington DM, Redline S, Benjamin EJ & Robbins JA (2004). Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Resp Crit Care Med 169, 354–360.
Osborn JL, Plato CF, Gordon E & He XR (1997). Long-term increases in renal sympathetic nerve activity and hypertension. Clin Exp Pharmacol Physiol 24, 72–76.[Medline]
Peng Y-J, Overholt JL, Kline D, Kumar GK & Prabhakar NR (2003). Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci U S A 100, 10073–10078.
Peng Y-J & Prabhakar NR (2004). Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96, 1236–1242.
Peppard PE, Young T, Palta M & Skatrud JB (2000). Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342, 1378–1384.
Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME & Somers VK (1999). Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17, 61–66.[Medline]
Prabhakar NR (1999). NO and CO as second messengers in oxygen sensing in the carotid body. Resp Physiol 115, 161–168.[CrossRef][Medline]
Prabhakar NR & Jacono FJ (2005). Cellular and molecular mechanisms associated with carotid body adaptations to chronic hypoxia. High Alt Med Biol 6, 112–120.[CrossRef][Medline]
Romero JC & Reckelhoff JF (1999). Role of angiotensin II and oxidative stress in essential hypertension. Hypertension 34, 943–949.
Rossi NF & Chen H (2001). PVN lesions prevent the endothelin 1-induced increase in arterial pressure and vasopressin. Am J Physiol Endocrinol Metab 280, E349–E356.
Rossi NF, O'Leary DS & Chen H (1997). Mechanisms of centrally administered ET-1-induced increases in systemic arterial pressure and AVP secretion. Am J Physiol Endocrinol Metab 272, E126–E132.
Rossi NF, O'Leary DS, Woodbury D & Chen H (2000). Endothelin-1 in hypertension in the baroreflex-intact SHR: a role independent from vasopressin release. Am J Physiol Endocrinol Metab 279, E18–E24.
Sun C, Du J, Sumners C & Raizada MK (2003). PI3-kinase inhibitors abolish the enhanced chronotropic effects of angiotensin II in spontaneously hypertensive rats. J Neurophysiol 90, 3155–3160.
Sun SY, Wang W, Zucker IH & Schultz HD (1999). Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. J Appl Physiol 86, 1273–1282.
Tun Y, Hida W, Okabe S, Kikuchi Y, Kurosawa H, Tabata M & Shirato K (2000). Effects of nasal continuous positive airway pressure on awake ventilatory responses to hypoxia and hypercapnia in patients with obstructive sleep apnea. Tohoku J Exp Med 190, 1578–1168.
Veerasingham SJ & Raizada MK (2003). Brain renin-angiotensin II system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139, 191–202.[CrossRef][Medline]
Veerasingham SJ, Yamazato M, Berecek KH, Wyss JM & Raizada MK (2005). Increased PI3-kinase in presympathetic brain areas of spontaneously hypertensive rat. Circ Res 96, 277–279.
Waradeker NV, Sinoway LI, Zwillich CW & Leuenberger UA (1996). Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Resp Crit Care Med 153, 1333–1338.[Abstract]
Young T, Palta M, Dempsey J, Skatrud JB, Weber S & Badr S (1993). The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328, 1230–1235.
Zalba G, San José G, Moreno MU, Fortuno MA, Fortuno A, Beaumont FJ & Diez J (2001). Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38, 1395–1399.
Zhang K, Mayhan WG & Patel KP (1997). Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 273, R864–R872.
Zhang K & Patel KP (1998). Effect of nitric oxide with the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. Am J Physiol Regul Integr Comp Physiol 275, R728–R734.
Ye S, Zhong H, Duong VN & Campese VM (2002). Losartan reduces central and peripheral sympathetic nerve actvity in a rat model of neurogenic hypertension. Hypertension 39, 1101–1106.
Zucker IH (2002). Brain angiotensin II: new insights into its role in sympathetic regulation. Circ Res 90, 503–505.
Zucker IH, Schultz HD, Li YF, Wang Y, Wang W & Patel KP (2004). The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide. Prog Biophys Mol Biol 84, 217–232.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  T. V. Serebrovskaya, E. B. Manukhina, M. L. Smith, H. F. Downey, and R. T. Mallet Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension? Experimental Biology and Medicine, June 1, 2008; 233(6): 627 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Smith Sleep Apnoea and Hypertension: Physiological Bases for a Causal Relation Themed Issue Exp Physiol, January 1, 2007; 92(1): 19 - 20. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
