HHS Public Access Author manuscript Author Manuscript
Hypertension. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Hypertension. 2016 July ; 68(1): 24–26. doi:10.1161/HYPERTENSIONAHA.116.07338.
Obesity, Hypoxemia and Hypertension: Mechanistic Insights and Therapeutic Implications Allyn L. Mark1 and Virend K. Somers2 1Department
of Internal Medicine, the Obesity Research and Education Initiative, and the Center for Hypertension Research, University of Iowa Carver College of Medicine, Iowa City, Iowa
Author Manuscript
2Department
of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Four decades ago, Trzebski and colleagues in Warsaw reported an astonishing discovery, namely that hypersensitivity and augmented tonic activity of arterial chemoreceptors contribute to increased arterial pressure in young hypertensive men (1). This discovery has stood the test of time. In addition to increasing ventilation, activation of carotid chemoreceptors increases sympathetic nerve activity and arterial pressure. Young borderline hypertensive humans have a striking augmentation of the sympathetic nerve responses to chemoreceptor activation by hypoxemia (2). Conversely, suppression of arterial chemoreceptors by breathing 100% oxygen decreases sympathetic nerve activity and arterial pressure in hypertensive but not normotensive humans (3).
Author Manuscript
Studies in spontaneously hypertensive (SHR) and normotensive (WKY) rats have paralleled and advanced these concepts (4,5). SHR display augmented increases in carotid sinus afferent activity during hypoxemia. In addition, carotid body denervation reduces the development and maintenance of increased sympathetic activity and arterial pressure in SHR but not normotensive WKY rats (4). The augmented sympathetic nerve response to hypoxemia is manifest in young prehypertensive SHR and appears to result from a membrane abnormality that underlies the increased chemoreceptor sensitivity and activity (5). This suggests a primary genetic molecular mechanism for increased chemoreceptor sensitivity and tonic activity in spontaneous hypertension. These and other studies in humans and rats have prompted interest in carotid body denervation as treatment for resistant, sympathetically-mediated essential hypertension in humans (6).
Author Manuscript
To this story of carotid chemoreceptors in spontaneous hypertension, Tom Lohmeier–a Mississippi master physiologist–and his colleagues add a new chapter in this issue of Hypertension (7). Lohmeier et al report that dogs with a secondary form of hypertension, namely obesity-induced hypertension, are hypoxemic and have augmented tonic activation of carotid chemoreceptors that contributes substantially to the obesity-induced hypertension.
Corresponding Author: Allyn L. Mark, University of Iowa Carver College of Medicine, 3187 MERF, Iowa City, Iowa 52242-1101, Ph: 319 384 8756, Fax: 319 384 6247, [email protected]. Disclosures. ALM has no disclosures. VKS has served as a consultant for Respicardia, Sorin Inc., Glaxo, Philips Respironics, UHealth, Biosense Webster and ResMed.
Mark and Somers
Page 2
Author Manuscript
Bilateral carotid sinus denervation (denervation of carotid chemoreceptors and baroreceptors) produced a substantial anti-hypertensive response, attributed to carotid body chemoreceptor denervation and not to carotid baroreceptor denervation which would be expected to increase arterial pressure.
Author Manuscript
The key characteristics highlighted by the Lohmeier study in dogs are obesity, hypoxemia, heightened chemoreflex sensitivity, tonic chemoreflex activation, increased sympathetic outflow, and hypertension (Figure). Although it is not known if the obese dogs had sleep apnea (Lohmeier: Personal Communication), the quintessential human equivalent of the phenotypic constellation in these dogs is obstructive sleep apnea (OSA). OSA patients are often obese, are exposed to repetitive nocturnal hypoxemia, and have increased peripheral chemoreflex sensitivity, high sympathetic drive, and increased risk of hypertension (Figure). Suppression of chemoreflex activity in OSA patients by breathing 100% oxygen (versus room air) elicits a reduction in sympathetic drive, heart rate and arterial pressure (8). These findings support the concept that sympathetically-mediated increases in arterial pressure in patients with OSA result substantially from chronic intermittent hypoxemia and tonic activation of arterial chemoreceptors.
Author Manuscript
Obesity adversely impacts lung function in humans. Lohmeier et al suggest that hypoxemia may be more common in obese humans than is currently recognized. We agree, and have long held that some of the cardiovascular pathophysiology attributed to severe obesity may reflect effects of undiagnosed OSA. Nevertheless, many patients with obesity and hypertension are presumably normoxemic. This prompts a question. Is hypoxemia the only contributor to chemoreceptor sensitivity in obesity? Surprisingly, there is a body of evidence for leptin signaling in carotid body glomus cells that translates into sensitization of carotid chemoreceptor afferent signaling (9). Increases in circulating and carotid body leptin are exaggerated by intermittent hypoxemia. In this regard, leptin is higher in patients with OSA and increased chemoreceptor activity than in comparably obese patients without OSA. These observations raise the possibility that in obesity and OSA, alterations in adipokines induced by hypoxemia might contribute to acquired sensitization of arterial chemoreceptors.
Author Manuscript
A second focus of the study by Lohmeier et al was an interaction of carotid baroreceptors and carotid chemoreceptors. Chronic baroreceptor activation produced by electrical stimulation of the carotid sinuses attenuated tachypnea in obese dogs in addition to decreasing arterial pressure. Studies in experimental animals and humans have demonstrated that acute activation of baroreceptors inhibits ventilatory and sympathetic responses to hypoxemic stimulation of chemoreceptors (10,11). Lohmeier’s study suggests that carotid baroreceptor inhibition of chemoreceptor reflexes can be sustained and contribute to the decrease in sympathetic activity and arterial pressure during chronic baroreceptor activation in hypertensive states characterized by tonic activation of chemoreflexes (Figure). This reinforces the concept of carotid body denervation as a potential anti-hypertensive treatment for sympathetically mediated hypertension with tonic activation of chemoreceptor reflexes (6). It is noteworthy, however, that the putative reduction in sympathetic activity following carotid body denervation in the obese dogs was not accompanied by a decrease in circulating norepinephrine (NE) whereas there was a pronounced fall in NE during carotid baroreflex activation. Alternative mechanisms could have contributed to the decrease in arterial
Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 3
Author Manuscript
pressure following chemoreceptor denervation. For example, chemoreceptor denervation was followed by significant hypoxemia (PaO2 of 65 mmHg) and hypercapnia (PaCO2 of 53 mmHg). Both hypoxemia and hypercapnia may elicit vasodilation and contribute to a fall in arterial pressure following chemoreceptor denervation.
Author Manuscript
What are the clinical implications of the Lohmeier study? Patients with OSA with heightened chemoreflex drive, increased sympathetic activity, and resistant hypertension would seem to be a target population for anti-hypertensive interventions such as carotid body denervation. Insofar as carotid body denervation has been proposed for treatment of resistant, sympathetically-mediated hypertension, it is relevant that patients with resistant hypertension have a very high likelihood of comorbid OSA, with some reports showing an OSA prevalence greater than 70% (12). The anti-hypertensive effects of chronic positive airway pressure (CPAP) in patients with OSA and resistant hypertension have been modest with blood pressure reductions of about 3 mmHg (13). Therefore, there is a need for alternative anti-hypertensive strategies in patients with OSA and resistant hypertension. However, chemoreceptor denervation has the theoretical potential for worsening apnea severity, given the role of chemoreflexes in driving breathing and terminating apneas. On the other hand, in a pilot study, we observed that renal denervation was accompanied by attenuation of OSA severity (14), findings supported by a subsequent meta-analysis. While renal denervation has not met expectations as a treatment for resistant hypertension in general, it may conceivably be more effective in lowering blood pressure in those resistant hypertensives with comorbid OSA, perhaps in part by mitigation of OSA severity (Figure).
Author Manuscript
In summary, in an elegant tour de force, Lohmeier et al have added a new chapter to the unfolding story of the surprising contribution of tonic activation of arterial chemoreceptors in hypertensive states. They demonstrate that tonic activation of carotid chemoreceptors contributes to a secondary form of hypertension, namely obesity-induced hypertension, in dogs. These studies have implications for the development of new strategies for the treatment of patients with OSA, obesity and resistant hypertension.
Acknowledgments Sources of Funding. The authors’ research is supported by HL-84207 (ALM) and by HL-65176 (VKS) from the National Heart Lung and Blood Institute.
References
Author Manuscript
1. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982; 16:163–172. [PubMed: 6805956] 2. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension. 1988; 11:608–612. [PubMed: 3391673] 3. Tafil-Klawe M, Trzebski A, Klawe J, Palko T. Augmented chemoreceptor reflex tonic drive in early human hypertension and in normotensive subjects with family background of hypertension. Acta Physiol Pol. 1985; 36:51–58. [PubMed: 3834754] 4. Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman ZJ, Fudim M, Sobotka PA, Gourine AV, Paton JF. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. J Physiol. 2012; 590:4269–4277. [PubMed: 22687617]
Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 4
Author Manuscript Author Manuscript Author Manuscript
5. Tan Z-Y, Lu Y, Whiteis CA, Simms AE, Paton JFR, Chapleau MW, Abboud FM. Chemoreceptor hypersensitivity, sympathetic excitation and overexpression of ASIC and TASK channels before the onset of hypertension in SHR. Circ Res. 2010; 106:536–545. [PubMed: 20019330] 6. Paton JFR, Sobotka PA, Fudim M, Engelman ZJ, Hart ECJ, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L, Nightingale A. The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension. 2013; 61:5– 13. [PubMed: 23172927] 7. Lohmeier TE, Iliescu R, Tudorancea I, Cazan R, Cates AW, Georgakopoulos D, Irwin ED. Chronic interactions between carotid baroreceptors and chemoreceptors in obesity hypertension. Hypertension. 2016 In Press. 8. Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998; 97:943–945. [PubMed: 9529260] 9. Messenger SA, Ciriello J. Effects of intermittent hypoxia on leptin signaling in the carotid body. Neuroscience. 2013; 232:216–225. [PubMed: 23201827] 10. Heistad DD, Abboud FM, Mark AL, Schmid PG. Interaction of baroreceptor and chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest. 1974; 53:1226–1236. [PubMed: 4825222] 11. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest. 1991; 87:1953–1957. [PubMed: 2040688] 12. Florczak E, Prejbisz E, Sliwinski P, Bielen P, Klisiewicz A, Michalowska I, Warchol E, Januszewicz M, Kala M, Witkowski A, Wiecek A, Narkiewicz K, Somers VK, Januszewicz A. Clinical characteristics of patients with resistant hypertension: the RESIST-POL study. J Human Hypertension. 2013; 27:678–685. 13. Martinez-Garcia M-A, Capote F. Campos-Rodriquez F for the Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: The HIPARCO Randomized Clinical Trial. JAMA. 2013; 310:2407–2415. [PubMed: 24327037] 14. Witkowski A, Prejbisz E, Florczak E, Kadziela J, Sliwinski P, Bielen P, Michalowska I, Kabat M, Warchol E, Januszewicz M, Narkiewicz K, Somers VK, Sobotka PA, Januszewicz A. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011; 58:559–565. [PubMed: 21844482]
Author Manuscript Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 5
Author Manuscript Author Manuscript
Figure.
A schematic diagram first, of the mechanisms and pathways involved in the role of arterial chemoreceptor reflexes in the hypertension of obese, hypoxemic dogs and of patients with obstructive sleep apnea, and second, of the sites of action of potential interventional therapies.
Author Manuscript Author Manuscript Hypertension. Author manuscript; available in PMC 2017 July 01.
Hypertension. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Hypertension. 2016 July ; 68(1): 24–26. doi:10.1161/HYPERTENSIONAHA.116.07338.
Obesity, Hypoxemia and Hypertension: Mechanistic Insights and Therapeutic Implications Allyn L. Mark1 and Virend K. Somers2 1Department
of Internal Medicine, the Obesity Research and Education Initiative, and the Center for Hypertension Research, University of Iowa Carver College of Medicine, Iowa City, Iowa
Author Manuscript
2Department
of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Four decades ago, Trzebski and colleagues in Warsaw reported an astonishing discovery, namely that hypersensitivity and augmented tonic activity of arterial chemoreceptors contribute to increased arterial pressure in young hypertensive men (1). This discovery has stood the test of time. In addition to increasing ventilation, activation of carotid chemoreceptors increases sympathetic nerve activity and arterial pressure. Young borderline hypertensive humans have a striking augmentation of the sympathetic nerve responses to chemoreceptor activation by hypoxemia (2). Conversely, suppression of arterial chemoreceptors by breathing 100% oxygen decreases sympathetic nerve activity and arterial pressure in hypertensive but not normotensive humans (3).
Author Manuscript
Studies in spontaneously hypertensive (SHR) and normotensive (WKY) rats have paralleled and advanced these concepts (4,5). SHR display augmented increases in carotid sinus afferent activity during hypoxemia. In addition, carotid body denervation reduces the development and maintenance of increased sympathetic activity and arterial pressure in SHR but not normotensive WKY rats (4). The augmented sympathetic nerve response to hypoxemia is manifest in young prehypertensive SHR and appears to result from a membrane abnormality that underlies the increased chemoreceptor sensitivity and activity (5). This suggests a primary genetic molecular mechanism for increased chemoreceptor sensitivity and tonic activity in spontaneous hypertension. These and other studies in humans and rats have prompted interest in carotid body denervation as treatment for resistant, sympathetically-mediated essential hypertension in humans (6).
Author Manuscript
To this story of carotid chemoreceptors in spontaneous hypertension, Tom Lohmeier–a Mississippi master physiologist–and his colleagues add a new chapter in this issue of Hypertension (7). Lohmeier et al report that dogs with a secondary form of hypertension, namely obesity-induced hypertension, are hypoxemic and have augmented tonic activation of carotid chemoreceptors that contributes substantially to the obesity-induced hypertension.
Corresponding Author: Allyn L. Mark, University of Iowa Carver College of Medicine, 3187 MERF, Iowa City, Iowa 52242-1101, Ph: 319 384 8756, Fax: 319 384 6247, [email protected]. Disclosures. ALM has no disclosures. VKS has served as a consultant for Respicardia, Sorin Inc., Glaxo, Philips Respironics, UHealth, Biosense Webster and ResMed.
Mark and Somers
Page 2
Author Manuscript
Bilateral carotid sinus denervation (denervation of carotid chemoreceptors and baroreceptors) produced a substantial anti-hypertensive response, attributed to carotid body chemoreceptor denervation and not to carotid baroreceptor denervation which would be expected to increase arterial pressure.
Author Manuscript
The key characteristics highlighted by the Lohmeier study in dogs are obesity, hypoxemia, heightened chemoreflex sensitivity, tonic chemoreflex activation, increased sympathetic outflow, and hypertension (Figure). Although it is not known if the obese dogs had sleep apnea (Lohmeier: Personal Communication), the quintessential human equivalent of the phenotypic constellation in these dogs is obstructive sleep apnea (OSA). OSA patients are often obese, are exposed to repetitive nocturnal hypoxemia, and have increased peripheral chemoreflex sensitivity, high sympathetic drive, and increased risk of hypertension (Figure). Suppression of chemoreflex activity in OSA patients by breathing 100% oxygen (versus room air) elicits a reduction in sympathetic drive, heart rate and arterial pressure (8). These findings support the concept that sympathetically-mediated increases in arterial pressure in patients with OSA result substantially from chronic intermittent hypoxemia and tonic activation of arterial chemoreceptors.
Author Manuscript
Obesity adversely impacts lung function in humans. Lohmeier et al suggest that hypoxemia may be more common in obese humans than is currently recognized. We agree, and have long held that some of the cardiovascular pathophysiology attributed to severe obesity may reflect effects of undiagnosed OSA. Nevertheless, many patients with obesity and hypertension are presumably normoxemic. This prompts a question. Is hypoxemia the only contributor to chemoreceptor sensitivity in obesity? Surprisingly, there is a body of evidence for leptin signaling in carotid body glomus cells that translates into sensitization of carotid chemoreceptor afferent signaling (9). Increases in circulating and carotid body leptin are exaggerated by intermittent hypoxemia. In this regard, leptin is higher in patients with OSA and increased chemoreceptor activity than in comparably obese patients without OSA. These observations raise the possibility that in obesity and OSA, alterations in adipokines induced by hypoxemia might contribute to acquired sensitization of arterial chemoreceptors.
Author Manuscript
A second focus of the study by Lohmeier et al was an interaction of carotid baroreceptors and carotid chemoreceptors. Chronic baroreceptor activation produced by electrical stimulation of the carotid sinuses attenuated tachypnea in obese dogs in addition to decreasing arterial pressure. Studies in experimental animals and humans have demonstrated that acute activation of baroreceptors inhibits ventilatory and sympathetic responses to hypoxemic stimulation of chemoreceptors (10,11). Lohmeier’s study suggests that carotid baroreceptor inhibition of chemoreceptor reflexes can be sustained and contribute to the decrease in sympathetic activity and arterial pressure during chronic baroreceptor activation in hypertensive states characterized by tonic activation of chemoreflexes (Figure). This reinforces the concept of carotid body denervation as a potential anti-hypertensive treatment for sympathetically mediated hypertension with tonic activation of chemoreceptor reflexes (6). It is noteworthy, however, that the putative reduction in sympathetic activity following carotid body denervation in the obese dogs was not accompanied by a decrease in circulating norepinephrine (NE) whereas there was a pronounced fall in NE during carotid baroreflex activation. Alternative mechanisms could have contributed to the decrease in arterial
Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 3
Author Manuscript
pressure following chemoreceptor denervation. For example, chemoreceptor denervation was followed by significant hypoxemia (PaO2 of 65 mmHg) and hypercapnia (PaCO2 of 53 mmHg). Both hypoxemia and hypercapnia may elicit vasodilation and contribute to a fall in arterial pressure following chemoreceptor denervation.
Author Manuscript
What are the clinical implications of the Lohmeier study? Patients with OSA with heightened chemoreflex drive, increased sympathetic activity, and resistant hypertension would seem to be a target population for anti-hypertensive interventions such as carotid body denervation. Insofar as carotid body denervation has been proposed for treatment of resistant, sympathetically-mediated hypertension, it is relevant that patients with resistant hypertension have a very high likelihood of comorbid OSA, with some reports showing an OSA prevalence greater than 70% (12). The anti-hypertensive effects of chronic positive airway pressure (CPAP) in patients with OSA and resistant hypertension have been modest with blood pressure reductions of about 3 mmHg (13). Therefore, there is a need for alternative anti-hypertensive strategies in patients with OSA and resistant hypertension. However, chemoreceptor denervation has the theoretical potential for worsening apnea severity, given the role of chemoreflexes in driving breathing and terminating apneas. On the other hand, in a pilot study, we observed that renal denervation was accompanied by attenuation of OSA severity (14), findings supported by a subsequent meta-analysis. While renal denervation has not met expectations as a treatment for resistant hypertension in general, it may conceivably be more effective in lowering blood pressure in those resistant hypertensives with comorbid OSA, perhaps in part by mitigation of OSA severity (Figure).
Author Manuscript
In summary, in an elegant tour de force, Lohmeier et al have added a new chapter to the unfolding story of the surprising contribution of tonic activation of arterial chemoreceptors in hypertensive states. They demonstrate that tonic activation of carotid chemoreceptors contributes to a secondary form of hypertension, namely obesity-induced hypertension, in dogs. These studies have implications for the development of new strategies for the treatment of patients with OSA, obesity and resistant hypertension.
Acknowledgments Sources of Funding. The authors’ research is supported by HL-84207 (ALM) and by HL-65176 (VKS) from the National Heart Lung and Blood Institute.
References
Author Manuscript
1. Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982; 16:163–172. [PubMed: 6805956] 2. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension. 1988; 11:608–612. [PubMed: 3391673] 3. Tafil-Klawe M, Trzebski A, Klawe J, Palko T. Augmented chemoreceptor reflex tonic drive in early human hypertension and in normotensive subjects with family background of hypertension. Acta Physiol Pol. 1985; 36:51–58. [PubMed: 3834754] 4. Abdala AP, McBryde FD, Marina N, Hendy EB, Engelman ZJ, Fudim M, Sobotka PA, Gourine AV, Paton JF. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. J Physiol. 2012; 590:4269–4277. [PubMed: 22687617]
Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 4
Author Manuscript Author Manuscript Author Manuscript
5. Tan Z-Y, Lu Y, Whiteis CA, Simms AE, Paton JFR, Chapleau MW, Abboud FM. Chemoreceptor hypersensitivity, sympathetic excitation and overexpression of ASIC and TASK channels before the onset of hypertension in SHR. Circ Res. 2010; 106:536–545. [PubMed: 20019330] 6. Paton JFR, Sobotka PA, Fudim M, Engelman ZJ, Hart ECJ, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L, Nightingale A. The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension. 2013; 61:5– 13. [PubMed: 23172927] 7. Lohmeier TE, Iliescu R, Tudorancea I, Cazan R, Cates AW, Georgakopoulos D, Irwin ED. Chronic interactions between carotid baroreceptors and chemoreceptors in obesity hypertension. Hypertension. 2016 In Press. 8. Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation. 1998; 97:943–945. [PubMed: 9529260] 9. Messenger SA, Ciriello J. Effects of intermittent hypoxia on leptin signaling in the carotid body. Neuroscience. 2013; 232:216–225. [PubMed: 23201827] 10. Heistad DD, Abboud FM, Mark AL, Schmid PG. Interaction of baroreceptor and chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest. 1974; 53:1226–1236. [PubMed: 4825222] 11. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest. 1991; 87:1953–1957. [PubMed: 2040688] 12. Florczak E, Prejbisz E, Sliwinski P, Bielen P, Klisiewicz A, Michalowska I, Warchol E, Januszewicz M, Kala M, Witkowski A, Wiecek A, Narkiewicz K, Somers VK, Januszewicz A. Clinical characteristics of patients with resistant hypertension: the RESIST-POL study. J Human Hypertension. 2013; 27:678–685. 13. Martinez-Garcia M-A, Capote F. Campos-Rodriquez F for the Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: The HIPARCO Randomized Clinical Trial. JAMA. 2013; 310:2407–2415. [PubMed: 24327037] 14. Witkowski A, Prejbisz E, Florczak E, Kadziela J, Sliwinski P, Bielen P, Michalowska I, Kabat M, Warchol E, Januszewicz M, Narkiewicz K, Somers VK, Sobotka PA, Januszewicz A. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011; 58:559–565. [PubMed: 21844482]
Author Manuscript Hypertension. Author manuscript; available in PMC 2017 July 01.
Mark and Somers
Page 5
Author Manuscript Author Manuscript
Figure.
A schematic diagram first, of the mechanisms and pathways involved in the role of arterial chemoreceptor reflexes in the hypertension of obese, hypoxemic dogs and of patients with obstructive sleep apnea, and second, of the sites of action of potential interventional therapies.
Author Manuscript Author Manuscript Hypertension. Author manuscript; available in PMC 2017 July 01.
