Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0037315 (sleep apnea)
 8,000 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The observation that the narcotic antagonist naloxone could inhibit analgesia produced by electrical stimulation of the brain indicated the involvement of an endogenous chemical in the relief of pain. Multiple endogenous opioid peptides have been identified that have similar pharmacological properties to known narcotic analgesics. The biosynthesis, release, and degradation of opioid peptides have been studied in order to better understand how the manipulation of endogenous opioid systems can be used to produce or augment analgesia. The results of our studies reveal that various conditions and manipulations, such as electrical brain stimulation, acupuncture, stress, and the administration of opioid analgesics, can cause the release of endogenous opioid peptides and possibly endogenous nonpeptide substances. It has also been discovered that nonopioid peptides, such as cholecystokinin, calcitonin, and angiotensin II, can alter the action of opioid analgesics by antagonizing or potentiating their effects. An understanding of the role of endogenous peptides in endogenous opioid mechanisms is necessary for the development of new ways to treat pain and such other disorders as sleep apnea in children (sudden infant death syndrome), head injury, and opioid addiction that involve the activation or alteration of endogenous opioid systems.
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PMID:The role of endogenous peptides in the action of opioid analgesics. 352 91

Previous studies in several strains of rats have demonstrated that 35 days of recurrent episodic hypoxia (EH) (7 hours per day), with a fractional concentration of inspired oxygen that produces desaturation equivalent to the recurrent hypoxemia of sleep apnea, results in an 8 to 13 mm Hg persistent increase in diurnal systemic blood pressure (BP). Carotid chemoreceptors and the sympathetic nervous system have been shown to be necessary for development of this BP increase. Both renal artery denervation and adrenal demedullation block the BP response to chronic EH. The present study was undertaken to define further the role of the kidneys and the renin-angiotensin system in this BP increase. Separate groups of male Sprague-Dawley rats had either (1) bilateral renal artery denervation with EH, (2) sham surgery with EH, (3) sham surgery with sham EH (compressed air), (4) EH with losartan, (5) unhandled with losartan, or (6) unhandled. The experimental period lasted 35 days. Both renal-artery denervated and losartan-treated animals showed no BP change or a lowering of BP in response to EH, whereas the sham-operated EH animals showed a progressive, sustained increase in resting room air BP. BP remained at basal levels or fell in unhandled and unhandled losartan-treated animals. Plasma renin activity was elevated 4-fold versus basal levels in EH animals with renal nerves intact but remained at baseline levels in denervated animals. At the end of the experiment, renal tissue catecholamines confirmed renal denervation in those animals. In conclusion, EH causes a progressive increase in BP, mediated in part through renal sympathetic nerve activity that acts to increase renin-angiotensin system activity through angiotensin II type 1 receptors.
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PMID:Renin activity and blood pressure in response to chronic episodic hypoxia. 1045 59

By using an inspired oxygen fraction that produces oxyhemoglobin desaturation equivalent to that seen in human sleep apnea, we have demonstrated that 35 days of recurrent episodic hypoxia (every 30 s for 7 h/day) results in an 8-13 mmHg persistent increase in diurnal systemic mean arterial blood pressure (MAP) in rats. Blockade of angiotensin II receptors (AT(1a)) eliminates this response. Separate groups of male Sprague-Dawley rats were fed high-salt (8%), ad libitum-salt, or low-salt (0.1%) diets for 7 wk: 2 wk of wash-in for baseline blood pressure measurement and 5 wk of experimental conditions. Rats in each salt group were subjected to episodic hypoxia whereas controls remained unhandled under normoxic conditions. MAP remained at basal levels in all nonepisodic hypoxia controls as well as high-salt-diet episodic hypoxia-exposed rats. Ad lib and low-salt episodic hypoxia rats showed an increase in MAP from 106 and 104 mmHg at baseline to 112 and 113 mmHg, respectively (P < 0.05). Whole kidney renin mRNA was suppressed in high-salt controls and episodic hypoxia rats, whereas kidney AT(1a) mRNA showed opposite changes. Suppression of the renin-angiotensin system with a high-salt diet blocks the increase in MAP in episodic hypoxia-challenged rats, in part by suppressing local tissue renin levels. Upregulation of the tissue angiotensin II system appears to be necessary for the chronic blood pressure changes that occur from episodic hypoxia.
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PMID:Blood pressure response to chronic episodic hypoxia: the renin-angiotensin system. 1179 74

Despite years of investigation our fundamental and clinical knowledge of the major public health problem, obesity-hypertension, is relatively meager and certainly inadequate. We are at a loss to explain why the pathophysiological mechanisms of obesity and hypertension are so inextricably intertwined. Adding to this frustration is the inadequacy of the treatment for obesity. Hemodynamically, we recognize that the expanded plasma volume caused by obesity imparts a significant volume overload on the heart, thereby increasing cardiac output, while the hypertension compounds this ventricular stress by an associated pressure overload. Thus, the ventricle has an eccentric as well as a concentric adaptive hypertrophy. Associated with obesity is an increased burden of pressor (e.g., catecholamine, angiotensin II); peptide (e.g., endothelin, insulin, leptin, natriuretic); hormonal (e.g., growth, steroids, thyroid); and neural mechanisms. Further complicating these alterations are electrolytic, lipid, uric acid, and other metabolic factors. Both diseases (obesity and hypertension) are exacerbated by frequently encountered comorbid pathophysiological disorders including atherosclerosis, ventricular dysfunction, diabetes mellitus, hyperlipidemias, and sleep apnea. To add to these issues, therapy for obesity-hypertension is suboptimal. Behavioral modification (of overweight and obesity) is commonly characterized by recidivism, and pharmacotherapy of obesity is woefully inadequate; the present agents either raise arterial pressure or are fraught with adverse effects. Fortunately, there are no contraindications imparted by obesity that complicate the drug treatment of the associated hypertension. Each of the lifestyle modifications and seven classes of antihypertensive therapy that is discussed herein is done in light of the coexistent hypertension and comorbid diseases.
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PMID:Clinical management of the obese hypertensive patient. 1204 91

Beginning with modest clinical observations in 1984, a picture has evolved suggesting that sympathetic nervous system over activity may be responsible in part for the elevated blood pressure seen in obstructive sleep apnea patients. Early studies of urinary and plasma catecholamines indirectly suggested sympathetic over activity carried to daytime, non-apneic conditions. Later intra-neuronal recordings of muscle sympathetic nerve activity directly demonstrated both acute and diumal (non-apneic) sympathetic over activity. Most importantly, diurnal sympathetic over activity has been shown to diminish with adequate treatment of apnea using nasal CPAP. Norepinephrine and angiotensin II are both released with increased peripheral sympathetic activity and are parallel vascular growth-promoting factors. Thus, one would expect alterations in vascular structure and function in a state of chronic sympathetic over activity. While changes in peripheral vascular structure have not been demonstrated in hypertension of sleep apnea, changes in peripheral vascular responsiveness have. There is reduced response to acetylcholine and isoproterenol vasodilation, and to norepinephrine and angiotensin vasoconstriction in humans with sleep apnea. Some of these vascular reactivity changes are shown to reversed with chronic nasal CPAP treatment. Finally, complimentary to the above evidence in humans, there is indirect evidence of sympathetic over activity as well as differences in vascular reactivity in intermittent hypoxia challenged rats. We have made significant strides in the past 15-20 years towards understanding systemic hypertension related to sleep apnea, especially the role of the sympathetic nervous system. Future research will need to look at exact mechanism of sympathetic nervous system over activity, particularly how central nervous system pathways may undergo facilitation, leading to daytime over activity. Furthermore, the mechanisms of sustained hypertension in sleep apnea patients is almost certainly of multiple etiologies. There is no marker for separating sleep apnea patients with hypertension derived solely from intermittent hypoxia from other secondary causes. Perhaps endothelial cell molecular markers could help to identify patients at risk for cardiovascular change associated with snoring and apnea, as well to guide treatment. Finally, studies demonstrating microvascular changes in blood vessels are extremely difficult to do, but promise to yield important knowledge about cellular mechanisms and results of long-term treatment of sleep apnea on cardiovascular disease.
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PMID:Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea. 1262 27

Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na+ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na+ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.
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PMID:Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis. 1617 84

Resistance to antihypertensive drugs is common in hypertensive patients with type 2 diabetes. This is unfortunate because hypertension is one of the most important risk factors for development of cardiovascular events, and the goal blood pressure level is set lower in diabetic subjects than in nondiabetic subjects. Previous outcome trials in diabetic subjects have mainly focused on end points such as microalbuminuria or the incidence of cardiovascular events rather than on reduction of blood pressure; some reports, however, have suggested mechanisms for the drug resistance. These include several clinical conditions known to be associated with difficulty in reducing blood pressure specifically in diabetes mellitus: change in the renin-angiotensin system and chymase, volume overload, central sympathetic hyperactivity, sleep apnea, secondary hypertension, pseudoresistance (white coat hypertension), and poor compliance related to subclinical depression. In this review, the authors focus on the mechanisms of resistance to antihypertensive therapy (particularly for monotherapy with either angiotensin-converting enzyme inhibitors or angiotensin II antagonists) in the treatment of diabetic hypertension.
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PMID:Why is blood pressure so hard to control in patients with type 2 diabetes? 1768 64

Intermittent hypoxia caused by sleep apnea is associated with cardiovascular disease. Chymase has been reported to play an important role in the development of cardiovascular disease, but it is unclear whether chymase is involved in the pathogenesis of left ventricular remodeling induced by intermittent hypoxia. The aim of this study was to evaluate the effect of a novel chymase inhibitor (NK3201) on hypoxia-induced left ventricular remodeling in mice. Male C57BL/6J mice (9 weeks old) were exposed to intermittent hypoxia or normoxia and were treated with NK3201 (10 mg/kg per day) or the vehicle for 10 days. Left ventricular systolic pressure showed no significant differences among all of the experimental groups. Exposure to intermittent hypoxia increased left ventricular chymase activity and angiotensin II expression, which were both suppressed by treatment with NK3201. Intermittent hypoxia also increased the mean cardiomyocyte diameter, perivascular fibrosis, expression of inflammatory cytokines, oxidative stress, and NADPH-dependent superoxide production in the left ventricular myocardium. These changes were all suppressed by NK3201 treatment. Therefore, chymase might play an important role in intermittent hypoxia-induced left ventricular remodeling, which is independent of the systemic blood pressure.
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PMID:Chymase plays an important role in left ventricular remodeling induced by intermittent hypoxia in mice. 1947 Aug 76

Analysis of the Framingham data has shown that the risk of heart failure is increased substantially among diabetic patients, while persons with the metabolic syndrome have an increased risk of both atherosclerosis and diabetes mellitus. Sleep apnea may be related to the metabolic syndrome and systemic inflammation through hypoxia, which might also cause the cardiac remodeling by increased oxidative stress. On the other hand, the renin-angiotensin system is activated in diabetes, and local angiotensin II production may lead to oxidative damage via the angiotensin II type 1 receptor. Basic and clinical data indicate that angiotensin II receptor blockers have the potential to preserve left ventricular function and prevent cardiac remodeling that is exaggerated by oxidative stress in patients with diabetes. Thus, alleviation of oxidative stress might be one possible strategy in the treatment of diabetic patients associated with sleep apnea.
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PMID:Regulation of oxidative stress and cardioprotection in diabetes mellitus. 2006 32

The brainstem is a major site in the central nervous system involved in the processing of the cardiovascular reflexes such as the baroreflex and the peripheral chemoreflex. The nucleus tractus solitarius and the rostral ventrolateral medulla are 2 important brainstem nuclei, and they play pivotal roles in autonomic cardiovascular regulation. Angiotensin II is one of the neurotransmitters involved in the processing of the cardiovascular reflexes within the brainstem. It is well-known that one of the mechanisms by which angiotensin II exerts its effect is via the activation of pathways that generate reactive oxygen species (ROS). In the central nervous system, ROS are reported to be involved in several pathological diseases such as hypertension, heart failure and sleep apnea. However, little is known about the role of ROS in the processing of the cardiovascular reflexes within the brainstem. The present review mainly discussed some recent findings documenting a role for ROS in the processing of the baroreflex and the peripheral chemoreflex in the brainstem.
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PMID:Angiotensin II-derived reactive oxygen species underpinning the processing of the cardiovascular reflexes in the medulla oblongata. 2178 98


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