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PubMed2006

Functional imaging of the trigeminal system: applications to migraine pathophysiology.

BACKGROUND: Based largely on data from animal models, migraine is hypothesized to involve changes in neural function in brain areas that mediate nociception--specifically, the trigeminal nerve, spinal trigeminal nucleus, and thalamus. These hypotheses about migraine pathophysiology can be tested directly in humans for the first time, with recent advances in functional neuroimaging techniques, which allow assessment of functional activity of specific brain areas. This article discusses the hypothesized role of the trigeminovascular pain system in migraine, reviews recent findings involving functional imaging of the human trigeminal system, and considers applications of functional imaging in the study of migraine pathophysiology. Functional neuroimaging is the only noninvasive approach for the objective measurement of changes in neural activity in humans. Functional magnetic resonance imaging has been applied to the measurement of neural activation of the trigeminal nociceptive system in healthy volunteers, and in patients with pain syndromes such as trigeminal pain. CONCLUSIONS: The demonstrated utility of functional magnetic resonance imaging at elucidating, in a regionally specific manner, the functional and temporal changes in neural activity in the trigeminal nociceptive system, promises to make it a useful tool for the study of migraine pathophysiology and the evaluation of therapeutic interventions.

Humans↗
PubMed2004

The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer's disease.

The causes of late onset Alzheimer disease (AD) are poorly understood. Although beta-amyloid (Abeta) is thought to play a critical role in the pathophysiology of AD, no genetic evidence directly ties Abeta to late onset AD. This suggests that the accumulation of Abeta and neurodegeneration associated with AD might result from an abnormality that indirectly affects Abeta production or accumulation. Increasing evidence suggests that abnormalities in the metabolism of cholesterol and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol might contribute to the pathophysiology of late onset AD by increasing production of Abeta. 24(S) Hydroxycholesterol is a member of a family of oxidized cholesterol catabolites, termed oxysterols, which function to regulate export of cholesterol from the cell and transcription of genes related to cholesterol metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in several different genes important for cholesterol physiology are associated with an increased load or level of Abeta in AD. These genes include apolipoprotein E, cholesterol 24 hydroxylase (Cyp46), acyl-CoA:cholesterol acetyltransferase (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of cholesterol, or its precursors, are elevated in subjects early in the course of AD. Finally, studies of the processing of amyloid precursor protein show that cholesterol and its catabolites modulate amyloid precursor protein processing and Abeta production. These lines of evidence raise the possibility that genetic abnormalities in cholesterol metabolism might contribute to the pathophysiology of AD.

Alzheimer Disease↗
PubMed1997

Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults.

OBJECTIVES: To review the epidemiology, pathophysiology, and etiology of congestive heart failure (CHF) in older adults. METHODS: Published reports relevant to the epidemiology, pathophysiology, and etiology of CHF were systematically reviewed. Studies involving older adults and more recent studies were emphasized. RESULTS: More than 75% of patients with CHF in the United States are older than 65 years of age, and CHF is the leading cause of hospitalization in older adults. CHF is also a major cause of chronic disability, and annual expenditures for CHF currently exceed $10 billion. In addition, both the incidence and prevalence of CHF are increasing, largely as a result of the aging of the population. Older adults are predisposed to developing CHF as a result of age-related changes in the cardiovascular system and the high prevalence of hypertension, coronary artery disease, and valvular heart disease in this age group. Although the fundamental pathophysiology of CHF is similar in younger and older patients, older individuals are more prone to develop CHF in the setting of preserved left ventricular systolic function. This syndrome, referred to as diastolic heart failure, accounts for up to 50% of all cases of CHF in adults more than 65 years of age. Coronary heart disease and hypertension are the most common etiologies of CHF in older adults, and they often coexist. Valvular heart disease, especially aortic stenosis and mitral regurgitation, are also common in older adults, whereas nonischemic dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy occur less frequently. CONCLUSIONS: Congestive heart failure is a major public health problem in the United States today as a result of its high and increasing prevalence in the older population as well as its substantial impact on healthcare costs and quality of life. There is an urgent need to develop more effective strategies for the prevention and treatment of CHF in older individuals.

Age Factors↗
PubMed2000

Insights into the pathophysiology and mechanisms of constipation, irritable bowel syndrome, and diverticulosis in older people.

OBJECTIVES: To review the epidemiology, pathophysiology and mechanisms of irritable bowel syndrome (IBS), constipation, and diverticulosis, for the purpose of addressing these three common conditions in older adults (>65 years of age). DESIGN: Using a MEDLINE search, we identified original English language journal articles and reviews from 1965 to December 1998. We also selected articles published before 1965 or after 1998 that were cross-referenced or pertinent to the topics researched. RESULTS: The prevalence of constipation and diverticulosis is higher in older than in younger adults. Significant risk factors for constipation in older women are failure of the anorectal angle to open or excessive perineal descent, which represent disturbances of pelvic floor function and rectal evacuation. In contrast, the prevalence of IBS is no greater than in younger adults. Nevertheless, these syndromes impact on the patient's functional status and quality of life. The mechanisms resulting in these gastrointestinal syndromes are unclear. Uncoordinated colonic activity and colonic segmentation may lead to IBS and diverticulosis, respectively, and these pathophysiological findings suggest disorders of inhibitory control of neuromuscular function. The total number of neurons in the myenteric plexus is decreased, and collagen deposited in the distal colon is increased with aging in humans. Animal studies suggest that senescent colonic muscle responds less to excitatory factors in vitro, and neural injury in older animals may result from apoptosis, defects of mitochondrial metabolism, and inadequate levels or response to neurotrophins. Future investigations will reveal whether similar mechanisms underlie human disease. Currently, treatment is aimed at relief of symptoms of IBS or constipation or dealing with the complications of diverticulosis. CONCLUSIONS: Constipation, IBS, and diverticulosis are common problems of aging. There is a need for further systematic research of the basic mechanisms in neuromuscular dysfunction with aging, including the studies of physical characteristics of the colonic wall, pelvic floor function (particularly in women with excessive perineal descent), and neurohormonal control of motility and sensation. Insights on the pathophysiology and mechanisms of neural injury may lead to more specific treatments in the future, e.g., serotonergic agents and neurotrophins. Meanwhile, collaborations between primary care physicians, geriatricians, and gastroenterologists can optimize management of these three common conditions that significantly impact the quality of life of older adults.

Age Distribution↗
PubMed1997

Ventricular tachycardia: pathophysiology and radiofrequency catheter ablation.

Limitations of pharmacological therapy for VT have led to great interest in alternative nonpharmacological therapies. The appeal of a curative therapy for VT initially led to the search for operative techniques to identify and destroy the underlying substrate, and more recently, has resulted in the development of catheter techniques to achieve the same goal in the electrophysiology laboratory. Investigations into the pathophysiology of VT have resulted in the recognition that this arrhythmia reflects a mechanistically and anatomically heterogeneous set of disorders. Recent growth in our understanding of these distinctions has both led to, and resulted from, simultaneous advances in catheter ablation techniques. The clinical electrophysiology laboratory has served as a testing ground for theories derived from in vitro and animal experiments while also providing its own set of human experimental data regarding the pathophysiology and treatment of VT. As a result of this process, several distinct forms of VT that are amenable to catheter ablation have been characterized. This article will summarize current knowledge of the pathophysiology of various VT subtypes and of techniques for catheter mapping and ablation.

Arrhythmias, Cardiac↗
PubMed2006

Etiology of ejaculation and pathophysiology of premature ejaculation.

INTRODUCTION: Ejaculation is comprised of three stages of the male sexual response cycle, namely emission, ejection, and orgasm; however, in comparison with erection, which is a well-understood component of male sexual response, the pathophysiology of ejaculation has yet to be fully delineated. Premature ejaculation (PE), the most common sexual disorder in men, while believed to have a multifactorial etiology, is even less well understood. AIM: This article reviews the physiology of ejaculation, and the multifactorial pathophysiology of PE. METHODS: The Sexual Medicine Society of North America hosted a State of the Art Conference on Premature Ejaculation on June 24-26, 2005 in collaboration with the University of South Florida. The purpose was to have an open exchange of contemporary research and clinical information on PE. There were 16 invited presenters and discussants; the group focused on several educational objectives. MAIN OUTCOME MEASURE: Data were obtained by extensive examination of published peer-reviewed literature. RESULTS: Evidence supports that biologic mechanisms associated with neurotransmitters such as norepinephrine, serotonin, oxytocin, Gamma-amino-butyric acid, and nitric oxide (NO) as well as the hormone estrogen play central roles in ejaculation, and subsequently may mediate PE. There is also emerging evidence to show that hyperthyroidism may be a causal factor in PE. Recent data also suggest that psychogenic factors include high level of any experience by some men with PE. CONCLUSIONS: The pathophysiology of both lifelong and acquired PE appears to be both neurobiogenic and psychogenic. While psychogenic factors appear to be contributory to PE, pharmacologic intervention of PE can modify intravaginal ejaculatory latency time (IELT), which suggests that IELT is a biological variable, and is likely biologically dependent upon neurotransmitters and hormones.

Adult↗
PubMed1995

Corticotropin releasing hormone in the pathophysiology of melancholic and atypical depression and in the mechanism of action of antidepressant drugs.

Hypercortisolism in depression seems to preferentially reflect activation of hypothalamic CRH secretion. Although it has been postulated that this hypercortisolism is an epiphenomenon of the pain and stress of major depression, our data showing preferential participation of AVP in the hypercortisolism of chronic inflammatory disease suggest specificity for the pathophysiology of hypercortisolism in depression. Our findings that imipramine causes a down-regulation of the HPA axis in experimental animals and healthy controls support an intrinsic role for CRH in the pathophysiology of melancholia and in the mechanism of action of psychotropic agents. Our data suggest that hypercortisolism is not the only form of HPA dysregulation in major depression. In a series of studies, commencing in patients with Cushing's disease, and extending to hyperimmune fatigue states such as chronic fatigue syndrome and examples of atypical depression such as seasonal affective disorder, we have advanced data suggesting hypofunction of hypothalamic CRH neurons. These data raise the question that the hyperphagia, hypersomnia, and fatigue associated with syndromes of atypical depression could reflect a central deficiency of a potent arousal-producing anorexogenic neuropeptide. In the light of data presented elsewhere in this symposium regarding the role of a hypofunctioning hypothalamic CRH neuron in susceptibility to inflammatory disease, these data also raise the question of a common pathophysiological mechanism in syndromes associated both with inflammatory manifestations and atypical depressive symptoms. This concept of hypofunctioning of hypothalamic CRH neurons in these disorders also raises the question of novel forms of neuropharmacological intervention in both inflammatory diseases and atypical depressive syndromes.

Adrenocorticotropic Hormone↗
PubMed1996

Pathophysiologic role of alpha 4 integrins in the lung.

Evidence for a central role for the integrins alpha 4 beta 1 and alpha 4 beta 7 in leukocyte pathophysiology is rapidly accumulating. Five distinct alpha 4 mAbs, each able to block alpha 4-dependent adhesion in vitro, show beneficial effects in vivo in six different species, and in a wide variety of organ systems, including colon, lung, skin, neural tissue, pancreas, peritoneum, and the vessel wall. In particular, a clear role for these integrins in lung pathophysiology is implied on the basis of in vivo studies in four different species. Although several issues remain to be resolved, including the relative importance of alpha 4 beta 1 and alpha 4 beta 7, and the relative roles of their counterligands, VCAM1, fibronectin, and MAdCAM, the data argue that alpha 4 integrins will likely be critical to both the normal physiology and pathology of the lung in man. To this end, we (Adams, Lin, Lobb, and Gill, unpublished data) and others have generated peptidomimetic small molecule antagonists of VLA4 based on the connecting segment 1 (CS1) peptide sequence of fibronectin that are potent blockers of integrin adhesive function in vitro and show efficacy in vivo. We have found that our inhibitors are excellent blockers of both murine contact hypersensitivity, and of the LPR and AHR in the sheep allergic airways model (Abraham, Lobb, Adams, and Gill, unpublished data), and are therefore possible candidates for clinical intervention in human asthma. The use of the VCAM-Ig fusion protein as a probe for high-affinity alpha 4 integrins has further enhanced our understanding of alpha 4 integrin function in the lung. While integrin upregulation in vitro has been observed many times, and high affinity (as opposed to avidity) of integrins seen in vitro in several systems, in vivo proof of integrin upregulation to a high-affinity state has been difficult to obtain in the absence of selective probes. Our data provide key information in this regard and strongly argue not only that integrin upregulation does indeed occur in vivo, but also that it is in fact obligatory for the leukocyte pathologies we have examined to date. Further studies are clearly warranted to further examine mechanisms of action, and to confirm and extend these studies, both with the alpha 4 integrins and with other integrin families. In summary, our studies of alpha 4 integrins continue to provide novel insights into the pathophysiology of integrin function and into future directions for drug discovery.

Animals↗
PubMed1994

The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia.

Nitrogen monoxide (NO) has recently emerged as an important mediator of cellular and molecular events which impacts the pathophysiology of cerebral ischemia. Although tempting to ask whether NO is "good or bad" for cerebral ischemia, the question underestimates the complexities of NO chemistry and physiology as well as oversimplifies the pathophysiology of focal cerebral ischemia. Important vascular and neuronal actions of NO have been defined which both enhance tissue survival and mediate cellular injury and death, and these will be reviewed. Strategies which modify NO synthesis and/or metabolism may someday assume therapeutic importance, but not until the tissue compartments generating NO, the activities of the enzymes that are inducibly and constitutively expressed, and the redox state of NO during the stages of ischemic injury, are defined with greater precision. Our knowledge of these processes is rudimentary. This review will summarize the evidence from animal models which supports an emerging role for NO in ischemic pathophysiology. Important aspects of NO synthesis and inhibitors of this process will also be discussed.

Amino Acid Oxidoreductases↗
PubMed1993

Pathogenesis and pathophysiology of bacterial meningitis.

Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder.

Animals↗
PubMed1997

Multivariate analysis of pathophysiological factors in reflux oesophagitis.

BACKGROUND: Reflux oesophagitis is considered a multifactorial disease, but the respective roles of the main factors involved in its pathophysiology have not been clearly established. AIMS: To attempt to assign these roles by means of a multivariate logistic regression analysis of the main parameters associated with reflux oesophagitis. PATIENTS: Eighty seven patients with gastro-oesophageal reflux disease were studied: 41 without oesophagitis and 46 with reflux oesophagitis grade 1 to 3. METHODS: (1) Monovariate comparison of patients' characteristics and of parameters derived from in hospital 24 hour oesophageal pH monitoring, oesophageal manometry, double isotope gastric emptying studies, and basal and pentagastrin stimulated gastric acid and pepsin output determinations, between patients with and without oesophagitis. (2) Multivariate logistic regression analysis including the parameters significant in the monovariate analysis. RESULTS: Among the 16 significant parameters from monovariate analysis, three significant independent parameters were identified by multivariate logistic regression analysis: number of refluxes lasting more than five minutes, reflecting oesophageal acid clearance (p = 0.002); basal lower oesophageal sphincter pressure (p = 0.008); and peak acid output (p = 0.012). These three parameters were not correlated with each other. The multivariate model was highly discriminant (correct classification of 81.3% of the cases (95% confidence intervals 0.723, 0.903). Risk for oesophagitis increased as a function of the tercile threshold values of the three parameters. Odds ratios of the three parameters for oesophagitis risk were similar, regardless of whether they were calculated when the patients were compared as a function of oesophagitis grade or the presence or absence of oesophagitis. CONCLUSIONS: This multivariate approach adds evidence that impaired oesophageal acid clearance and hypotonic lower oesophageal sphincter are the two major independent pathophysiological factors of oesophagitis, but also showed that the acid secretion level is an independent pathophysiological factor.

Adult↗
PubMed1992

Pathophysiology of uterine leiomyomas.

Uterine leiomyomas is the most common benign neoplasia in women, one of the most frequent causes of infertility in reproductive years, and the leading cause for hysterectomy. The pathophysiology of uterine leiomyomas is uncertain. Therefore, therapeutic approaches have been primarily empirical. It is now well documented that growth factors control the functional and possibly the histological integrity of several tissues. Recently the presence of growth substances in uterine tissues suggested that the role of sex steroid hormones in the pathophysiology of leiomyomas may be mediated by substances influencing the proliferation of smooth muscle cells and fibroblasts. This report summarizes the data related to the pathophysiology of leiomyomas, which indicate a possible role of growth factors in uterine leiomyomas.

Chromosome Aberrations↗
PubMed1993

Pathogenesis and pathophysiology of bacterial meningitis.

Despite the availability of bactericidal antibiotics with potent in vitro activity against the major meningeal pathogens, the morbidity and mortality from bacterial meningitis remains unacceptably high. Animal models have proven to be extremely valuable in the study of the pathogenesis and pathophysiology of bacterial meningitis, with the hopes of providing new information that may lead to an improved outcome from this disorder. Bacterial meningitis usually begins with nasopharyngeal colonization by a new organism, followed by invasion and bacteremia. Subsequently there is central nervous system invasion, although the exact site and mechanism of meningeal invasion are unknown. The generation of an intense subarachnoid space inflammatory response, induced by release of bacterial virulence factors and/or inflammatory cytokines, contributes to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema, increased intracranial pressure, and alterations of cerebral blood flow. Attenuation of this inflammatory response (e.g. by co-administration of antiinflammatory agents) may diminish many of these pathophysiologic consequences of meningitis, and perhaps improve morbidity and mortality from this disorder.

Animals↗
PubMed1997

Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine.

Cell death of gastrointestinal epithelial cells occurs by a process referred to as apoptosis. In this review, we succinctly define apoptosis and summarize the role of apoptosis in the physiology and pathophysiology of epithelial cells in the liver, pancreas, and small and large intestine. The physiological mediators regulating apoptosis in gastrointestinal epithelial cells, when known, are discussed. Selected pathophysiological consequences of excessive apoptosis and inhibition of apoptosis are used to illustrate the significance of apoptosis in disease processes. These examples demonstrate that excessive apoptosis may result in epithelial cell atrophy, injury, and dysfunction, whereas inhibition of apoptosis results in hyperplasia and promotes malignant transformation. The specific cellular mechanisms responsible for dysregulation of epithelial cell apoptosis during pathophysiological disturbances are emphasized. Potential future areas of physiological research regarding apoptosis in gastrointestinal epithelia are highlighted when appropriate.

Animals↗
PubMed1998

Neural injury, repair, and adaptation in the GI tract. IV. Pathophysiology of GI motility related to interstitial cells of Cajal.

Our understanding of the physiological roles played by interstitial cells of Cajal (ICC) in relation to gastrointestinal (GI) motility is still rudimentary. Nevertheless, studies into the pathophysiology of ICC are emerging at a rapid pace. Caution should be exercised, however, in assuming correlations between changes in Kit immunoreactivity, findings of ultrastructural abnormalities in ICC, and the pathophysiology and symptoms of the patients. Recent studies have revealed reduced numbers or the absence of ICC in small intestine and colon that do not exhibit normal peristaltic activity. Furthermore, important evidence is emerging that motor abnormalities in newborns may be associated with delayed maturation of the ICC network. These preliminary clinical studies provide plausible hypotheses toward the pathophysiology of certain motor disorders and strongly encourage basic scientific studies directed toward discovering the intrinsic properties of ICC as well as obtaining a deeper understanding of the physiological roles played by these cells.

Adaptation, Physiological↗
PubMed2004

Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs.

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.

Adenosine↗
PubMed2003

Pathophysiology of orthostatic hypotension after bed rest: paradoxical sympathetic withdrawal.

Although orthostatic hypotension is a common clinical syndrome after spaceflight and its ground-based simulation model, 6 degrees head-down bed rest (HDBR), the pathophysiology remains unclear. The authors' hypothesis that a decrease in sympathetic nerve activity is the major pathophysiology underlying orthostatic hypotension after HDBR was tested in a study involving 14-day HDBR in 22 healthy subjects who showed no orthostatic hypotension during 15-min 60 degrees head-up tilt test (HUT) at baseline. After HDBR, 10 of 22 subjects demonstrated orthostatic hypotension during 60 degrees HUT. In subjects with orthostatic hypotension, total activity of muscle sympathetic nerve activity (MSNA) increased less during the first minute of 60 degrees HUT after HDBR (314% of resting supine activity) than before HDBR (523% of resting supine activity, P < 0.05) despite HDBR-induced reduction in plasma volume (13% of plasma volume before HDBR). The postural increase in total MSNA continued during several more minutes of 60 degrees HUT while arterial pressure was maintained. Thereafter, however, total MSNA was paradoxically suppressed by 104% of the resting supine level at the last minute of HUT (P < 0.05 vs. earlier 60 degrees HUT periods). The suppression of total MSNA was accompanied by a 22 +/- 4-mmHg decrease in mean blood pressure (systolic blood pressure <80 mmHg). In contrast, orthostatic activation of total MSNA was preserved throughout 60 degrees HUT in subjects who did not develop orthostatic hypotension. These data support the hypothesis that a decrease in sympathetic nerve activity is the major pathophysiological factor underlying orthostatic hypotension after HDBR. It appears that the diminished sympathetic activity, in combination with other factors associated with HDBR (e.g., hypovolemia), may predispose some individuals to postural hypotension.

Adult↗
PubMed2006

Physiology and pathophysiology of Na+/H+ exchange and Na+ -K+ -2Cl- cotransport in the heart, brain, and blood.

Maintenance of a stable cell volume and intracellular pH is critical for normal cell function. Arguably, two of the most important ion transporters involved in these processes are the Na+/H+ exchanger isoform 1 (NHE1) and Na+ -K+ -2Cl- cotransporter isoform 1 (NKCC1). Both NHE1 and NKCC1 are stimulated by cell shrinkage and by numerous other stimuli, including a wide range of hormones and growth factors, and for NHE1, intracellular acidification. Both transporters can be important regulators of cell volume, yet their activity also, directly or indirectly, affects the intracellular concentrations of Na+, Ca2+, Cl-, K+, and H+. Conversely, when either transporter responds to a stimulus other than cell shrinkage and when the driving force is directed to promote Na+ entry, one consequence may be cell swelling. Thus stimulation of NHE1 and/or NKCC1 by a deviation from homeostasis of a given parameter may regulate that parameter at the expense of compromising others, a coupling that may contribute to irreversible cell damage in a number of pathophysiological conditions. This review addresses the roles of NHE1 and NKCC1 in the cellular responses to physiological and pathophysiological stress. The aim is to provide a comprehensive overview of the mechanisms and consequences of stress-induced stimulation of these transporters with focus on the heart, brain, and blood. The physiological stressors reviewed are metabolic/exercise stress, osmotic stress, and mechanical stress, conditions in which NHE1 and NKCC1 play important physiological roles. With respect to pathophysiology, the focus is on ischemia and severe hypoxia where the roles of NHE1 and NKCC1 have been widely studied yet remain controversial and incompletely elucidated.

Animals↗