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PubMed1996

Anorexia induced by cytokine interactions at pathophysiological concentrations.

Interleukin (IL)-1 beta, IL-8, and tumor necrosis factor-alpha (TNF-alpha) induce anorexia when administered intracerebroventricularly at doses that yield estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Our hypothesis is that pivotal cytokines released during pathological processes interact to induce anorexia during disease. In the present study, we investigated the effects of the intracerebroventricular microinfusion of individual or multiple combinations (8 dyads and 5 triads) of IL-1 beta, IL-8, and TNF-alpha on feeding and the microstructure of eating in rats maintained ad libitum. Estimated pathophysiological concentrations of cytokine combinations exhibited additive or synergistic activities in inducing anorexia. Computerized analysis of behavioral patterns demonstrated that the most effective treatment (triad of 1.0 ng IL-1 beta + 20 ng IL-8 + 20 ng TNF-alpha/rat, n = 11) decreased nighttime meal size by 42% and feeding rate (meal size/meal duration) by 26%, whereas it increased the satiety ratio (postprandial intermeal intervals/meal size) by 80%; meal duration and meal frequency were not significantly affected. Analysis of meal parameters in 4-h intervals revealed a maximum effect during the first 4-h interval after the intracerebroventricular administration. The time course during this initial 4-h interval analyzed in 10-min periods was similar for IL-8 (n = 10) and TNF-alpha (n = 11), and both were significantly different from the time course induced by IL-1 beta (n = 10) and the most effective triad (n = 11). Intracerebroventricular microinfusion of heat-inactivated triad or intraperitoneal administration of the most effective triad, in doses-equivalent to those administered centrally, had no effect on feeding. The results suggest that estimated pathophysiological concentrations of cytokines in the CSF act centrally and additively or synergistically to decrease feeding, and this effect may participate in the anorexia frequently accompanying pathological processes.

Animal Feed↗

PubMed1980

Angiotensin I conversion and vascular reactivity in pathophysiological states in dogs.

To determine if angiotension converting enzyme activity is altered by acute pathophysiological insults, we assessed angiotensin I conversion using a blood pressure response technique in anesthetized dogs studied during acute 100% O2 breathing and acute acid-base derangements. Also, we determined systemic vascular reactivity to angiotensin II by measuring the magnitude and duration of the arterial blood pressure response to intra-arterial injections of angiotensin II under these same conditions. Angiotensin I conversion found in normoxia [91 +/- 7 (SD)%] was unchanged by acute acidosis, alkalosis, and hyperoxia. During acute hyperoxia the mean half time of the hypertensive response increased from 68 +/- 25 (SD) s at a PaO2 of 112 +/- 18 (SD) Torr to 100 +/- 34 (SD) s at a PaO2 of 491 +/- 47 (SD) Torr (P less than 0.01). No other pathophysiological condition studied had any effect on reactivity of systemic vasculature to angiotensin II. We conclude that, except during acute hypoxia as previously shown, converting enzyme activity is resistant to other pathophysiological insults and that vascular responsiveness to angiotensin II is enhanced by hyperoxia.

Acid-Base Imbalance↗

PubMed2001

Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.

Adaptation, Physiological↗

PubMed1999

Pathophysiology of gene-targeted mouse models for cystic fibrosis.

Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193-S214, 1999. - Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models.

Animals↗

PubMed2004

Pathophysiology of reno-ureteral colic.

INTRODUCTION: Reno-ureteral colic presents with a complex of acute symptoms that usually indicate the presence of a stone in the collecting system, The aim of any treatment is pain relief, stone removal and preservation of kidney function. We focused our review on the pathophysiological aspects of reno-ureteral colic and, briefly, on its treatment. MATERIALS AND METHODS: A complete overview of contemporary literature regarding reno-ureteral colic was performed by using MEDLINE and website on-line publications like EAU Guidelines. RESULTS: Clinical presentation of reno-ureteral colic, of mechanisms of ureteral peristalsis and pathophysiology of renal colic is described. An overview of the available medical treatments is presented. CONCLUSIONS: An accurate comprehension of the pathophysiology of reno-ureteral colic allows the physician to tailor the best treatment for each patient.

Acute Disease↗

PubMed2004

Cerebral venous infarction: the pathophysiological concept.

Cerebral venous occlusion represents an often underdiagnosed cause for acute or slowly progressive neurological deterioration. The underlying pathophysiological basis is not well understood, but is different from those of arterial occlusion reflecting therefore different anatomical and physiological features of the cerebral venous system. Extensive collateral circulation within the cerebral venous system allows for a significant degree of compensation in the early stages of venous occlusion. Elevated cerebral venous pressure due to cerebral venous occlusion can result in a spectrum of phenomena including a dilated venous and capillary bed, development of interstitial edema, increased cerebrospinal fluid production, decreased cerebrospinal fluid absorption and rupture of venous structures (hematoma). All of these pathophysiological changes may explain the clinical observation that cerebral venous occlusion, if promptly diagnosed and adequately managed, contains reversible alterations and need not always lead to venous infarction. The present review outlines this different pathophysiological behavior of venous compared to arterial occlusion in the cerebral vasculature; special reference is given to the effect of these changes on the therapeutic impact.

Animals↗

PubMed2005

Pathophysiology of acute experimental pancreatitis: lessons from genetically engineered animal models and new molecular approaches.

The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field.

Animals↗

PubMed1994

Pathophysiologic assessment of data from a stroke data bank.

Stroke data banks have been instrumental in helping us to clarify stroke etiology and in the investigation of clinical-topographic correlations. For these purposes they have relied upon results from noninvasive vascular and cardiac methods, including extra- and transcranial Doppler sonography and echocardiography, as well as from procedures such as cranial computed tomography and magnetic resonance imaging. Conventional database concepts have also been used to assess pathophysiologic aspects of stroke. Although such applications have made important contributions in this multidiscipline area of investigation, they are limited by a lack of explicit representation of pathophysiologic knowledge for data interpretation. Recent results from artificial intelligence research suggest exciting new frontiers for medical database design with concepts stemming from second generation expert systems. We propose an extended concept for stroke data banks to include a knowledge-based system which incorporates current patient data, heuristic knowledge relating clinical features to functional impairment, and pathophysiologic models of neurological disease.

Cerebrovascular Disorders↗

PubMed1991

Endothelin has biological actions at pathophysiological concentrations.

BACKGROUND: Endothelin is an endothelium-derived peptide that produces sustained contraction of arterial and venous smooth muscle in vitro. Several studies have established endothelin as a systemic, renal, and coronary vasoconstrictor in vivo at pharmacological concentrations. Such concentrations of endothelin were antinatriuretic in association with activation of the renin-angiotensin-aldosterone system. Recent studies have demonstrated that endothelin is present in the plasma and that its plasma concentrations are increased in various pathological states associated with systemic and renal vasoconstriction. To date, it remains unclear if such increases in circulating endothelin are associated with biological activity. Thus, the objective of this study was to determine the biological action of endothelin on cardiorenal and endocrine function through administration of exogenous endothelin, which achieves plasma concentrations that have been reported in various pathophysiological conditions. METHODS AND RESULTS: Experiments were conducted in two groups of anesthetized dogs. In group 1, endothelin-1 was infused intravenously at 2.5 ng/kg/ml (n = 6), which produced a doubling of circulating concentrations. Group 2 (n = 8) received saline vehicle to serve as a time control. The current studies demonstrate that a twofold increase in plasma endothelin concentrations did not affect mean blood pressure or coronary blood flow. Heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. CONCLUSIONS: The present studies demonstrate that endothelin at pathophysiological plasma concentrations produced by exogenous endothelin has biological action. These studies support a functional role for endogenous endothelin as a potentially pathophysiological vasoconstrictor peptide hormone in the regulation of cardiovascular, renal, and endocrine function.

Animals↗

PubMed1995

Endothelin at pathophysiological concentrations mediates coronary vasoconstriction via the endothelin-A receptor.

BACKGROUND: Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations. METHODS AND RESULTS: ET-1 (group 1, n = 5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n = 6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n = 5), the same dose of ET-1 was infused with 4 micrograms/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n = 5), the same dose of sarafotoxin was infused with 50 micrograms/kg per minute of the specific inhibitor of nitric oxide formation, NG-monomethyl-L-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (-12 +/- 3% versus -48 +/- 6% [P < .001] and -4.6 +/- 0.8 versus 1.0 +/- 0.3 [P < .05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7 +/- 5% versus 105 +/- 21%, P < .005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (-28 +/- 7% versus -8 +/- 2% [P < .05]). CONCLUSIONS: The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.

Animals↗

PubMed2026

Progressive HNF1A-MODY pathophysiology revealed by a translational mouse model.

HNF1A-MODY, the most common monogenic diabetes, exhibits progressive β cell dysfunction, but existing mouse models fail to recapitulate human disease progression, limiting understanding of pathogenic mechanisms. We developed mice with heterozygous deletion of the Hnf1a transactivation domain (Hnf1a+/Δe4-10) to model human HNF1A haploinsufficiency, conducted cross-sectional metabolic characterization, and validated our findings in HNF1A-deficient human islets. Unlike previous models, Hnf1a+/Δe4-10 mice successfully recapitulated temporal HNF1A-MODY progression. Male mice developed sequential pathophysiology: early insulin resistance in young adults (7 weeks), followed by testosterone deficiency and fasting hyperglycemia in adult mice (10 weeks). Glucose intolerance emerged in middle-aged mice (30 weeks), progressing to multi-organ dysfunction in aged mice (44-70 weeks), characterized by elevated hepatic gluconeogenesis, impaired renal glucose handling, and hepatic steatosis/fibrosis. This dual pathophysiology involving β cell dysfunction and peripheral insulin resistance was associated with dysregulated hormone secretion from both α and β cells in aged mice (40-70 weeks). Human islet studies with HNF1A knockdown confirmed translational relevance, demonstrating reduced SGLT2 protein expression and inappropriate glucagon and insulin secretion. This work established a physiologically relevant HNF1A-MODY model, identified early insulin resistance as a key mechanism triggering hormonal dysfunction, and revealed HNF1A's role in multi-organ pathophysiology beyond traditional β cell dysfunction.

Animals↗

PubMed2001

The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.

Animals↗

PubMed2004

The pathophysiology of schizophrenia disorders: perspectives from the spectrum.

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.

Atrophy↗

PubMed2002

Pathophysiology of facial nerve paralysis induced by herpes simplex virus type 1 infection.

Herpes simplex virus type 1 (HSV-1) has been proven to be a cause of Bell's palsy; however, the underlying pathophysiology of the facial nerve paralysis is not fully understood. We established a mouse model with facial nerve paralysis induced by HSV-1 infection simulating Bell's palsy and investigated the pathophysiology of the facial nerve paralysis. The time course of the R1 latency in the blink reflex tests paralleled the recovery of the facial nerve paralysis well, whereas electroneurographic recovery tended to be delayed, compared to that of the paralysis; these responses are usually seen in Bell's palsy. On histopathologic analysis, intact, demyelinated, and degenerated nerves were intermingled in the facial nerve in the model. The similarity of the time course of facial nerve paralysis and the electrophysiological results in Bell's palsy and the model strongly suggest that the pathophysiological basis of Bell's palsy is a mixed lesion of various nerve injuries.

Animals↗

PubMed2005

Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction.

OBJECTIVE: Tardive dyskinesia (TD) is the principal adverse effect of long-term treatment with conventional antipsychotic agents. Several mechanisms may exist for this phenomenon. Mechanisms for the lower incidence of TD with atypical antipsychotics also remain to be fully understood. We undertook to explore and better understand these mechanisms. METHODS: We conducted a comprehensive review of TD pathophysiology literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, neuroleptics, antipsychotics, pathophysiology, and mechanisms. Additional articles were obtained by searching the bibliographies of relevant references. Articles were considered if they contributed to the current understanding of the pathophysiology of TD. RESULTS: Current TD vulnerability models include genetic vulnerability, disease-related vulnerability, and decreased functional reserve. Mechanisms of TD induction include prolonged blockade of postsynaptic dopamine receptors, postsynaptic dopamine hypersensitivity, damage to striatal GABA interneurons, and damage of striatal cholinergic interneurons. Atypical antipsychotics may cause less TD because they have less impact on the basal ganglia and are less likely to cause postsynaptic dopamine hypersensitivity. CONCLUSION: Although the ultimate model for TD is not yet understood, it is plausible that several of these vulnerabilities and mechanisms act together to produce TD. The lower incidence of TD with atypical antipsychotics has helped to elucidate the,mechanisms of TD.

Antipsychotic Agents↗

PubMed1997

Tetanus: pathophysiology and management.

OBJECTIVE: To review the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of tetanus and its complications. DATA SOURCES: MEDLINE and Iowa Drug Information Services databases were searched for literature pertaining to tetanus. Additional literature was obtained from the references of selected articles identified in the search. Information from all articles was considered for inclusion in the manuscript. STUDY SELECTION AND DATA EXTRACTION: Articles selected were those considered by the authors to assist in providing the reader an understanding of the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of tetanus. DATA SYNTHESIS: While the number of tetanus cases has decreased markedly since data reporting for the disease began in 1947, mortality among those who acquire the disease remains high. Elderly patients are particularly susceptible to tetanus and its complications. Prevention of tetanus focuses on primary immunization and scheduled boosters. Management of tetanus involves initial stabilization of the patient and protection of the airway, prevention of tetanospasmin absorption by administration of human tetanus immune globulin 3000-6000 IU, and eradication of Clostridium tetani with antimicrobial therapy (metronidazole 500 mg q8h). Supportive measures include the administration of neuromuscular blocking agents such as pancuronium in patients requiring artificial ventilation, as well as benzodiazepines (midazolam 5-15 mg/h) for sedation and muscle relaxation. Autonomic dysfunction should be managed with beta-adrenergic blockers such as propranolol or labetalol. CONCLUSIONS: Despite the relative infrequency of tetanus cases, mortality among untreated patients remains significantly high. Clinicians should become knowledgeable in the pathophysiology, clinical manifestations, and management of this potentially fatal disease.

Humans↗

PubMed1999

Soluble adhesion molecules in the HIT syndrome: pathophysiologic role and therapeutic modulation.

Heparin-induced thrombocytopenia pathophysiology is now known to be a complex process that involves platelets, vascular endothelium, and leukocytes/lymphocytes. The activation products from these sites also contribute to the activation of coagulation and fibrinolytic deficit. While many of the markers of hemostatic activation processes have been found to be increased during the acute phase of heparin-induced thrombocytopenia syndromes, the circulating levels of soluble adhesion molecules such as the P, E, and L selectins, and intracellular and vascular cell adhesion molecules have not been reported. Since the pathophysiology of heparin-induced thrombocytopenia involves the activation of platelets, endothelium, and leukocytes, it is expected that the activation products related to these hemostatic systems including soluble selectins and cellular adhesion molecules will also be increased in circulating blood. These alterations may also provide an index of the pathophysiologic process. With the availability of highly sensitive enzyme-linked immunosorbent assays for soluble P, E, and L selectins, intracellular and vascular cell adhesion molecules, it is now possible to measure these adhesion molecules in biological fluids. This study reports on the circulating levels of various adhesion molecules in patients with heparin-induced thrombocytopenia and their modulation after therapeutic interventions by the use of direct thrombin inhibitors. With the availability of recombinant hirudin, it is now possible to treat these patients with alternate antithrombin agents. However, the immunoactivation of platelets and other cells as shown here indicates the possible need for additional adjunct therapeutic approaches to suppress their participation in the thrombotic process. The reported increase in the circulating levels of the soluble adhesion molecules during the heparin-induced thrombocytopenia and heparin-induced thrombocytopenia with thrombosis syndrome suggests that the antiheparin platelet factor 4 antibody is capable of modulating their regulation. The prognostic role of these mediators in the management of heparin-induced thrombocytopenia syndrome warrants further investigation.

Antithrombins↗

PubMed1998

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Animals↗