SEARCH · Search PubMed

Results for “pathophysiology”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources

PubMed2002

Will improved understanding of the pathophysiological mechanisms involved in acute spinal cord injury improve the potential for therapeutic intervention?

At the dawning of the present decade, deemed appropriately the Decade of the Spine, acute spinal cord injury lingers as a formidable disorder affecting society. The enormous physical, emotional and socioeconomic impact of acute spinal cord injury on society is well known. Consequently, intensive clinical and laboratory research efforts have focused on furthering contemporary understanding of the mechanisms involved in primary and secondary injury following spinal cord injury. Additionally, research has been devoted to investigations concerning the treatment of acute spinal cord injury using a myriad of strategies, some of which involve rational targeting of known pathophysiological mechanisms. A recent surge of studies endeavoring to dissect the cellular and molecular mechanisms involved in the development and perpetuation of acute spinal cord injury appear particularly promising as a basis for identifying candidate pathways of injury for therapeutic manipulation. Meritorious investigations examining changes in gene expression, especially pertaining to pathways of cell death and inflammation, are increasingly reported. Molecular therapies harnessing knowledge gleaned from the aforementioned groundwork, including stem cell transplantation, likely represent the future direction of treatment for acute spinal cord injury. The Decade of the Spine is poised to be a phase of advancement in the treatment of acute spinal cord injury and the importance of further elucidation of underlying pathophysiological mechanisms to targeted, rational therapy will likely become clearly evident.

Acute Disease↗

PubMed2006

Apoptosis in schizophrenia: pathophysiologic and therapeutic considerations.

PURPOSE OF REVIEW: A role for apoptosis in schizophrenia has long been hypothesized, but only recently have studies begun to examine this issue. This paper will review studies of apoptotic regulatory proteins, DNA fragmentation, and gene microarrays to highlight the potential role of apoptosis in the pathophysiology and treatment of schizophrenia. RECENT FINDINGS: Although several studies indicate a possible increase in apoptotic susceptibility, accumulating evidence suggests that apoptotic activity may actually be downregulated in chronic schizophrenia. Furthermore, antipsychotics produce complex effects on apoptotic regulation in the central nervous system, activating both proapoptotic and antiapoptotic signaling pathways. SUMMARY: Somewhat paradoxically, apoptosis appears to be downregulated in cortex of patients with chronic schizophrenia. This could reflect either a pathophysiological failure to mount an effective response to an apoptotic insult or an appropriate compensatory response to an earlier insult. The former could account for evidence indicating reduced neuronal viability without large-scale neuronal death in schizophrenia. The latter could reflect an earlier period of increased apoptotic activity in response to one or more proapoptotic insults. Antipsychotic treatment can modify the apoptotic response. This suggests implications for treatment, especially if future studies indicate that gray matter loss occurs via apoptotic mechanisms.

Animals↗

PubMed2024

Multiple urinary peptides are associated with hypertension: a link to molecular pathophysiology.

OBJECTIVES: Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology. METHODS: Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n  = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms. RESULTS: Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed. CONCLUSION: Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation.

Humans↗

PubMed2005

NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology.

Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease.

Cardiomyopathy, Hypertrophic↗

PubMed2005

Peripheral CD8+ T cell tolerance against melanocytic self-antigens in the skin is regulated in two steps by CD4+ T cells and local inflammation: implications for the pathophysiology of vitiligo.

Experimental evidence has suggested a role for CD8+ cytotoxic T lymphocytes (CTL) in the pathophysiology of vitiligo, a pigmentation disorder with focal loss of melanocytes in the skin. The discovery of tyrosinase-related protein 2 (TRP2) as a model melanocytic self-antigen recognized by CD8+ CTL in C57BL/6 mice allowed us to analyze the requirements for CD8+ T cell-mediated autoimmune destruction of melanocytes in an experimental model. Using two different genetic methods for the induction of cellular immunity in vivo, gene gun bombardment of the skin and injection of recombinant adenovirus, we show that peripheral tolerance of CD8+ T cells recognizing a single TRP2-derived H2-Kb-binding peptide is regulated in two steps. In the induction phase, stimulation and expansion of TRP2-specific CD8+ T cells in vivo depend on CD4+ T cell help. In the effector phase, autoimmune destruction of melanocytes in the skin depends on local inflammation. Our results suggest that accidental stimulation of CD8+ CTL recognizing major histocompatibility complex class I-binding peptides derived from melanocytic proteins in the context of an inflammatory skin disease may play an important role in the pathophysiology of vitiligo.

Animals↗

PubMed2005

An in vivo model for gastric physiological and pathophysiological studies in the mouse.

AIM: In vivo models for studying gastrointestinal physiology and pathophysiology are well established in rats. Since a number of genetically modified mice are available there is a need for reliable mouse models. The aim of this project was to develop an in vivo mouse model for gastrointestinal studies. METHODS: C57bl/6, NMRI and transgenic FVB/N (expressing human alpha-1,3/4-fucosyltransferase) mice were anaesthetized with isoflurane and the gastric mucosa exteriorized for intravital microscopy. Acid-base status and acid secretion were measured and blood pressure was continuously monitored. Gastric mucosal blood flow was recorded by laser-Doppler flowmetry. Mucus thickness and accumulation rate were measured with micropipettes. RESULTS: We have developed an in vivo mouse model for studies of the gastric mucosa. With isoflurane anaesthesia the preparation can be studied for up to 5 h with stable blood pressure and mucosal blood flow. Acid-base status agrees with results from other laboratories. Blood flow increased in both C57bl/6 and alpha1.3/4-FT mice in response to luminal HCl, and the mucus gel could be divided into a firmly and a loosely adherent layer, all comparable with results in the rat. However, the firmly adherent mucus layer was thinner (45 +/- 2 microm), and the mucus accumulation rate lower, than in the rat. Furthermore, both basal and stimulated acid secretion showed lower outputs than in the rat. CONCLUSIONS: This model has great potential for investigations of gastrointestinal physiology and pathophysiology and can be applied for Helicobacter pylori infection studies.

Acid-Base Equilibrium↗

PubMed2004

New pathophysiological mechanisms in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post-infectious IBS), who are probably unable to down-regulate the initial inflammatory stimulus efficiently. Furthermore, low-grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post-infectious and non-specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.

Central Nervous System Diseases↗

PubMed1994

Clinical pharmacology, physiology and pathophysiology of superficial veins--1.

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.

Aging↗

PubMed1980

Pathophysiological classification of Raynaud's phenomenon.

The main types of underlying mechanism in Raynaud's phenomenon were tested separately in thirty-six patients. Within each of three groups of patients who were clinically classified according to strict definitions as having primary Raynaud's disease, systemic sclerosis or rheumatoid arthritis, there was pathophysiological heterogeneity. It is therefore suggested that in studies of treatment, at least when it is aimed primarily at one pathophysiological mechanism, the patients whould be selected according to the mechanism rather than what is commonly done now, according to the associated disorder.

Arthritis, Rheumatoid↗

PubMed2004

Myelodysplasia-associated autoimmunity: clinical and pathophysiologic concepts.

Myelodysplastic syndrome (MDS), an acquired clonal disorder of haemopoietic progenitor cells, is characterized by haemopoietic insufficiency associated with cytopenias, leading to serious morbidity plus the additional risk of leukaemic transformation. In MDS an acquired insult to the haemopoietic stem cell leads to impaired differentiation and myelodysplasia. However, there is increasing evidence that the marrow failure of MDS is immune-mediated. A model of MDS pathophysiology suggests that transformation of normal stem cells induces an autoimmune T-cell response with the bone marrow as the target organ. This autoimmune attack results in chronic overproduction of pro-apoptotic cytokines, especially tumour necrosis factor alpha (TNFalpha). In addition, several reports have revealed that approximately 10% of MDS patients have clinical autoimmune disorders. This review illustrates the cellular/molecular mechanisms and the implication of the tumour suppressor gene interferon regulatory factor-1 (IRF-1) in the pathophysiology of MDS-associated autoimmune deregulation.

Apoptosis↗

PubMed2004

New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology.

Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processes are interwoven and present two sides of one coin. On a molecular level, hyperglycaemia and proteins altered by high blood glucose such as Amadori products and advanced glycation end-products (AGEs) are key players in the development of diabetic nephropathy. Recent evidence suggests that an increase in reactive oxygen species (ROS) formation induced by high glucose-mediated activation of the mitochondrial electron-transport chain is an early event in the development of diabetic complications. A variety of growth factors and cytokines are then induced through complex signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-kappaB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines. Particularly, TGF-beta is important in the development of renal hypertrophy and accumulation of extracellular matrix components. Activation of the renin-angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes many of the pathophysiological changes associated with diabetic nephropathy. In fact, it has been shown that angiotensin II is involved in almost every pathophysiological process implicated in the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, interstitial inflammation). Consequently, blocking these deleterious effects of ANG II is an essential part of every therapeutic regiment to prevent and treat diabetic nephropathy. Recent evidence suggests that regression of diabetic nephropathy could be achieved under certain circumstances.

Angiotensin II↗

PubMed1993

Roles of eosinophils and catecholamines in pathophysiology of exercise-induced asthma.

To study the roles of eosinophils and catecholamines in the pathophysiology of exercise-induced asthma (EIA), an exercise challenge test was performed in 22 asthmatic children, using a bicycle ergometer, and the changes in lung function, plasma norepinephrine (NE), epinephrine (E) and eosinophil cationic protein (ECP) levels with exercise were evaluated. Subjects were classified into three groups from the results of lung function test, respectively: EIA-negative group. EIA-positive groups with good recovery and poor recovery. Eosinophil counts before exercise in the EIA-positive groups were significantly higher than those in the EIA-negative group. The ECP levels rose with exercise in all groups. Five minutes after exercise, ECP values fell to the pre-exercise level in the EIA-negative group, but rose to higher levels in EIA-positive groups. Plasma E levels rose with exercise and showed 4-fold increase in the EIA-negative group, whereas only 1.5-fold increase of plasma E levels was observed in the EIA-positive group with poor recovery. From these findings, a possible contribution of sympathoadrenal hypofunction and a probable involvement of eosinophils in the pathophysiology of EIA have been suggested.

Adolescent↗

PubMed2005

Pathophysiological levels of the obesity related peptides resistin and ghrelin increase adhesion molecule expression on human vascular endothelial cells.

1. In the present study, we sought to determine whether physiological or pathophysiological concentrations of obesity related peptides influence the key early atherogenic events of monocyte adhesion to endothelial cells and adhesion molecule expression using primary human cells. 2. Human umbilical vein endothelial cells were grown to confluence and human monocytes were obtained by elutriation. Adhesion was assessed by automated cell counting and cell adhesion molecule expression (E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)) was assayed by ELISA. 3. Experimental conditions included untreated control, ghrelin (100, 150, 450 and 1350 pmol/L), resistin (15, 40 and 100 ng/mL) and combined leptin and insulin (combinations of 30 and 120 pmol/L insulin and 5, 50 and 500 ng/mL leptin). 4. Both resistin and ghrelin produced modest but significant increases in VCAM-1 expression (110 +/- 4 and 117 +/- 13% compared with controls, respectively; both P <or= 0.01). Ghrelin also increased ICAM-1 expression (119 +/- 17% of control; P <or= 0.01). 5. However, despite these increases in adhesion molecule expression, neither ghrelin nor resistin altered monocyte adhesion values. 6. Neither leptin nor insulin altered monocyte adhesion to endothelial cells or cell adhesion molecule expression. 7. Pathophysiologically relevant concentrations of ghrelin and resistin, within the range of concentrations exhibited by patients with anorexia nervosa or the Prader-Willi syndrome and type 2 diabetes, respectively, increase endothelial cell adhesion molecule expression, possibly contributing to increased atherosclerosis risk in such subjects.

Cell Adhesion↗

PubMed1995

Obstructed defecation: current status of pathophysiology and management.

Obstructed defecation poses a challenging clinical problem and in many patients presenting with this syndrome the underlying pathophysiology cannot be determined. Up to now, attempts to diagnose and treat obstructed defecation (anismus) have focused on the function of the somatic pelvic floor musculature surrounding the anorectum, and concepts such as 'puborectalis paradox' and 'spastic pelvic floor' have gained widespread acceptance despite there being no objective data to support such concepts. New evidence showing that defecation is an integrated process of colonic and rectal emptying suggests that anismus may be much more complex than a simple disorder of the pelvic floor muscles. In a small number of patients obstructed defecation is caused by a more simple mechanism, such as internal sphincter hypertonia or a large rectocele, which is easily corrected surgically. Careful selection of patients for treatment, based on identifying the underlying pathophysiological disorder, is emphasized.

Anal Canal↗

PubMed2006

A polymorphism in lipoprotein lipase affects the severity of Alzheimer's disease pathophysiology.

Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases.

Aged↗

PubMed2006

The pathophysiology of lower urinary tract symptoms after brachytherapy for prostate cancer.

OBJECTIVES: To determine the spectrum of pathophysiology underlying the lower urinary tract symptoms (LUTS) persisting for > or = 6 months after brachytherapy for localized prostate cancer. PATIENTS AND METHODS: A database of men from two practice settings was searched for men who developed LUTS persisting for > or = 6 months after completing brachytherapy for localized prostate cancer. Patients were evaluated with a structured history and physical examination, International Prostate Symptom Score (IPSS), 24-h voiding diary, noninvasive free-flow uroflowmetry, postvoid residual urine volume (PVR), cystoscopy and a video-urodynamic study. Specific data collected included symptoms, elapsed time since brachytherapy, Gleason score, IPSS, total number of voids/24 h, maximum voided volume, cystoscopic findings, and urodynamics findings (PVR, maximum urinary flow rate, Schaefer obstruction grade, Watts factor, incidence of detrusor overactivity (DO) urethral obstruction and low bladder compliance). These data were compared with those from a previous study of men with LUTS who did not have prostate cancer. RESULTS: The study included 47 men (aged 54-88 years); the median (range) interval between brachytherapy and evaluation was 1.5 (0.5-13) years. Thirty-seven men complained of overactive bladder symptoms (79%), and 31 of incontinence (71%), 21 of obstructive symptoms (44%), and persistent dysuria in 12 (26%). Comparison of urodynamic findings in men with unselected causes of LUTS vs LUTS due to brachytherapy revealed the following comparisons: DO in 252 of 541 (47%) unselected vs 28 of 33 (85%) brachytherapy, (P < 0.001); and urethral obstruction in 374 of 541 (69%) unselected vs 24 of 33 (73%) brachytherapy (P = 0.85). CONCLUSION: The pathophysiology and severity of persistent LUTS in men after brachytherapy differs from that of men with LUTS in the general population. Men after brachytherapy have a much higher incidence of DO, prostatic and urethral strictures and prostatic urethral stones.

Aged↗

PubMed2004

Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity.

We previously found that pathophysiological concentrations (< or = 10 nm) of an amyloid beta protein (Abeta25-35) reduced the plasma membrane phosphatidylinositol monophosphate level in cultured rat hippocampal neurons with a decrease in phosphatidylinositol 4-monophosphate-dependent Cl- -ATPase activity. As this suggested an inhibitory effect of Abeta25-35 on plasma membrane phosphatidylinositol 4-kinase (PI4K) activity, in vitro effects of Abetas on PI4K activity was examined using rat brain subcellular fractions and recombinant human type II PI4K (PI4KII). Abeta25-35 (10 nm) inhibited PI4KII activity, but neither PI 3-kinase (PI3K) nor type III PI4K (PI4KIII) activity, in microsomal fractions, while 100 nm Abeta25-35 inhibited PI3K activity in mitochondrial fractions. In plasma membrane-rich fractions, Abetas (> 0.5 nm) dose-dependently inhibited PI4KII activity, the maximal inhibition to 77-87% of control being reached around 10 nm of Abetas without significant changes in apparent Km values for ATP and PI, suggesting non-competitive inhibition by Abetas. The inhibition by 10 nm Abeta25-35 was reversible. In recombinant human PI4KIIalpha, inhibition profiles of Abetas were similar to those in rat brain plasma membranes. Therefore, pathophysiological concentrations of Abetas directly and reversibly inhibited plasma membrane PI4KII activity, suggesting that plasma membrane PI4KII is a target of Abetas in the pathogenesis of Alzheimer's disease.

1-Phosphatidylinositol 4-Kinase↗

PubMed1997

Modulation of the calcium sensitivity of the smooth muscle contractile apparatus: molecular mechanisms, pharmacological and pathophysiological implications.

Smooth muscle contraction is the basis of the physiological reactivity of several systems (vascular, respiratory, gastrointestinal, urogenital ...). Hyperresponsiveness of smooth muscle may also contribute to a variety of problems such as arterial hypertension, asthma and spontaneous abortion. An increase in cytoplasmic calcium concentration ([Ca2+]i) is the key event in excitation-contraction coupling in smooth muscle and the relationship linking the [Ca2+]i value to the force of contraction represents the calcium sensitivity of the contractile apparatus (CaSCA). Recently, it has become evident that CaSCA can be modified upon the action of agonists or drugs as well as in some pathophysiological situations. Such modifications induce, at a fixed [Ca2+]i value, either an increase (referred to as sensitization) or a decrease (desensitization) of the contraction force. The molecular mechanisms underlying this modulation are not yet fully elucidated. Nevertheless, recent studies have identified sites of regulation of the actomyosin interaction in smooth muscle. Sensitization primarily results from the inhibition of myosin light chain phosphatase (MLCP) by intracellular messengers such as arachidonic acid or protein kinase C. In addition, phosphorylation of thin filament-associated proteins, caldesmon and calponin, increases CaSCA. Activation of small (monomeric) G-proteins such as rho or ras is also involved. Desensitization occurs as a consequence of phosphorylation of myosin light chain kinase (MLCK) by the calcium-calmodulin activated protein kinase II, or stimulation of MLCP by cyclic GMP-activated protein kinase. In the present review, examples of physiological modulation of CaCSA as well as pharmacological and pathophysiological implications are illustrated for some smooth muscles.

Anesthetics↗