Increase In Smooth Muscle Mass Research Articles

Biased TAS2R Bronchodilators Inhibit Airway Smooth Muscle Growth by Downregulating Phosphorylated Extracellular Signal-regulated Kinase 1/2.

Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides their coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) extracellular signal-related kinase 1/2 (ERK1/2), but the cellular effects are not known. In the present study, we show in HASM cells that TAS2R agonists initially stimulate phosphorylated ERK1/2 (pERK1/2) but by 24 hours cause a marked (50-70%) downregulation of pERK1/2 without a change in total ERK1/2. It was hypothesized that TAS2R agonists suppress cell growth through this pERK1/2 downregulation. Agonist-dependent inhibition of cell proliferation was indeed found in HASM cells derived from normal and asthmatic human lungs, as well as in an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase). Various structurally diverse TAS2R agonists evoked a range of inhibition of HASM proliferation, the magnitude of which directly correlated with the downregulation of pERK1/2 (R2 = 0.86). Some TAS2R agonists were as effective as pharmacological inhibitors of Raf1 and MEK1/2 in suppressing growth. siRNA silencing of TAS2Rs (subtypes 10, 14, and 31) ablated the pERK1/2 and growth-inhibitory effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G protein Gαi and by knocking down β-arrestin 1/2, indicating a dual pathway, although there may be additional mechanisms involved in this HASM TAS2R multidimensional signaling. Thus, TAS2R agonist structure can be manipulated to maintain the relaxation response and can be biased toward suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, in which an increase in smooth muscle mass contributes to airway obstruction.

Oral exposure to cadmium and mercury alone and in combination causes damage to the lung tissue of Sprague-Dawley rats

Environmental presence and human exposure to heavy metals in air and cigarette smoke has led to a worldwide increase in respiratory disease. The effects of oral exposure to heavy metals in liver and kidney structure and function have been widely investigated and the respiratory system as a target is often overlooked. The aim of the study was to investigate the possible structural changes in the lung tissue of Sprague-Dawley rats after oral exposure for 28 days to cadmium (Cd) and mercury (Hg), alone and in combination at 1000 times the World Health Organization’s limit for each metal in drinking water. Following exposure, the general morphology of the bronchiole and lungs as well as collagen and elastin distribution was evaluated using histological techniques and transmission electron microscopy. In the lungs, structural changes to the alveoli included collapsed alveolar spaces, presence of inflammatory cells and thickening of the alveolar walls. In addition, exposure to Cd and Hg caused degeneration of the alveolar structures resulting in confluent alveoli. Changes in bronchiole morphology included an increase in smooth muscle mass with luminal epithelium degeneration, detachment and aggregation. Prominent bronchiole-associated lymphoid tissue was present in the group exposed to Cd and Hg. Ultrastructural examination confirmed the presence of fibrosis where in the Cd exposed group, collagen fibrils arrangement was dense, while in the Hg exposed group, additional prominent elastin was present. This study identified the lungs as target of heavy metals toxicity following oral exposure resulting in cellular damage, inflammation and fibrosis and increased risk of respiratory disease where Hg showed the greatest fibrotic effect, which was further, aggravated in combination with Cd.

Bronchial smooth muscle increase proliferation is associated to p53 dysfunction in asthma

Introduction Asthma is a frequent respiratory disease characterized by bronchial hyperresponsiveness, inflammation and remodeling. Bronchial remodeling corresponds to structural modification of the bronchial wall. Increase of smooth muscle mass is a crucial feature of such a remodeling in asthma. Indeed, it correlates with the decrease in lung function and bronchial thermoplasty, which is supposed to decrease BSM mass, was associated with a decrease in exacerbation rate. The mechanisms of such an increased BSM mass are complex and remain controversial. However, increased proliferation of asthmatic BSM cells has been proposed and largely documented both in vitro and in vivo. We previously demonstrated that such an increased BSM cell proliferation involved an increased mitochondrial biogenesis and mitochondrial mass through the increase of PGC-1α and Tfam expression. Major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated so far. We thus hypothesized that, p53 can modulate BSM cell mitochondrial biogenesis and proliferation and that this modulation is disrupted in asthmatic cells. Methods Using shRNA lentivirus targeting p53, we assessed the role of p53 in both asthmatic and control BSM cells proliferation using both BrdU and cell counting. We analyzed the effect of the down-regulation of p53 protein on the regulation of p21, Bax, TFAM and PGC-1α mRNA. Finally, we assessed the expression of p53 in vitro using flow cytometry and western blot but also ex vivo using laser microdissection and RT-PCR. Results We found that, p53 is unable to inhibit the transcription of Tfam and PGC1α in asthmatic BSM. As a consequence, p53 cannot slow down the increased mitochondrial biogenesis and the subsequent increased proliferation of asthmatic BSM cells. We also found that p53 expression was increased in asthmatic BSM, which was related with a loss of Mdm2 activation by p53. Conclusions In conclusion, this work highlights p53 as a new potential therapeutic target against BSM remodeling in asthma.

Evidence for airway remodeling in chronic asthma

This review focuses on recent findings in relation to potential functional consequences of structural changes in the asthmatic airway. Increases in smooth muscle mass have been shown to be an early finding in childhood asthma, related to clinical severity and predictive of greater airflow obstruction. Both hyperplasia and hypertrophy contribute to the increase in smooth muscle mass. A phenotypic shift in the epithelium of asthmatic airways related to stress and injury is suggested by recent data, with likely direct transformation of epithelial cells into mesenchymal cells. Fibrocyte in-migration from the vasculature may be an additional source of increased smooth muscle mass. The increased smooth muscle may contribute to neovascularization via vascular endothelial growth factor. Computed tomography studies continue to show some correlations between wall thickness and airway physiology. Exacerbations are predictive of greater lung function decline and hence remodeling. On balance, recent evidence continues to show that structural changes contribute to asthma persistence, airflow obstruction, lung function decline, and clinical severity, though there is increased recognition of the heterogeneity of asthma and in some phenotypes inflammatory cell influx or vascular effects may be more important than structural effects.

Anatomy, pathology, and physiology of the tracheobronchial tree: Emphasis on the distal airways

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma.

Airway remodelling: the future: Table 1—

The research of structural changes in airway diseases is relatively recent compared with studies on physiological or inflammatory features. In airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), structural alterations have been observed, such as: epithelial desquamation or hyperplasia; increases in smooth muscle mass; angiogenesis; increases in subepithelial collagen deposition, proteoglycans and elastin content; cartilage changes; and goblet cell and glandular hyperplasia, in addition to increased airway wall thickening 1. During the past months, the European Respiratory Journal has published a series on airway remodelling in order to review the state of knowledge in this increasingly important domain 2–6. We learnt from this series that airway remodelling is by no means a single entity. It is a complex and dynamic process with multiple components, evolving differently in various conditions, according to the type and extent of the structural responses to inflammatory or physical stimuli, probably under genetic influences modulating host response to the latter. The various in vitro and animal models developed to study the pathways involved in the changes in the bronchial structure induced by airways allergic reactions or other stimuli confirm this vast heterogeneity. The possible clinical significance of these structural changes and the effects of treatment are even more diverse. Hence, at this stage we will need to further elaborate on the main challenges for research in this field in order to help better understand the mechanisms of airway remodelling and to decide if, how and when to intervene on this process. Some of the key questions on airway remodelling are itemised in table 1⇓. Here are some of what we consider to be the vital remaining domains of research in this field. View this table: Table 1— Remaining questions on airway remodelling ### What is the time-course of the various remodelling changes? Animal models and studies of groups such as asymptomatic subjects with …

TGF-β: Its Role in Asthma and Therapeutic Potential

Asthma is a chronic disease of the airways affecting around 10% of the population. The majority of cases are well controlled with current therapies, however in approximately 20% of severe asthmatics the available therapeutic strategies are inadequate. Structural changes in the asthmatic airway, including an increase in smooth muscle mass and an increased deposition of extracellular matrix proteins, which correlate with airway hyperresponsivenes, reduced lung function and an increase in fibroblast/myofibroblast numbers, are not specifically targetted by current therapeutic agents and therefore represent an area of unmet need. The mechanisms involved in the development of airway remodelling are incompletely understood but are thought to involve one or more isoforms of transforming growth factor-beta (TGF-beta). The TGF-betas are pleiotropic mediators which have important roles in the regulation of inflammation, cell growth, differentiation and wound healing. All three mammalian isoforms of TGF-beta are present in the airways and at least TGF-beta1 and TGF-beta2 have been shown to be increased in asthmatic airways and cells, together with evidence of increased TGF-beta signalling. In addition, evidence from animal models suggests that airway remodelling may be prevented or reversed using agents which target TGF-beta. Therefore modulation of TGF-betas or their activity represent a potential therapeutic target for asthma. This review focuses on the current knowledge of TGF-beta1-3, their their role in normal and asthmatic airways, as well as the potential for modulating the TGF-betas and their effects as a therapeutic approach to asthma.

Mast cell myositis: a new feature of allergic asthma?

There is some evidence that, in asthma, mast cells infiltrate the airway smooth muscle layer and, as a consequence, alter the functional and structural properties of myocytes. This inflammation so-called mast-cell myositis, probably contributes to both bronchial hyperresponsiveness and airway remodelling. Previous observations have pointed out the presence of mast cells within airway smooth muscle of atopic patients and recent data obtained in asthmatic patients demonstrate that this infiltration is more important in asthmatic patients with atopy. Although the mechanism of such a mast cell attraction remains to be fully understood, experimental data demonstrate that, upon stimulation by tryptase or cytokines, smooth muscle cells can attract mast cells through the production of TGF-beta1 or SCF. Once at the site of inflammation, activated mast cells are responsible for an important extracellular deposition of inflammatory products that may facilitate the increase in smooth muscle mass. In addition, comparison of asthmatic patients with and without atopy suggests that mast cell myositis is closely related with atopy.

Role of airway smooth muscle in airway remodeling

Editor’s note: This feature, Images in allergy and immunology, is designed to highlight current concepts of the immunopathology of allergic diseases and other common immunologically mediated diseases. The presentation will appear as sets of images that involve cross-pathology, histopathology, and molecular pathology and will cover a range of topics of interest to allergists and immunologists. Increase in smooth muscle mass is a key structural change that occurs in the large and small airways of asthmatic subjects (Figs 1 and 2). The mechanisms underlying the increase in airway smooth muscle mass are still unknown. Some reports described hyperplasia of airway smooth muscle cells (ASMCs) in asthmatic airways, 1 whereas other studies found an increase in ASMC size. 2 More recently, migration of ASMCs toward the epithelium (Fig 3) and from surrounding bundleshasbeenraisedasapotentialcontributortothe increased smooth muscle mass (Fig 4). 3 Whether this phenomenon occurs in vivo remains unknown.

Structural changes in the airways in asthma: observations and consequences

Structural changes reported in the airways of asthmatics include epithelial fragility, goblet cell hyperplasia, enlarged submucosal mucus glands, angiogenesis, increased matrix deposition in the airway wall, increased airway smooth muscle mass, wall thickening and abnormalities in elastin. Genetic influences, as well as fetal and early life exposures, may contribute to structural changes such as subepithelial fibrosis from an early age. Other structural alterations are related to duration of disease and/or long-term uncontrolled inflammation. The increase in smooth muscle mass in both large and small airways probably occurs via multiple mechanisms, and there are probably changes in the phenotype of smooth muscle cells, some showing enhanced synthetic capacity, others enhanced proliferation or contractility. Fixed airflow limitation is probably due to remodelling, whereas the importance of structural changes to the phenomenon of airways hyperresponsiveness may be dependent on the specific clinical phenotype of asthma evaluated. Reduced compliance of the airway wall secondary to enhanced matrix deposition may protect against airway narrowing. Conversely, in severe asthma, disruption of alveolar attachments and adventitial thickening may augment airway narrowing. The encroachment upon luminal area by submucosal thickening may be disadvantageous by increasing the risk of airway closure in the presence of the intraluminal cellular and mucus exudate associated with asthma exacerbations. Structural changes may increase airway narrowing by alteration of smooth muscle dynamics through limitation of the ability of the smooth muscle to periodically lengthen.

Allergen exposure of mouse airways evokes remodeling of both bronchi and large pulmonary vessels.

Remodeling of airway structures is a well-documented feature of allergic airway inflammation. To investigate whether bronchial remodeling is associated with remodeling of adjacent pulmonary vessels, sensitized mice were subjected to repeated ovalbumin inhalations, and bronchi and pulmonary vessels were subjected to histologic analysis. Allergen challenges induced peribronchial as well as perivascular eosinophilia. Remodeling of systemic airway microcirculation, as studied in tracheal whole-mount preparations, revealed an allergen-induced increase in both the diameter and length of the airway microvessels. Immunostaining for alpha-smooth muscle actin disclosed an increase in smooth muscle mass in both bronchi and large pulmonary vessels. Both bronchi and pulmonary vessels also displayed increased expression of procollagen I and procollagen III. Staining for proliferating cell nuclear antigen revealed increased proliferation of bronchial epithelial and smooth muscle cells as well as pulmonary vascular endothelial and smooth muscle cells. We conclude that central features of remodeling that take place in allergen-exposed airways are present also in the pulmonary vessels. The significance of this finding with respect to occurrence in disease, pathophysiologic importance, and involved mechanisms warrants further investigation.

Airway basement membrane perimeter in human airways is not a constant; potential implications for airway remodeling in asthma.

Many studies that demonstrate an increase in airway smooth muscle in asthmatic patients rely on the assumption that bronchial internal perimeter (P(i)) or basement membrane perimeter (P(bm)) is a constant, i.e., not affected by fixation pressure or the degree of smooth muscle shortening. Because it is the basement membrane that has been purported to be the indistensible structure, this study examines the assumption that P(bm) is not affected by fixation pressure. P(bm) was determined for the same human airway segment (n = 12) fixed at distending pressures of 0 cmH(2)O and 21 cmH(2)O in the absence of smooth muscle tone. P(bm) for the segment fixed at 0 cmH(2)O was determined morphometrically, and the P(bm) for the same segment, had the segment been fixed at 21 cmH(2)O, was predicted from knowing the luminal volume and length of the airway when distended to 21 cmH(2)O (organ bath-derived P(i)). To ensure an accurate transformation of the organ bath-derived P(i) value to a morphometry-derived P(bm) value, had the segment been fixed at 21 cmH(2)O, the relationship between organ bath-derived P(i) and morphometry-derived P(bm) was determined for five different bronchial segments distended to 21 cmH(2)O and fixed at 21 cmH(2)O (r(2) = 0.99, P < 0.0001). Mean P(bm) for bronchial segments fixed at 0 cmH(2)O was 9.4 +/- 0.4 mm, whereas mean predicted P(bm), had the segments been fixed at 21 cmH(2)O, was 14.1 +/- 0.5 mm (P < 0.0001). This indicates that P(bm) is not a constant when isolated airway segments without smooth muscle tone are fixed distended to 21 cmH(2)O. The implication of these results is that the increase in smooth muscle mass in asthma may have been overestimated in some previous studies. Therefore, further studies are required to examine the potential artifact using whole lungs with and without abolition of airway smooth muscle tone and/or inflation.

ERK activation and mitogenesis in human airway smooth muscle cells.

Asthmatic airways are characterized by an increase in smooth muscle mass, due mainly to hyperplasia. Many studies suggest that extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2, respectively), one group of the mitogen-activated protein (MAP) kinase superfamily, play a key role in the signal transduction pathway leading to cell proliferation. PGE(2) and forskolin inhibited mitogen-induced ERK activation. Inhibition of MAP kinase kinases 1 and 2 (MEK1 and MEK2, respectively), which are upstream from ERK, with the specific MEK inhibitor U-0126 blocked both cell proliferation and ERK activation. In addition, U-0126 inhibited mitogen-induced activation of p90 ribosomal S6 kinase and expression of c-Fos and cyclin D1, all of which are downstream from ERK in the signaling cascade that leads to cell proliferation. Antisense oligodeoxynucleotides directed to ERK1 and -2 mRNAs reduced ERK protein and cell proliferation. These results indicate that ERK is required for human airway smooth muscle cell proliferation. Thus targeting the control of ERK activation may provide a new therapeutic approach for hyperplasia seen in asthma.

Tissue remodeling as a feature of persistent asthma

A chronic inflammatory process is almost invariably associated with tissue damage and healing. Healing results in repair and replacement of dead or damaged cells by viable cells. Repair usually involves 2 distinct processes: regeneration, which is the replacement of injured tissue by parenchymal cells of the same type, and replacement by connective tissue and its eventual maturation into scar tissue. In many instances both processes contribute to the healing response. Chronic inflammatory disease can therefore lead to a wide variety of consequences, from complete or partial restitution of organ structure and function to fibrosis. Asthma is characterized by a chronic inflammatory process of the airways. The ensuing healing process results in structural alterations referred to as a remodeling of the airways. The mechanisms underlying these structural alterations are still largely unknown. They are likely to be heterogeneous, leading—through the highly dynamic process of cell de-differentiation, migration, differentiation, and maturation—to changes in connective tissue deposition and to the altered restitution of airways structure, resulting in mucus gland hyperplasia, neovascularization, fibrosis, and an increase in smooth muscle mass. (J Allergy Clin Immunol 2000;105:1041-53.)

Balance in asthma between matrix metalloproteinases and their inhibitors

Balance in asthma between matrix metalloproteinases and their inhibitors

Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats.

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min. Lung resistance (RL), responsiveness to inhaled methacholine (MCh), the airway epithelium and bronchoalveolar lavage (BAL) were assessed over a 3 month period after exposure. RL increased significantly up to 3 days after exposure, reaching a maximal change of 110+/-16% from baseline. There was a significant decrease in the concentration of MCh required to increase RL by 0.20 cmH2O x mL(-1) x s from days 1-7 after exposure. In some rats, MCh hyperresponsiveness and RL changes persisted after exposure for as long as 1 and 3 months, respectively. Histological evaluation with morphometric evaluation revealed epithelial flattening, necrosis, increase in smooth muscle mass and evidence of epithelial regeneration. BAL showed an increased number of neutrophils. The timing of maximal abnormality in the appearance of the epithelium (days 1-3) corresponded to that of the maximal functional changes. Acute high chlorine exposure results in functional and pathological abnormalities that resolve in the majority of animals after a variable period; however, these changes can persist in some animals. Functional abnormalities in the initial stages may be related to airway epithelial damage.

The Effect of Obstruction on the Developing Bladder

Congenital bladder obstruction causes significant immediate and long-term consequences yet its pathophysiology remains poorly understood. A model of early fetal bladder obstruction in sheep has been developed to study the response of the developing bladder to high grade obstruction, with particular emphasis on the regulation of growth and development. Congenital bladder obstruction was produced in fetal sheep at 60 days of gestation and studied at 95 days of gestation (14 sheep) or term (12 sheep). A total of 24 age-matched normal sheep served as controls. Bladders were analyzed by total weight, stereological estimation of smooth muscle cell size, number and total mass, deoxyribonucleic acid concentration, muscarinic cholinergic receptor density, myosin isoform analysis and/or passive cystometries.Congenital bladder obstruction caused a 4.6 times increase in bladder weight at term reflecting a 5.8 times increase in smooth muscle mass. This increase was predominantly that of cellular hypertrophy and less so of hyperplasia, based upon increased cell volume, increased protein-to-deoxyribonucleic acid ratio, and no significant increase in total cell number. Muscarinic cholinergic receptor number per smooth muscle cell increased 3.2 times but it did not change relative to myosin content. The ratio of myosin heavy chain isoforms SM1:SM2 is developmentally regulated and was seen to change from 1.6 at 100 days of gestation to 1.13 at term in normals. After 5 weeks of obstruction SM1:SM2 was 1.27 and it was 1.25 at term, indicating an effect on the developmental regulation of smooth muscle. Rapid fill cystometry in vivo measured the rate of stress relaxation to assess accommodative properties. The half-decay time was increased in all 3 obstructed bladders tested to greater than 15 seconds at 50% capacity (normal less than 5 seconds), suggesting reduced compliance. This study shows that an in utero model of bladder obstruction is feasible. Congenital bladder obstruction produces a variety of structural, biochemical and functional changes in the developing bladder indicative of alterations in the regulation of growth and differentiation.

Structural and functional characteristics of muscle from diabetic rodent small intestine

After 30 days of streptozotocin-induced diabetes, the small intestine from untreated diabetic, insulin-treated diabetic, and nondiabetic rodents was excised in toto and measured. Despite a net loss in body weight, the diabetic animals showed a near twofold increase in small intestinal weight. This was characterized by a 148% increase in mucosal mass as well as a 39% increase in intestinal smooth muscle mass (P less than 0.05, respectively). The diabetic intestine was significantly longer and had a greater diameter and surface area. Diabetes significantly increased mucosal mass per unit surface area but produced an insignificant decrease in smooth muscle mass per unit surface area. Insulin treatment of the diabetic animals prevented the increase in total mucosal mass and mucosal mass per unit surface area. Insulin treatment also prevented the increase in smooth muscle mass, but reduced smooth muscle mass per unit surface area to a level significantly less than that found in nondiabetic intestine. In vitro dose-response studies of circular and longitudinal small intestinal muscle from the diabetic animals showed normal tension development and sensitivity to both bethanechol chloride and physostigmine. These observations show that the diabetic state produces alterations in not only mucosal but also smooth muscle mass in the small intestine. However, despite these morphological changes, diabetic intestinal smooth muscle retains its sensitivity to cholinergic stimulation and its capacity for tension generation.

Changes in vascular endothelium and its function in systemic arterial hypertension

The various functions of arterial endothelium may be altered during pulmonary and arterial hypertension. Changes in the endothelium (or function) associated with hypertension are described. In both acute and chronic hypertension, permeability of the endothelium is enhanced. During the acute phase of hypertension, hyperplasia (cell replication) of the endothelium occurs while cell hypertrophy (enlarged cell size) and an increase in homocellular tight junctions are associated with sustained elevations of blood pressure. Endothelium may contribute to the increase in smooth muscle mass or cell number reported with various models of hypertension. Increased endothelial uptake or metabolism of norepinephrine and serotonin occurs during hypertension. The biotransformation of adenine nucleotides and various peptides by the endothelium is not altered by hypertension. Synthesis of prostacyclin is enhanced in the spontaneously hypertensive and Goldblatt hypertensive rat. Metabolism of prostaglandin E 2, prostaglandin F 2α and prostacyclin by prostaglandin 15-hydroxydehydrogenase is impaired in the genetic models. Responses to endothelium-dependent vasodilators are impaired in acute and chronic models of hypertension. Production of relaxing factor by the endothelium is not inhibited, but rather the vascular smooth muscle fails to respond. Acute, severe hypertension potentiates the response to serotonin, presumably by attenuating the release or response to relaxing factor(s). In the aorta of the spontaneously hypertensive rat, the endothelium releases a constricting factor in response to acetylcholine. Pulmonary arterial endothelium (and other vessels) releases a vasoconstrictor that is blocked by inhibitors of cyclooxygenase. It is not clear whether this pressor factor is thromboxane A 2. Cultured endothelial cells release a polypeptide that contracts arteries; however, any relation to hypertension is not known.

Longitudinal study of the hindquarter vasculature during development in spontaneously hypertensive and Dahl salt-sensitive rats.

The purpose of this study was to examine vascular structural alterations longitudinally in spontaneous and Dahl genetic hypertension. Hypertensive and control animals were studied at 5,9-11, and 17-19 weeks of age to permit analysis of prehypertensive, early and established hypertensive stages. Minimal and maximal resistance of the hindquarter vasculature was used as a functional assessment of structural alterations. At 5 weeks of age, the minimal vascular resistance of the spontaneously hypertensive rats (SHR) was elevated over Wistar-Kyoto (WKY) (p less than 0.02) but there was no difference between Dahl salt-sensitive (S) and resistant (R) rats. In both sets of animals, the minimal vascular resistance of the hypertensive group was significantly elevated over controls with age: p less than 0.001 in SHR; p less than 0.001 in Dahl S. The maximal vasoconstrictor response was significantly greater with age in SHR than in WKY, (p less than 0.001), but was not different in Dahl S compared to R. Thus, structural alterations, determined by assessing minimal vascular resistance, are present in both spontaneous and Dahl salt-sensitive hypertension, but the origin of the two differ. An increase in smooth muscle mass, assessed by maximal constriction, contributes importantly to the structural alterations in spontaneous hypertension; in Dahl S, other factors appear to contribute to structural alterations. Further, structural alterations precede frank hypertension in SHR but not in Dahl S hypertension.