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Smooth muscle exhibits biophysical characteristics and physiological behaviors that are not readily explained by present paradigms of cytoskeletal and cross-bridge mechanics. There is increasing evidence that contractile activation of the smooth muscle cell involves an array of cytoskeletal processes that extend beyond cross-bridge cycling and the sliding of thick and thin filaments. We review here the evidence suggesting that the biophysical and mechanical properties of the smooth muscle cell reflect the integrated interactions of an array of highly dynamic cytoskeletal processes that both react to and transform the dynamics of cross-bridge interactions over the course of the contraction cycle. The activation of the smooth muscle cell is proposed to trigger dynamic remodeling of the actin filament lattice within cellular microdomains in response to local mechanical and pharmacological events, enabling the cell to adapt to its external environment. As the contraction progresses, the cytoskeletal lattice stabilizes, solidifies, and forms a rigid structure well suited for transmission of tension generated by the interaction of myosin and actin. The integrated molecular transitions that occur within the contractile cycle are interpreted in the context of microscale agitation mechanisms and resulting remodeling events within the intracellular microenvironment. Such an interpretation suggests that the cytoskeleton may behave as a glassy substance whose mechanical function is governed by an effective temperature.
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1. Repeated allergen challenge has been shown to increase the role of Rho-kinase in airway smooth muscle (ASM) contraction. We considered the possibility that active allergic sensitization by itself, that is, without subsequent allergen exposure, could be sufficient to enhance Rho-kinase-mediated ASM contraction. 2. Guinea pigs were actively IgE-sensitized to ovalbumin (OA), using Al(OH)(3) as adjuvant. Contractile responsiveness to G(q)-coupled receptor agonists (methacholine, histamine or PGF(2alpha)) was investigated in tracheal rings. No effect of sensitization was observed on basal- and methacholine-induced myogenic tone. In contrast, potency of histamine and PGF(2alpha) increased, that is, EC(50) decreased, after OA-sensitization by 2.6- and 4.7-fold, respectively, without effect on maximal contraction (E(max)). 3. Basal tone in preparations from both control and OA-sensitized animals was strongly decreased in the presence of the Rho-kinase inhibitor (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide (Y-27632) (1 microm). In control preparations, the E(max) and potency of histamine were unaffected by Y-27632, but were decreased for PGF(2alpha) (by 38.2% and 2.0-fold, respectively). However, in preparations from OA-sensitized animals, Y-27632 induced a significant reduction in E(max) (33.5%) and potency (2.3-fold) of histamine and of PGF(2alpha) (48.3% and 6.6-fold, respectively), normalizing the OA-sensitization-induced increase in sensitivity toward these agonists. 4. We also investigated the contribution of Rho-kinase in vivo by measuring airway responsiveness toward inhaled histamine in permanently instrumented, unanaesthetized control and OA-sensitized guinea pigs. Treatment with Y-27632 by inhalation (5 mm, nebulizer concentration) decreased airway responsiveness toward histamine both in control and OA-sensitized animals. However, the histamine PC(100) ratio pre/post Y-27632 inhalation was significantly smaller in OA-sensitized animals as compared to control animals, indicating an enhanced contribution of Rho-kinase. 5. Expression of RhoA, an upstream activator of Rho-kinase, was significantly increased (2.6-fold) in lung homogenates of OA-sensitized guinea pigs compared to control animals, as determined by Western analysis. 6. In conclusion, the results show a receptor-dependent role of Rho-kinase in agonist-induced ASM contraction. The contribution of Rho-kinase to contractile airway responsiveness, both in vivo and ex vivo, is augmented after active allergic sensitization, as a consequence of increased expression of RhoA presumably. Inhibition of the RhoA/Rho-kinase pathway may be considered a useful pharmacotherapeutical target in allergy and asthma.
1. The initial heart rate (HR) response evoked by standing, 70 degrees head-up tilt, handgrip and contraction of abdominal and leg muscles was analysed in diabetic patients with autonomic neuropathy and in matched controls. 2. In healthy subjects standing induced an immediate, large, HR increase lasting 20s that far exceeded the small HR rise induced by tilt. The HR response with handgrip and to contraction of abdominal and leg muscles was strikingly similar for the first 5 s to the HR increase after standing. 3. In diabetic patients handgrip and standing induced a small HR increase starting after 2-3 s. Contraction of abdominal and leg muscles evoked little or no HR changes. The HR rise after tilt up was delayed by 10 s compared with healthy controls. 4. It is concluded that the circulatory response to active and passive changes of posture differs fundamentally. Standing and handgrip are superior to head-up tilt as a test for vagal HR control. An abrupt and large HR increase after standing excludes cardiac parasympathetic neuropathy. A modified response, however, may be due to afferent as well as to efferent lesions, e.g. in muscle afferents or in vagal afferents from cardiopulmonary receptors.
We examined the effect of urokinase (uPA) and its fragments on vascular smooth muscle cell contraction. Single-chain uPA inhibits phenylepherine (PE) -induced contraction of rat aortic rings, whereas two-chain uPA exerts the opposite effect. Two independent epitopes mediating these opposing activities were identified. A6, a capped peptide corresponding to amino acids 136-143 (KPSSPPEE) of uPA, increased the EC(50) of PE-induced vascular contraction sevenfold by inhibiting the release of calcium from intracellular stores. A6 activity was abolished by deleting the carboxyl-terminal Glu or by mutating the Ser corresponding to position 138 in uPA to Glu. A single-chain uPA variant lacking amino acids 136-143 did not induce vasorelaxation. A second epitope within the kringle of uPA potentiated PE-induced vasoconstriction. This epitope was exposed when single-chain uPA was converted to a two-chain molecule by plasmin. The isolated uPA kringle augmented vasoconstriction, whereas uPA variant lacking the kringle had no procontractile activity. These studies reveal previously undescribed vasoactive domains within urokinase and its naturally derived fragments.
The slowly hydrolyzed ATP analog adenosine 5'-(gamma-thiotriphosphate) (ATP gamma S) has been used in many studies of the muscle motor protein myosin in order to form a stable "weak binding" state analogous to the actin-S1-ATP complex However, the results from studies using ATP gamma S do not always agree with the results of experiments using ATP. The binding of myosin subfragment-1-ATP gamma S to actin has now been studied in some detail to determine its relationship to the actin-S1-ATP state. The binding of myosin subfragment-1-ATP gamma S to actin-troponin-tropomyosin is similar in affinity to the binding of myosin subfragment-1-ATP. Like myosin subfragment-1-ATP, the binding is not Ca(2+)-dependent, and most importantly, myosin subfragment-1-ATP gamma S does not stabilize the active configuration of actin-troponin-tropomyosin. Thus, myosin subfragment-1-ATP gamma S is an analog of myosin subfragment-1-ATP but must be used with caution for two reasons: (1) The binding of ATP gamma S to regulated actomyosin subfragment-1 is Ca(2+)-sensitive, and errors can be made in the interpretation of results if proteins are not fully saturated with nucleotide and a mixture of weak and strong binding states is present. (2) At the high concentrations of myosin subfragment-1 used in some experiments, significant amounts of ADP may form.(ABSTRACT TRUNCATED AT 250 WORDS)
An attempt is made to establish dependence between stimulation of smooth-muscle contraction and the concentration of prostanoids in biologically active sera of women on the basis of two various methods: physiological test with smooth-muscle strips in vitro and radioimmunological determination of prostanoids. Three prostanoids are examined PgF2 alpha PgI2, TxA2 are examined and it is found that lineal dependence between the prostanoid concentration and activation of contraction (for the whole range) is observed only for PgF2 alpha, which allows graphic interpolation for this prostaglandin.
The purpose of this study was to examine variations in the amplitude of the perioral reflex that may occur during the reaction time interval before voluntary muscle contraction for speech. Four normal adults produced the syllable /wi/ as quickly as possible in response to a low level electric shock while electromyographic recordings of the orbicularis oris inferior muscle (OOI) were made. During the reaction time interval a precise mechanical stretch was applied at the corner of the mouth to elicit the first component of the perioral reflex. Analysis of the resulting data revealed a significant increase in perioral reflex amplitude occurring between 30 and 50 msec before the onset of voluntary OOI contraction. It is concluded that the observed increases in reflex amplitude were the result of increased excitability of brainstem interneurons and/or motoneurons mediating the perioral reflex. The central mechanisms underlying such excitability increases and their significance for understanding speech motor control are discussed.
The vascular smooth muscle cell is a highly specialized cell whose primary function is contraction and relaxation. It expresses a variety of contractile proteins, ion channels, and signalling molecules that regulate contraction. Upon contraction, vascular smooth muscle cells shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. Contractile activity in vascular smooth muscle cells is initiated by a Ca(2+)-calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca(2+)-sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase, thereby maintaining force. Removal of Ca(2+) from the cytosol and stimulation of myoson phosphatase initiate the relaxation of vascular smooth muscle.
We investigated the mode of relaxant effects of cytochalasin D, a capping agent of actin filaments, on contractile responses in the rat aorta and chicken gizzard smooth muscles. Cytochalasin D inhibited the contraction induced by high K+ or noradrenaline (10 nM-1 microM) without changing cytosolic Ca2+ level ([Ca2+]i) in the rat aorta. In the absence of external Ca2+, 12-deoxyphorbol 13-isobutylate (DPB) (1 microM) induced sustained contraction without increasing in [Ca2+]i and cytochalasin D also inhibited this contraction. In the permeabilized chicken gizzard smooth muscle, cytochalasin D inhibited the Ca2+ (1-10 microM)-induced contraction. Cytochalasin D also inhibited the Ca(2+)-independent contraction in the muscle which had been thiophosphorylated by ATP gamma S. Cytochalasin D decreased the velocity of superprecipitation in the chicken gizzard native actomyosin (myosin B) affecting neither the level of MLC phosphorylation nor Mg(2+)-ATPase activity. These results suggest that cytochalasin D inhibits smooth muscle contractions without any effect on the Ca(2+)-dependent MLC phosphorylation or subsequent activation of myosin ATPase activity. Based on these evidences, it is concluded that cytochalasin D may inhibit smooth muscle contraction possibly through uncoupling of the force generation from the activated actomyosin Mg(2+)-ATPase.
AIM: To investigate influences of p-chlorobenzyltetrahydroberberine (CPU-86017) and levothyroxin (Lev) on vascular smooth muscle (VSM) contractions by intracellular Ca2+ release and calcium entry. METHODS: Three kinds of contractions of rat thoracic aortic rings were used to compare suppression by CPU-86017, bepridil (Bep), verapamil (Ver), and nimodipine (Nim) in euthyroid- and Lev-induced hyperthyroidism rats. RESULTS: The IC50 of CPU-86017 on KCl-induced contractions of euthyroid and hyperthyroid VSM were 80 (36-179) and 121 (62-236) mumol.L-1, respectively. The potency of CPU-86017 was approximate to 1/10 of Bep and 1/100 of Ver and Nim. Suppressions of Ver and Nim on hyperthyroid VSM in Ca(2+)-free solution were greatly attenuated by -86% and -95%, respectively. Slight or no change in activity of CPU-86017 and Bep was found. Contractions on adding Ca2+ into Ca(2+)-free medium were suppressed by CPU-86017 and its potencies in euthyroid and hyperthyroid rats were not different. CONCLUSION: CPU-86017 is more potent to suppress Ca2+ entry than intracellular calcium mobilization and Lev enhances both.
The flight muscles of many insects have a form of regulation enabling them to contract at high frequencies. The muscles are activated by periodic stretches at low Ca2+ levels. The same muscles also give isometric contractions in response to higher Ca2+. We show that the two activities are controlled by different isoforms of TnC (F1 and F2) within single myofibrils. F1 binds one Ca2+ with high affinity in the C-terminal domain and F2 binds one Ca2+ in the C-terminal domain and one exchangeable Ca2+ in the N-terminal domain. We have characterised the isoforms and determined their effect on the development of stretch-activated and Ca2+-activated tension by replacing endogenous TnC in Lethocerus flight muscle fibres with recombinant isoforms. Fibres with F1 gave stretch-activated tension and minimal isometric tension; those with F2 gave Ca2+-dependent isometric tension and minimal stretch-activated tension. Regulation by a TnC responding to stretch rather than Ca2+ is unprecedented and has resulted in the ability of insect flight muscle to perform oscillatory work at low Ca2+ concentrations, a property to which a large number of flying insects owe their evolutionary success.