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PubMed1988

Inositol trisphosphate, calcium and muscle contraction.

The identity of organelles storing intracellular calcium and the role of Ins(1,4,5)P3 in muscle have been explored with, respectively, electron probe X-ray microanalysis (EPMA) and laser photolysis of 'caged' compounds. The participation of G-protein(s) in the release of intracellular Ca2+ was determined in saponin-permeabilized smooth muscle. The sarcoplasmic reticulum (SR) is identified as the major source of activator Ca2+ in both smooth and striated muscle; similar (EPMA) studies suggest that the endoplasmic reticulum is the major Ca2+ storage site in non-muscle cells. In none of the cell types did mitochondria play a significant, physiological role in the regulation of cytoplasmic Ca2+. The latency of guinea pig portal vein smooth muscle contraction following photolytic release of phenylephrine, an alpha 1-agonist, is 1.5 +/- 0.26 s at 20 degrees C and 0.6 +/- 0.18 s at 30 degrees C; the latency of contraction after photolytic release of Ins(1,4,5)P3 from caged Ins(1,4,5)P3 is 0.5 +/- 0.12 s at 20 degrees C. The long latency of alpha 1-adrenergic Ca2+ release and its temperature dependence are consistent with a process mediated by G-protein-coupled activation of phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) hydrolysis. GTP gamma S, a non-hydrolysable analogue of GTP, causes Ca2+ release and contraction in permeabilized smooth muscle. Ins(1,4,5)P3 has an additive effect during the late, but not the early, phase of GTP gamma S action, and GTP gamma S can cause Ca2+ release and contraction of permeabilized smooth muscles refractory to Ins(1,4,5)P3. These results suggest that activation of G protein(s) can release Ca2+ by, at least, two G-protein-regulated mechanisms: one mediated by Ins(1,4,5)P3 and the other Ins(1,4,5)P3-independent. The low Ins(1,4,5)P3 5-phosphatase activity and the slow time-course (seconds) of the contractile response to Ins(1,4,5)P3 released with laser flash photolysis from caged Ins(1,4,5)P3 in frog skeletal muscle suggest that Ins(1,4,5)P3 is unlikely to be the physiological messenger of excitation-contraction coupling of striated muscle. In contrast, in smooth muscle the high Ins(1,4,5)P3-5-phosphatase activity and the rate of force development after photolytic release of Ins(1,4,5)P3 are compatible with a physiological role of Ins(1,4,5)P3 as a messenger of pharmacomechanical coupling.

Animals↗

PubMed1992

Effect of extracellular calcium concentration on angiotensin AT1 receptor-mediated smooth muscle contraction and antagonism in rabbit aorta.

Angiotensin-II (AII) stimulates smooth muscle contraction by activating angiotensin AT1 receptor which induces intracellular Ca2+ release and Ca2+ influx from extracellular space. In this study, effect of extracellular Ca2+ concentration ([Ca2+]0) on angiotensin AT1 receptor-mediated contractile response to AII has been examined in the absence and presence of [Sar1,Ala8]AII in rabbit aorta. A decrease in agonist potency and an increase in antagonist potency for depression were observed in low [Ca2+]0. Data were interpreted by applying an explanatory model developed previously. The result indicates that [Ca2+]0 is linked to the efficacy expression of AII at angiotensin AT1 receptor and this prompted speculation about the underlying mechanism.

Angiotensin II↗

PubMed2001

Back muscle contraction patterns of patients with low back pain before and after rehabilitation treatment: an electromyographic evaluation.

The aims of this study were to conduct a comparative investigation of muscle function between patients with low back pain (LBP) and healthy persons, and to determine whether intensive rehabilitation can change back muscle contraction synergy. Twenty healthy persons and 20 patients with chronic LBP were asked to perform symmetrical and asymmetric tasks. The patients with LBP were tested in the weeks immediately before and after 12 weeks of LBP rehabilitation. Tasks include "carrying" weights up and down and with a 45 degrees left rotation. Eight-channel surface electromyographic electrodes were placed on the surface of paraspinal muscles over the lumbar region. Correlations between the right and left corresponding muscles and between values before and after treatment were determined. Lifting capacity for patients with LBP were also measured before and after treatment. Results from electromyographic profiles showed that the muscle activity strategies varied between healthy persons and patients with LBP. The correlation coefficients for spinal muscles have shown very reproducible intrasubject muscle contraction synergies. Unbalanced electromyographic patterns found in patients with LBP given symmetrical tasks were not affected by rehabilitation treatment.

Adult↗

PubMed1978

Correlation between the effects of salbutamol on contractions and cyclic AMP content of isolated fast-and slow-contracting muscles of the guinea pig.

The effects of isoprenaline and salbutamol on incomplete tetanic contractions of the isolated soleus (slow contracting) and extensor digitorum longus (EDL-fast-contracting) muscles of the guinea pig were studied and an attempt made to correlate these effects on contractility with changes in cyclic AMP concentrations. Salbutamol was 10-12 times less potent than (+/-)isoprenaline in decreasing the force of subtetanic contractions in the soleus and between 5-6 times less potent in increasing the force of subtetanic contractions in the EDL. This observation plus the lack of activity of both the selective beta1-adrenoceptor antagonist (atenolol) and the selective beta1 agonist (H 133/22) in the EDL implies involvement of beta2-adrenoceptors in these responses of the muscles to isoprenaline and salbutamol. The soleus muscle was about 6-12 times more sensitive to effects of beta-adrenoceptor agonists than the EDL. In concentrations which produced effects on muscle contractility, salbutamol significantly elevated cyclic AMP concentrations in both types of muscle. These effects were antagonised by propranolol. It seems clear that the contrasting effects of sympathomimetic amines on slow-and fast contracting muscle are mediated through a common mechanism-elevation of cyclic AMP. Possible explanations of this apparent paradox are discussed.

Albuterol↗

PubMed1997

Mapping of a second actin-tropomyosin and a second troponin C binding site within the C terminus of troponin I, and their importance in the Ca2+-dependent regulation of muscle contraction.

To investigate the functional importance of the C-terminal residues 116 to 148 of troponin I (TnI) in the Ca2+-dependent regulation of vertebrate skeletal muscle contraction, we have prepared several synthetic TnI peptide analogs corresponding to various regions within residues 96 to 148 of rabbit skeletal TnI, and analyzed each of these peptides in reconstituted thin filament assays. Our results show that the TnI peptide 96 to 148 (TnI96-148) constitutes the minimal sequence of TnI capable of mediating an inhibitory activity similar to that of intact TnI protein. Truncation of residues 140 to 148 from this region (TnI96-139) or substitution of residues K141, K142 and K144 with alanine (TnI96-148A2) completely abolishes the enhanced inhibitory effect of this region when compared with TnI96-115. A synthetic peptide, residues 128 to 148 of TnI, containing residues 140 to 148, now termed the "second actin-tropomyosin (actin-Tm) binding site" is able to bind specifically to the actin-Tm filament and can induce a weak inhibitory activity on its own. Residues 116 to 131 of TnI do not appear to be important for inhibition, but are critical for interacting with troponin C (TnC). Specific investigations into this region have shown that residues 116 to 126, located directly adjacent to the "inhibitory region" (residues 96 to 115), are critical for allowing TnC to neutralize fully and rapidly the acto-S1-Tm inhibition caused by the various TnI peptides. Furthermore, residues 116 to 131 of TnI, now termed the "second TnC binding site", can significantly enhance the binding affinity of the inhibitory region, residues 96 to 115, for TnC in a Ca2+-dependent manner as determined by affinity chromatography analysis. The implication that TnI residues 116 to 131 bind to the N domain of TnC, and thus the inhibitory region (residues 96 to 115) binds to the C domain of TnC, has made us re-investigate the structural/functional role of the NH2-terminal region of TnI. Studies of competition between the N terminus of TnI (Rp1-40, residues 1 to 40) with the C-terminal peptides TnI96-115, TnI96-131 and TnI96-148 showed that only TnI96-115 could be easily displaced from TnC. These results thus suggest that Ca2+ binding to the regulatory sites of TnC (N domain) alters the binding affinity between the NH2 terminus and the C terminus of TnI for TnC, i.e. a Ca2+-dependent switch between these two sites of TnI for the C domain of TnC. These results have been incorporated into a general model describing the Ca2+-dependent regulation of muscle contraction.

Actins↗

PubMed1981

Responses of isolated Golgi tendon organs of the cat to muscle contraction and electrical stimulation.

1. Responses of Golgi tendon organs isolated from cat tail muscles to contraction of muscle fibers inserting directly into the receptor (GTO-muscle fibres) as well as to pulses of electrical current applied extracellularly through the sensory axon were studied. 2. Analysis of the responses to GTO-muscle fibre contraction indicated that the active force developed by each muscle fibre constituted an equally potent input to the receptor in proportion to the developed force. 3. The sensitivity of a Golgi tendon organ remained almost constant with changes in muscle length up to a length where maximum active tension was developed (lo). Beyond lo, the sensitivity tended to decrease. 4. The absolute force threshold (passive + active) at 1o for initiating an impulse in the afferent nerve was estimated for five preparations to be 4.5-14 mg. It was also demonstrated that the contraction of a single GTO-muscle fibre may initiate impulse discharge from the receptor. 5. A constant depolarizing current applied extracellularly to a GTO through its axon initiated a train of impulses, probably originating from a site near or within the receptor capsule. Analysis of responses to constant currents of various intensities suggested that a single impulse initiation site was involved. 6. During combined stimulation, responses of a tendon organ to GTO-muscle fibre contraction simply added to the response initiated by a constant current pulse, suggesting that the impulse initiation sites activated by each mode of stimulation were identical, or situated very close to each other in the nerve terminal.

Action Potentials↗

PubMed1986

The mechanism of ergonovine-induced airway smooth muscle contraction.

There have been three articles in the clinical literature of ergonovine maleate-induced bronchospasm. The effect of the alkaloid on isolated canine tracheal smooth muscle was analyzed to investigate the mechanism of ergonovine-induced airway smooth muscle contraction. Both ergonovine and 5-hydroxytryptamine (5HT, serotonin) contracted the smooth muscle preparations with EC50s of 1.35 X 10(-8) mol/L and 5.06 X 10(-7) mol/L, respectively. The maximal contractile response observed with ergonovine was approximately 30% less than that observed with 5HT. Methysergide competitively blocked both ergonovine and 5HT responses with similar calculated pKB values (8.33 against ergonovine and 8.46 against 5HT) and also similar pA2 values determined by Schild plots (8.50 and 8.45, respectively). The relative affinity and efficacy of ergonovine versus 5HT were determined by use of a concentration of the irreversible antagonist, phenoxybenzamine, which partially blocked receptor sites. The calculated affinity of ergonovine was about 16 times higher than that of 5HT. The relative efficacy at EC100 for ergonovine was 0.2, but at EC10 it was 41.9 (5HT efficacy = 1). Ergonovine 10(-9) or 10(-8) mol/L shifted the 5HT dose-response curve to the right without reducing the maximal response, but the shift was nonparallel. Blockade of muscarinic (atropine), alpha 1-adrenergic (prazosin), beta-adrenergic (propranolol), H1 (pyrilamine), or H2 (cimetidine) receptors did not alter ergonovine-induced contraction. These data indicate that ergonovine directly contracts canine tracheal smooth muscle as a result of its combination with 5HT receptors. This effect may result in precipitation of an asthmatic attack in susceptible individuals.

Animals↗

PubMed2000

Cervical muscle response during whiplash: evidence of a lengthening muscle contraction.

OBJECTIVE: To assess the potential for cervical muscle injury from a rear-end automobile collision. DESIGN: Experimental design in which human subjects were exposed to low-speed rear-end collisions. The influence of independent variable (gender, speed change, muscle group, and motion phase) on dependent variables (kinematic response, muscle onset and muscle activation level) was examined using repeated-measures analysis of variance. BACKGROUND: Injuries to various tissues of the cervical spine have been proposed, yet little attention has been focused on the cervical muscles as a site of injury. METHODS: 42 subjects (21 males, 20-40 yr) were exposed to collisions of 4 and 8 km/h speed change while measuring kinematic response of the head and torso and electromyography of the sternocleidomastoid and cervical paraspinal muscles. RESULTS: Muscle activation occurred earlier in females and in the 8 km/h speed change. Sternocleidomastoid onset preceded paraspinal onset. Muscle activation level varied significantly with speed change, motion phase and muscle group. Initial rearward retraction of the head relative to the torso resulted in lengthening of the activated sternocleidomastoid, consistent with a contraction-induced muscle injury. CONCLUSIONS: The cervical muscles contract rapidly in response to impact and the potential exists for muscle injury due to lengthening contractions. RELEVANCE: The clinician should recognize the role of cervical retraction in the mechanism of whiplash injury and avoid aggressive motion in that plane during diagnosis and treatment. An understanding of whiplash injury mechanisms should improve patient education and preventative measures.

Accidents, Traffic↗

PubMed1980

The use of synchrotron radiation in time-resolved X-ray diffraction studies of myosin layer-line reflections during muscle contraction.

Experiments on striated muscle have been carried out at the EMBL Outstation at DESY, Hamburg, using the electron-positron storage ring DORIS as a high-intensity X-ray source. The low-angle reflections from the myosin cross-bridges could be recorded more than 1,000 times more rapidly than with the best conventional X-ray sources, and could be followed during contraction with a time resolution of 10 ms.

Animals↗

PubMed2006

Assessment of voluntary pelvic floor muscle contraction in continent and incontinent women using transperineal ultrasound, manual muscle testing and vaginal squeeze pressure measurements.

The aims of the study were: (1) to assess women performing voluntary pelvic floor muscle (PFM) contractions, on initial instruction without biofeedback teaching, using transperineal ultrasound, manual muscle testing, and perineometry and (2) to assess for associations between the different measurements of PFM function. Sixty continent (30 nulliparous and 30 parous) and 60 incontinent (30 stress urinary incontinence (SUI) and 30 urge urinary incontinence (UUI)) women were assessed. Bladder neck depression during attempts to perform an elevating pelvic floor muscle (PFM) contraction occurred in 17% of continent and 30% of incontinent women. The UUI group had the highest proportion of women who depressed the bladder neck (40%), although this was not statistically significant (p=0.060). The continent women were stronger on manual muscle testing (p=0.001) and perineometry (p=0.019) and had greater PFM endurance (p<0.001) than the incontinent women. There was a strong tendency for the continent women to have a greater degree of bladder neck elevation than the incontinent women (p=0.051). There was a moderate correlation between bladder neck movement during PFM contraction measured by ultrasound and PFM strength assessed by manual muscle testing (r=0.58, p=0.01) and perineometry (r=0.43, p=0.01). The observation that many women were performing PFM exercises incorrectly reinforces the need for individual PFM assessment with a skilled practitioner. The significant correlation between the measurements of bladder neck elevation during PFM contraction and PFM strength measured using MMT and perineometry supports the use of ultrasound in the assessment of PFM function; however, the correlation was only moderate and, therefore, indicates that the different measurement tools assess different aspects of PFM function. It is recommended that physiotherapists use a combination of assessment tools to evaluate the different aspects of PFM function that are important for continence. Ultrasound is useful to determine the direction of pelvic floor movement in the clinical assessment of pelvic floor muscle function in a mixed subject population.

Adult↗

PubMed2002

Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs.

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH(2)O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P < 0.01) and smooth muscle strips (P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

Acetylcholine↗

PubMed1977

Equatorial x-ray reflections from contracting muscle after an applied stretch.

The equatorial X-ray reflections were recorded from contracting muscle after a slow stretch. The intensity ratio of the 1,0 to the 1,1 reflections (I10/I11) after the stretch was not significantly different from that during an isometric tetanus at the same sarcomere length, although the tension after the stretch was considerably greater than isometric. This suggests that an almost identical number of cross-bridges produce a greater tension after a slow stretch than during an isometric tetanus.

Animals↗

PubMed2006

Electrically induced muscle contractions influence bone density decline after spinal cord injury.

STUDY DESIGN: Longitudinal repeated-measures; within-subject control. OBJECTIVE: We examined the extent to which an isometric plantar flexion training protocol attenuates bone loss longitudinally after SCI. SUMMARY OF BACKGROUND DATA: After spinal cord injury (SCI), bone mineral density (BMD) of paralyzed extremities rapidly declines, likely because of loss of mechanical loading of bone via muscle contractions. METHODS: Six individuals with complete paralysis began a 3-year unilateral plantar flexor muscle activation program within 4.5 months after SCI. The opposite limb served as a control. Compliance with recommended dose was > 80%. Tibia compressive force was > 140% of body weight. RESULTS: Bilateral hip and untrained tibia BMD declined significantly over the course of the training. Lumbar spine BMD showed minimal change. Percent decline in BMD (from the baseline condition) for the trained tibia (approximately 10%) was significantly less than the untrained tibia (approximately 25%) (P < 0.05). Trained limb percent decline in BMD remained steady over the first 1.5 years of the study (P < 0.05). CONCLUSIONS: Compressive loads of approximately 1 to 2 times body weight, induced by muscle contractions, partially prevent the loss of BMD after SCI. Future studies should establish dose-response curves for attenuation of bone loss after SCI.

Adult↗

PubMed1991

Effects of denervation on the contents of cholesterol and membrane systems involved in muscle contraction in rabbit fast-twitch sarcotubular system.

Denervated fast-twitch rabbit muscles were progressively losing their fresh weight and the yield of sarcotubular protein was increasing. The activity of Ca(2+)-ATPase was affected but very slightly, the basal Mg(2+)-ATPase and the Mg(2+)-ATPase/Ca(2+)-ATPase ratio however increased together with a simultaneous depression of the membrane-bound acetylcholinesterase activity. We did not observe any differences in density properties of sarcotubular fractions between control and denervated muscle. However, a relative enrichment in SM and H fraction could be seen after denervation with small changes in the content of the Ca(2+)-pump protein, increased levels of calsequestrin and cholesterol, mostly in the heavy and the SM fraction. After denervation the binding sites for 3H-PN-200-110 did not show any changes in receptor affinity, but the number of putative Ca(2+)-channels increased twice along with a depression of 3H-ouabain binding sites. We suggest that the denervation of fast-twitch muscle leads to the hypertrophy of the junctional sarcoplasmic reticulum and the T-system. Changes in the cholesterol content, in the number of putative Ca(2+)-channels and in Na+, K(+)-ATPase can affect the muscle contraction.

Acetylcholinesterase↗

PubMed1991

A limited role for leukotrienes and platelet-activating factor in food protein induced jejunal smooth muscle contraction in sensitized rats.

To determine whether the release of newly formed mediators such as the peptidoleukotrienes and platelet-activating factor might modulate the food protein induced jejunal smooth muscle contraction observed in sensitized rats, Hooded-Lister rats were sensitized by injection of ovalbumin (10 micrograms i.p.) and controls were sham sensitized with saline. Fourteen days later the contractility of longitudinally (n = 9) and circularly (n = 9) oriented jejunal segments (mucosa intact) were examined in standard tissue baths in response to antigen, leukotrienes, and platelet-activating factor alone and in the presence of a specific leukotriene receptor antagonist (MK-571), a 5-lipoxygenase inhibitor (L651,392), and a platelet-activating factor receptor antagonist (WEB 2086). Although the responses of control and sensitized tissues to stretch and 10(-4) M bethanechol were similar, only sensitized tissues contracted in response to antigen (1 mg/mL). MK-571 (10(-5) M) reduced or significantly inhibited the contractile response of sensitized longitudinally and circularly oriented tissues to 10(-7) M leukotrienes C4, D4, or E4, but neither L651,392 (10(-4) M) nor MK-571 (10(-5) M) significantly reduced the contractile response of sensitized tissues to antigen challenge. WEB 2086 (10(-4) M) significantly (p less than 0.01) reduced the contractile response of sensitized longitudinally and circularly oriented tissues to 10(-7) M platelet-activating factor but did not significantly alter the response to antigen in longitudinally (45% of control, p = 0.14) or circularly (118% of control, ns) oriented jejunal smooth muscle. In this model leukotrienes and platelet-activating factor play an insignificant role in modulating food protein induced jejunal smooth muscle contraction in intestinal anaphylaxis.

Anaphylaxis↗

PubMed2003

Ca2+-dependent activation of Rho and Rho kinase in membrane depolarization-induced and receptor stimulation-induced vascular smooth muscle contraction.

Ca2+ sensitization of vascular smooth muscle (VSM) contraction involves Rho-dependent and Rho-kinase-dependent suppression of myosin phosphatase activity. We previously demonstrated that excitatory agonists in fact induce activation of RhoA in VSM. In this study, we demonstrate a novel Ca2+-dependent mechanism for activating RhoA in rabbit aortic VSM. High KCl-induced membrane depolarization as well as noradrenalin stimulation induced similar extents of sustained contraction in rabbit VSM. Both stimuli also induced similar extents of time-dependent, sustained increases in the amount of an active GTP-bound form of RhoA. Consistent with this, the Rho kinase inhibitors HA1077 and Y27632 inhibited both contraction and the 20-kDa myosin light chain phosphorylation induced by KCl as well as noradrenalin, with similar dose-response relations. Either removal of extracellular Ca2+ or the addition of a dihydropyridine Ca2+ channel antagonist totally abolished KCl-induced Rho stimulation and contraction. The calmodulin inhibitor W7 suppressed KCl-induced Rho activation and contraction. Ionomycin mimicked W7-sensitive Rho activation. The expression of dominant-negative N19RhoA suppressed Ca2+-induced Thr695 phosphorylation of the 110-kDa regulatory subunit of myosin phosphatase and phosphorylation of myosin light chain in VSM cells. Finally, either the combination of extracellular Ca2+ removal and depletion of the intracellular Ca2+ store or the addition of W7 greatly reduced noradrenalin-induced and the thromboxane A2 analogue-induced Rho stimulation and contraction. Taken together, these results indicate the existence of the thus-far unrecognized Ca2+-dependent Rho stimulation mechanism in VSM. Excitatory receptor agonists are suggested to use this pathway for simulating Rho.

Adrenergic alpha-Agonists↗

PubMed1968

The independence of corticomotoneuronal and fusimotor pathways in the production of muscle contraction by motor cortex stimulation.

1. The response of thirty spindle afferents was studied during cortical stimulation of the ;best point' for eliciting a contraction of tibialis anticus in baboons anaesthetized with N(2)O/O(2) mixtures supplemented by small doses of barbiturates.2. No evidence of fusimotor activity before a contraction of the muscle was found. Evidence of fusimotor activity during the contraction and after the cortical stimulus was found. The various problems associated with interpretation of this activity are discussed.3. Depression of the spindle afferent response by tetanic cortical stimulation, which produced no detectable tension change, was found for four spindle afferents. This depression was particularly well documented for one spindle afferent. The depression could be explained by a decrease of static fusimotor activity.4. The spindle afferent response to muscle stretch was studied during light anaesthesia. The effect of barbiturates on this response suggested a depression of static fusimotor activity.

Action Potentials↗

PubMed1996

Effects of a prostaglandin I2 analog iloprost on cytoplasmic Ca2+ levels and muscle contraction in isolated guinea pig aorta.

In the isolated guinea pig aorta, the prostaglandin I2 analog iloprost (0.01-10 microM) inhibited the contractions induced by the thromboxane A2 analog U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F2 alpha; 30 nM) and prostaglandin F2 alpha (PGF2 alpha, 1 microM) in a concentration-dependent manner. In contrast, iloprost only partially inhibited the high K+ (65.4 mM)-induced contraction. In the muscle stimulated with high K+, verapamil (0.3 and 10 microM) inhibited [Ca2+]i and muscle tension in parallel, whereas iloprost (1 microM) inhibited muscle tension with only a small decrease in [Ca2+]i. In the muscle stimulated with U46619 (30 nM), verapamil and iloprost decreased both [Ca2+]i and muscle tension. However, as compared with the effect of verapamil, iloprost more strongly inhibited muscle tension than [Ca2+]i. The iloprost (0.1-1 microM)-induced relaxation was accompanied by a concentration-dependent increase in cAMP content. It was further demonstrated that inhibition of the U46619-contractions was augmented in the presence of cycloxygenase inhibitors, such as indomethacin (10 microM), ibuprofen (10 microM) and aspirin (10 microM). In contrast, the inhibition of PGF2 alpha-induced contraction was not affected by indomethacin. Similarly, the inhibitory effect of forskolin on U46619-induced contractions, but not on PGF2 alpha-induced contraction, was enhanced by indomethacin. These results suggest that iloprost inhibits vascular smooth muscle contraction by decreasing [Ca2+]i and the Ca2+ sensitivity of contractile elements through a cAMP-dependent mechanism. The results also suggest that in U46619-stimulated muscle, vasoactive prostaglandins that counterbalance the relaxing action of cAMP may be generated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗