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Relationship between phosphodiesterase inhibition induced by several Kampo medicines and smooth muscle relaxation of gastrointestinal tract tissues of rats.

Given a lack of information, we assessed the effects of Kampo medicines: Dai-saiko-to, Tsu-do-san, San'o-shashin-to, and Sairei-to, which have been used for various gastrointestinal diseases, on the phosphodiesterase activity and smooth muscle tone of the gastrointestinal tract. Clinically relevant concentrations of each Kampo extract (0.1 - 1 mg/ml) decreased the phosphodiesterase activity as well as smooth muscle tone. The extent of phosphodiesterase inhibition as well as smooth muscle relaxation by these Kampo extracts was prominent for the lower gastrointestinal tract. Also, there was a good correlation between the extents of drug-induced phosphodiesterase inhibition and smooth muscle relaxation, indicating the presence of their causal link. These results may partially provide the basis for understanding the mechanism of the clinical utility of Kampo extracts in gastrointestinal tract diseases.

Animals↗

Toxicology and pharmacology of some ruthenium compounds: Vascular smooth muscle relaxation by nitrosyl derivatives of ruthenium and iridium.

A series of compounds were synthesized from ruthenium trichloride, and their ip LD50s were determined in mice: pentamminenitrosylruthenium(II) chloride, 8.9; chloronitrobis(2,2'-dipyridyl)ruthenium(II), 55;dichlorobis(2,2'-dipyridyl)ruthenium(II), 63; ruthenium trichloride, 108; and potassium pentachloronitrosylruthenate(II), 127 mg/kg. The two bis-bipyridyl complexes produced death in convulsions within minutes, whereas the remaining compounds resulted in long, debilitating courses with death occurring in 4-7d. When given in massive overdoses, however, the compounds with inorganic ligands also produced rapid convulsive death in mice, and when given iv to anesthetized cats, they produced respiratory arrest. The major toxic effects of all the complexes appeared to be due to the metal and not to its associated ligands. Only complexes having nitrosyl ligand specifically relaxed vascular smooth muscle. Potassium pentabromoiridate(III) also relaxed rabbit aortic strips that had been contracted by adrenergic agonists, but potassium pentachloroiridate(III) did not. None of the complexes was as active as nitroprusside in relaxing aortic strips or in decreasing arterial blood pressure in cats. No compound tested was as potent as cisplatin in antitumor activity. The pentamminenitrosylruthenium(II) complex also relaxed guinea pig ileum and frog rectus abdominus when these isolated muscles had been contracted by acetylcho line. It appears that these organoruthenium compounds may produce death in central respiratory arrest, as do the inorganic complexes when given iv or ip in massive overdoses. In minimally lethal doses, the complexes with inorganic ligands may affect a variety of contractile tissues, perhaps by a general mechanism involving Ca. These complexes are apt to be generally cytotoxic as well.

Animals↗

Quantification of train-of-four responses during recovery of block from non-depolarising muscle relaxants.

Train-of-four (TOF) responses were assessed in 70 patients (seven groups of ten patients each) during recovery of neuromuscular block from atracurium (226 or 452 micrograms/kg), vecuronium (40 or 80 micrograms/kg), pancuronium (60 or 120 micrograms/kg) and tubocurarine (450 micrograms/kg) in order to quantify the height of T1 (first response in the TOF sequence) at which T2, T3 and T4 (2nd, 3rd and 4th response in TOF sequence) reappear. Patients were anaesthetised with thiopentone, nitrous oxide in oxygen and fentanyl. There were small but significant differences between relaxants. The clinically useful parameter, i.e. the 4th response in the TOF sequence, appeared at approximately 30% height of the first response (T1) rather than at 25% as generally believed. It is suggested that the third response in the TOF sequence, which reappeared at an average height of T1 of about 25% be used for administration of further supplements of muscle relaxants since abdominal muscle relaxation becomes inadequate at this stage.

Adult↗

Abnormal cortical mechanisms in voluntary muscle relaxation in de novo parkinsonian patients.

This study aimed at elucidating how the cortical mechanism underlying the preparation and the postmovement phase of voluntary hand muscle relaxation is affected in Parkinson's disease. Event-related mu and beta (de)synchronization (ERD/S) related to voluntary muscle contraction and relaxation were recorded in 16 untreated, akineto-rigid, predominantly hemiparkinsonian patients. The results were compared with data from 10 age-matched, healthy subjects. In the muscle relaxation task, the subject held the wrist in an extended position and then let the hand drop by voluntarily relaxing wrist extensor contraction, i.e., without any overt, associated muscle contraction. In the muscle contraction task, subjects performed a self-initiated brief wrist extension. A same pattern of ERD/S was observed in control subjects and parkinsonian patients performing the motor tasks with their less affected limb. In contrast, related to voluntary relaxation performed with the more affected limb, a delayed mu and beta ERD and a disappearance of beta ERS were revealed. These results demonstrate that the pattern of cortical oscillatory activity in a relaxation task is abnormal in parkinsonian patients. The authors suggest that this may be due to anomalous activity in inhibitory motor cortical systems and impaired sensorimotor integration of afferent inputs from muscle and joint receptors.

Adult↗

Development of ultra short-acting muscle relaxant agents: history, research strategies, and challenges.

Author has reviewed the literature and his own work related to the chemistry, pharmacology, and clinical aspects of new muscle relaxants. Emphasis has been placed on the basic science concepts and technologies (e.g. structure-activity relationships, nicotinic receptor pharmacology, and investigation of side effects) behind the development of rapidly and short acting nondepolarizing muscle relaxants.

Anaphylaxis↗

Direct effects of smooth muscle relaxation and contraction on in vivo human brachial artery elastic properties.

The direct effect of smooth muscle relaxation on arterial elastic properties is controversial. Studies in animals show both a decrease and an increase in elastic modulus. In human subjects, the contribution of smooth muscle to arterial elastic mechanics has been limited by difficulty in separating the direct effects of a vasodilator drug on the arterial wall from the indirect effects due to reduced blood pressure. The purpose of the present study was to assess the direct contribution of vascular smooth muscle to brachial artery elastic mechanics in normal human subjects in vivo. We measured brachial artery compliance and incremental elastic modulus (Einc) in eight normal subjects (age, 22 to 51 years) by using intravascular ultrasound. A 3.5F 30-MHz intravascular ultrasound catheter was placed through a sheath into the brachial artery, and intraarterial pressure, cross-sectional area, and wall thickness were measured simultaneously under baseline conditions and after the administration of intra-arterial nitroglycerin (100 micrograms) and norepinephrine (1.2 micrograms). A pressurized cuff surrounding the brachial artery was inflated to reduce transmural brachial artery pressure. Using this technique, we were able to measure the following arterial characteristics for the first time in human subjects in vivo: (1) the effective unstressed arterial radius and (2) the pressure-area, stress-strain, and pressure-Einc relations over a wide pressure range (0 to 100 mm Hg). Intra-arterial nitroglycerin increased brachial artery area by 22% and intraarterial norepinephrine decreased brachial artery area by 17% at 100 mm Hg transmural pressure (P < .001 versus baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Sevoflurane promotes endothelium-dependent smooth muscle relaxation in isolated human omental arteries and veins.

Anesthesia with sevoflurane is accompanied by vasodilatation. This could be due to the effects of sevoflurane on endothelium-dependent relaxation. We measured muscle tension of isolated human omental arteries and veins in response to substance P or glyceryl trinitrate in the presence of sevoflurane (0%, 1%, 2%, or 4%). Vascular levels of guanosine 3', 5'-cyclic monophosphate were measured with enzyme-linked immunosorbent assay. Substance P induced an endothelium- and concentration-dependent relaxation in omental vessels that was not affected by sevoflurane. In the presence of L-N(G)-nitroarginine methyl ester (nitric oxide synthase inhibitor), KCl (prevention of hyperpolarization), or both, sevoflurane at 4% enhanced the relaxation in the arteries (P < 0.05). In the vein segments, the relaxation was enhanced by sevoflurane at 4% in the presence of KCl and 2% and 4% in the presence of both L-N(G)-nitroarginine methyl ester and KCl (P < 0.05). The glyceryl trinitrate-induced endothelium-independent relaxation was enhanced by sevoflurane at 4% in both artery and vein segments (P < 0.05). Substance P increased the levels of guanosine 3', 5'-cyclic monophosphate similarly in the presence and absence of sevoflurane. These results show that sevoflurane, in contrast to its effect in animal models, promotes endothelium-dependent relaxation in human omental arteries and veins via an enhancement of the smooth muscle response to relaxing second messengers.

Adult↗

Urethral pressure response to smooth and skeletal muscle relaxants in anesthetized, adult male cats with naturally acquired urethral obstruction.

The effects of the skeletal muscle-relaxing drug dantrolene sodium alone, and in combination with the alpha 1-adrenergic antagonist prazosin, on the urethral pressure profile were investigated in male cats with obstructive lower urinary tract disease. Decreases in mean segmental intraurethral pressure induced by dantrolene (n = 3) or dantrolene in combination with prazosin (n = 3) were evaluated statistically, using a paired design. Statistical analysis was applied to absolute (mm of Hg) pressure values. Intravenous administration of dantrolene alone (1 mg/kg of body weight, n = 3) significantly decreased pressure in the postprostatic/penile urethral segment, but did not decrease prostatic urethral pressures. Dantrolene in combination with prazosin (0.03 mg/kg IV) caused a 20% pressure decrease in the prostatic segment (P = 0.060). Preprostatic urethral pressure was not significantly affected by either treatment regimen in the small pool of cats studied. There was no difference in baseline pressures (mm of Hg) in the 3 intraurethral segments of these 6 recently obstructed male cats, compared with historic baseline pressures (mm of Hg) in the 3 intraurethral segments of 28 healthy male cats. These results indicate that dantrolene and prazosin may be effective in relaxing intraurethral skeletal and smooth musculature in male cats clinically afflicted with obstructive lower urinary tract disease. However, it is not certain that administration of muscle relaxants would facilitate urethral catheterization and removal of the obstruction in male cats with blockage of the lower urinary tract. Strikingly, results of this study suggest that urethral muscle spasm had a minor role in these cats.

Animals↗

Muscle relaxation training and quality of life in rheumatoid arthritis. A randomized controlled clinical trial.

The purpose of the study was to investigate the effects of supervised muscle relaxation training in individuals with rheumatoid arthritis (RA). Sixty-eight participants were allocated at random either to a muscle relaxation training group or to a control group. Every participant was evaluated for health-related quality of life, muscle function, pain, and disease activity. The training group exercised 30 minutes, twice a week for 10 weeks, while no intervention was made in the control group. The results indicated improvements in the training group regarding self-care according to the Arthritis Impact Measurement Scales 2, and in recreation and pastimes according to the Sickness Impact Profile-RA (p < 0.05) directly after the intervention. Mobility and arm function (p < 0.01) according to the Arthritis Impact Measurement Scales 2, and muscle function of the lower limbs (p < 0.05) were improved after six months. No improvements remained after twelve months. It thus seems that 10 weeks' relaxation training might have some short-term influence in individuals with RA.

Adult↗

Tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines: vascular smooth muscle relaxants and antihypertensive agents.

A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.

Animals↗

[Studies of synthesis and structure-activity relationships of analogs of the muscle relaxant--baclofen].

In an effort to study the structure-activity relationship of analogs of baclofen and to search for more potent and less toxic muscle relaxants and analgesics, fifteen 3-substituted pheny-4-aminobutyric acids and their derivatives were synthesized. Preliminary pharmacological tests in albino mice showed that some of the target compounds exhibited muscle relaxant and analgesic effects. Compounds Ib, IIb, IIIa, IIIc and compounds Ib, IIb, IIIa, IIIb were, respectively, more potent in hot plate tests and morphine-induced straub tail reaction tests than other analogs, but they were still less potent than baclofen. The structure-activity relationship showed that the effects of baclofen were strongly structure specific, and the results also suggested that at least three groups in baclofen-phenyl, amino and carboxy--take important parts in the combination of baclofen with GABAB receptor.

Animals↗

Beta-adrenoceptors, cAMP and airway smooth muscle relaxation: challenges to the dogma.

beta-Adrenoceptor agonists are assumed to induce airway smooth muscle relaxation through the cAMP-protein kinase A (PKA) phosphorylation cascade system. This traditional second messenger paradigm of beta-adrenoceptor agonist action is deeply engrained, but in this article Theodore Torphy reviews recent observations that force a re-examination of the dogma. For example, cAMP can activate protein kinase G as well as PKA, and this unanticipated dual action may contribute to the relaxant activity of cAMP. Other studies suggest that beta-adrenoceptor agonists can induce relaxation by a cAMP-independent mechanism involving a direct coupling of the beta-adrenoceptor to Ca(2+)-dependent K+ channels. Consequently, it is possible that multiple cAMP-dependent pathways act in concert with cAMP-independent pathways to mediate bronchodilation in response to beta-adrenoceptor agonists.

Adrenergic beta-Agonists↗

Interaction of NO and VIP in gastrointestinal smooth muscle relaxation.

Gastrointestinal (GI) smooth muscle cell activity is controlled by contractile cholinergic neurons and relaxant non-adrenergic non-cholinergic (NANC) neurons in the myenteric plexus between the circular and longitudinal muscle layer. Decreased or increased NANC relaxation might be involved in the pathophysiology of functional GI motility disorders. Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) are the primary inhibitory NANC neurotransmitters. As classic neurotransmitters, VIP is stored in vesicles in the nerve endings, while NO is synthetized on demand by the neuronal isoform of NO synthase (nNOS). The VIP/nNOS co-localization in myenteric neurons, reported for various regions of the GI tract in different species, suggests that VIP and NO are co-transmitters. At the presynaptic level, VIP and NO can induce each others release. Most clear-cut evidence for this mechanism was obtained in isolated myenteric ganglia where VIP induced NO release, and NO facilitated VIP release. At the postsynaptic level, many studies support that VIP and NO are parallel co-transmitters, acting via the adenylate cyclase/3'5' adenosine cyclic monophosphate (cAMP) and guanylate cyclase/3'5' cyclic guanosine monophosphate pathway respectively. Mainly based on results obtained in isolated GI smooth muscle cells, a serial postsynaptic VIP/NO interaction model was proposed, whereby VIP is the principle neurotransmitter, acting partially via a VPAC receptor and the adenylate cyclase/cAMP pathway but also by induction of muscular NO production. Recent results suggest that the capacity of VIP to release NO from isolated smooth muscle cells is related to the induction of inducible NOS (iNOS) in the cells during the isolation procedure. The relative contribution of NO and VIP to GI NANC relaxation differs upon tissue and nerve firing frequency, so that interference with either of them will lead to varying effects.

Animals↗

[Combined use of non-depolarizing muscle relaxants in clinical anesthesiology].

Clinical observations in 99 patients and 74 experiments in cats enabled the authors to suggest that nondepolarizing myorelaxants when used in combination affected different portions of cholinergic receptors of the end plate of motor nerves causing greater inhibition of neuromuscular transmission. So an associated simultaneous application of such myorelaxants as tubocurarine and tercuronium as well as tercuronium and Arduan in special sub-blocking doses gives a complete relaxation of skeletal muscles without side effects which allows such methods to be recommended in surgical practice for anesthetic maintenance of operations on high risk patients.

Adolescent↗

Acetylcholine-induced endothelium-dependent vascular smooth muscle relaxation in nitroglycerin-tolerant isolated rat aorta.

Nitroglycerin (NTG) tolerance is recognized clinically, and its pharmacological mechanism has been thought to be due to a decrease in the accumulation of cyclic GMP (cGMP) which is a second messenger of NTG. Endothelium-derived relaxing factor (EDRF) also relaxes vascular smooth muscle through the activation of soluble guanylate cyclase and the production of cGMP. The purpose of this study was to investigate acetylcholine (ACh)-induced endothelium-dependent relaxation and cGMP response in NTG-tolerant isolated rat aorta. Ring strips prepared from the thoracic aorta of male Wistar rats were mounted in tissue baths and contracted with 10(-6) M norepinephrine. NTG and ACh relaxation responses were compared before and after 1 h treatment with 5 x 10(-4) M NTG. The chronological changes in tissue cGMP levels by 10(-6) M NTG and ACh were compared between a control group (untreated) and NTG-tolerant group (treated with 5 x 10(-4) M NTG for 1 h). The NTG dose-response curve shifted markedly to the right, but the ACh dose-response curve shifted to the left after the induction of NTG tolerance. In the control group, both NTG and ACh elevated the tissue cGMP levels, but in the NTG-tolerant group only ACh elevated cGMP significantly. However, in the NTG-tolerant group, the cGMP increase induced by ACh was smaller than that in the control group. These results suggest that NTG tolerance does not decrease, but rather augments ACh-induced endothelium-dependent vascular smooth muscle relaxation in isolated rat aorta.

Acetylcholine↗

Prenatal muscle relaxation in congenital diaphragmatic hernia.

An infant with congenital diaphragmatic hernia was given 2 mg vecuronium bromide intramuscularly in utero 40 min before vaginal delivery at 40 weeks gestation. At birth the infant had complete muscle relaxation, which facilitated decompression of the bowel and surgical correction. Prenatal muscle relaxation may improve the care of infants with congenital diaphragmatic hernia.

Adult↗

Changes in cytosolic cGMP and calcium in airway smooth muscle relaxed by 3-morpholinosydnonimine.

Nitrovasodilators relax airway smooth muscle by both guanosine 3',5'-cyclic monophosphate (cGMP)-dependent and cGMP-independent mechanisms and by mechanisms that reduce cytosolic calcium concentration ([Ca2+]i). This study was conducted to determine the relative importance of these mechanisms in relaxation of canine tracheal smooth muscle (CTSM) induced by 3-morpholinosydnonimine (SIN-1). We measured 1) the effect of SIN-1 on force, [cGMP]i, and [Ca2+]i, and 2) the ability of methylene blue (MB) to antagonize SIN-1-induced relaxation and cGMP accumulation. The ratio of fura 2 emission fluorescence intensities due to excitation at 340- and 380-nm wavelengths (F340/F380) was used as an index of [Ca2+]i. In strips contracted with 0.3 microM acetylcholine (ACh, n = 8) or 24 mM KCl (n = 8), SIN-1 (1-100 microM) caused a concentration-dependent decrease in force which was correlated with a concentration-dependent increase in [cGMP]i. MB (10 microM) proportionally attenuated both relaxation and cGMP accumulation. In fura 2-loaded strips contracted with 0.3 microM ACh (n = 7) or 30 mM KCl (n = 7), reductions in force induced by SIN-1 (1-100 microM) were accompanied by decreases in F340/F380. These findings suggest that in CTSM contracted with ACh or KCl, SIN-1 causes relaxation which appears to be mediated by cGMP-dependent mechanisms that reduce [Ca2+]i.

Animals↗

Audiovisual sexual stimulation by virtual glasses is effective in inducing complete cavernosal smooth muscle relaxation: a pharmacocavernosometric study.

Audiovisual sexual stimulation (AVSS) is frequently employed to promote cavernosal smooth muscle relaxation (SMR) in hemodynamic diagnostic settings for erectile dysfunction. Our aim has been to adapt conventional AVSS to the particular test conditions of pharmacocavernosometry and pharmacocavernosography (DICC), by the use of virtual glasses. Thirty-seven consecutive patients undergoing DICC were randomized in two groups: no-AVSS and AVSS through commercially available virtual glasses (VG-AVSS) with tri-dimensional capabilities and stereophonic headphones. Such device partially excludes the patient from the surrounding environment. In both groups a standard dose of vasoactive agents was intracavernosally administered, and possibly repeated (re-dosing), until complete SMR was obtained (3 doses/patient maximum). Psychometric tests (State Trait Anxiety Inventory and ad hoc visual analogue scales for embarrassment, stress and pain) were administered before and after DICC. The no-AVSS group consisted of 18 patients, the AVSS group of 19. Number of needed vasoactive agent doses: in the no-AVSS group 6 patients needed 1 dose, 3 patients 2, 9 patients 3 (mean dose number: 2.17); in the AVSS group 15 patients needed 1 dose, 1 patient 2, 3 patients 3 (mean dose number: 1.37). The difference in the number of doses used in the two groups was statistically significant (Student's t-test P = 0.007). Complete SMR, regardless of the number of used doses: in the no-AVSS group 9 patients (50%) achieved complete SMR, in the AVSS group 16 patients (84.2%). The difference in the two groups was statistically significant (chi-square P = 0.026). From evaluated psychometric measures no statistically significant difference between the two groups was detected. VG-AVSS significantly promotes complete SMR without increasing test related stress or anxiety. Its induced arousal suggests the possibility of performing dynamic evaluations of the erectile function with the oral agent sildenafil in place of intracavernosally administered vasoactive agents. VG-AVSS furthermore constitutes a promising tool for the investigation of normal physiology and pathophysiology of female sexual function.

Adult↗