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PubMed1996

Secretory immunoglobulin A increases during relaxation in children with and without recurrent upper respiratory tract infections.

A diminished mucosal concentration of secretory immunoglobulin A (sIgA) in the upper respiratory tract may increase susceptibility to colds and flu. The aim of the present study was to determine whether sIgA increases during relaxation in children aged between 8 and 12 years with recurrent upper respiratory tract infections. Forty-five healthy children and 45 children with 10 or more upper respiratory tract infections in the previous year were randomly assigned to one of three experimental conditions: relaxation with suggestions to increase immune system proteins, relaxation alone, or a control condition. Samples of saliva were obtained before and after each condition. The concentration of sIgA in the saliva samples was later determined by measuring the rate of precipitation of antigen-antibody complexes to known concentration of sIgA antigen. The concentration of sIgA increased in the relaxation conditions but not in the control condition. The sIgA/albumin ratio (a more specific measure of local mucosal immunity than concentration) increased during the relaxation-suggestion condition but not during the relaxation or control conditions; however, both the concentration of sIgA and the sIgA/albumin ratio increased in proportion to subjective relaxation ratings. Neither response differed between healthy children and children with recurrent infections. The findings indicate that a disturbance in mucosal immunity in children with recurrent colds and flu does not limit increases in sIgA during relaxation. Higher preinfection levels of sIgA correlate with resistance to upper respiratory tract infection, so enhancing the sIgA concentration with relaxation techniques may help children with recurrent infection problems.

Albumins↗
PubMed2003

Muscle relaxants for non-specific low back pain.

BACKGROUND: The use of muscle relaxants in the management of non-specific low back pain is controversial. It is not clear if they are effective, and concerns have been raised about the potential adverse effects involved. OBJECTIVES: The aim of this review was to determine if muscle relaxants are effective in the treatment of non-specific low back pain. SEARCH STRATEGY: A computer-assisted search of the Cochrane Library (Issue 2, 2002), MEDLINE (1966 up to October 2001) and EMBASE (1988 up to October 2001) was carried out. These databases were searched using the algorithm recommended by the Cochrane Back Review Group. References cited in the identified articles and other relevant literature were screened. SELECTION CRITERIA: Randomised and/or double-blinded controlled trials, involving patients diagnosed with non-specific low back pain, treated with muscle relaxants as monotherapy or in combination with other therapeutic modalities, were included for review. DATA COLLECTION AND ANALYSIS: Two reviewers independently carried out the methodological quality assessment and data extraction of the trials. The analysis comprised not only a quantitative analysis (statistical pooling) but also a qualitative analysis ("best evidence synthesis"). This involved the appraisal of the strength of evidence for various conclusions using a rating system based on the quality and outcomes of the studies included. Evidence was classified as "strong", "moderate", "limited", "conflicting" or "no" evidence. MAIN RESULTS: Thirty trials met the inclusion criteria. Twenty-three trials (77%) were of high quality, 24 trials (80%) were on acute low back pain. Four trials studied benzodiazepines, 11 non-benzodiazepines and two antispasticity muscle relaxants in comparison with placebo. Results showed that there is strong evidence that any of these muscle relaxants are more effective than placebo for patients with acute LBP on short-term pain relief. The pooled RR for non-benzodiazepines versus placebo after two to four days was 0.80 [95% CI; 0.71 to 0.89] for pain relief and 0.49 [95% CI; 0.25 to 0.95] for global efficacy. Adverse events, however, with a relative risk of 1.50 [95% CI; 1.14 to 1.98] were significantly more prevalent in patients receiving muscle relaxants and especially the central nervous system adverse effects (RR 2.04; 95% CI; 1.23 to 3.37). The various muscle relaxants were found to be similar in performance. REVIEWER'S CONCLUSIONS: Muscle relaxants are effective in the management of non-specific low back pain, but the adverse effects require that they be used with caution. Trials are needed that evaluate if muscle relaxants are more effective than analgesics or non-steroidal anti-inflammatory drugs.

Acute Disease↗
PubMed1993

Mechanisms of acetylcholine-induced relaxation in dog external and internal ophthalmic arteries.

Mechanisms underlying the relaxant response to acetylcholine (ACh) were examined in dog external (EOA) and internal ophthalmic arteries (IOA). Acetylcholine produced relaxation in EOA and IOA, partially contracted with prostaglandin (PG) F2 alpha. The relaxations induced by ACh in these arteries were not inhibited by endothelium denudation. The ACh (10(-8)-10(-5) M)-induced relaxations in EOA and IOA were abolished by treatment with atropine or indomethacin and markedly suppressed by tranylcypromine, a PGI2 synthesis inhibitor, but not influenced by hexamethonium. On the other hand, the relaxant response to the highest concentration used (10(-4) M) was partially attenuated but not abolished by treatment with atropine, indomethacin or hexamethonium. This relaxation under treatment with atropine was abolished by NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor, but not by indomethacin, whereas the response under treatment with hexamethonium was abolished by indomethacin, but not by L-NA. Combined treatment with indomethacin and L-NA or oxyhaemoglobin abolished the ACh (10(-4) M)-induced relaxation, or reversed it to a contraction. It may be concluded that relaxations induced by low concentrations of ACh in dog EOA and IOA are associated possibly with the release of PGI2 through activation of muscarinic receptors located in subendothelial tissues, including smooth muscle, and the relaxant response to the high concentration (10(-4) M) of ACh is mediated mainly by the release of nitric oxide through activation of nicotinic receptors in nitroxidergic nerves.

Acetylcholine↗
PubMed2001

Time-dependent reduction of acetylcholine-induced relaxation in aortic rings of cholestatic rats.

Changes in vascular responsiveness are the basis for some of the cardiovascular complications in cholestasis. Since the duration of cholestasis is important in determining the degree of the complications, we investigated the time-course dependent evolution of vascular relaxation responsiveness in the aortic rings of cholestatic rats. Acetylcholine-induced endothelium-dependent relaxation was investigated in the isolated aortic rings of unoperated, sham-operated and two-, five-, seven- and fourteen-day bile-duct ligated rats. There was a significant reduction in acetylcholine-induced relaxation of the aortic rings by the second day after the bile-duct ligation operation, compared to those of unoperated and sham-operated groups, but more reduction still occurs in 5- and 7-day bile-duct ligated groups, reaching a plateau by the seventh day. The relaxation response to sodium nitroprusside in the aortic rings of the unoperated and the 7-day bile-duct ligated rats did not differ, implying the intact smooth muscle component of the relaxation pathway. L-NAME ( N(omega)-nitro-L-arginine methyl ester), a nitric oxide (NO) synthase inhibitor, attenuated the acetylcholine-induced relaxation in both groups (unoperated and bile-duct ligated), while L-arginine prevents this inhibitory effect. Indomethacin potentiated the acetylcholine-induced relaxation in the aortic rings of the bile-duct ligated rats while it has no effect on unoperated controls, providing evidence for the possible role of vasoconstrictor prostanoids in cholestasis-induced reduction in acetylcholine-induced relaxation. These results state that the reduced acetylcholine-induced relaxation in the cholestatic aortic rings during the first week, when no portal hypertension was reported to be present, may be due to the decreased acetylcholine-induced NO release from endothelium or increased NO inactivation.

Acetylcholine↗
PubMed2003

Myofibrillar determinants of rate of relaxation in skinned skeletal muscle fibers.

The influence of Ca2+ dissociation rate from TnC and decreased cross-bridge detachment rate on the time course of relaxation induced by flash photolysis of diazo-2 in rabbit skinned psoas fibers was investigated at 15 degrees C. A TnC mutant (M82Q TnC) that exhibited increased Ca2+ sensitivity caused by a decreased Ca2+ dissociation rate in solution also increased the Ca2+ sensitivity of force and decreased the rate of relaxation in fibers approximately 2-fold. In contrast, a TnC mutant (NHdel TnC) with decreased Ca2+ sensitivity caused by an increased Ca2+ dissociation rate in solution decreased Ca2+ sensitivity of force but did not accelerate relaxation. Decreasing the rate of cross-bridge kinetics by reducing [Pi] slowed relaxation -2-fold and led to two phases of relaxation, a linear phase followed by an exponential phase. In fibers, M82Q TnC further slowed relaxation in low [Pi] approximately 2-fold whereas NHdel TnC had no significant effect on relaxation. These results are consistent with the interpretation that the Ca2+ dissociation rate and cross-bridge detachment rate are similar in fast twitch skeletal muscle such that decreasing either rate slows relaxation but accelerating Ca2+ dissociation has little effect on relaxation.

Animals↗
PubMed1992

Kinin-induced relaxations of the rat duodenum.

Both bradykinin (BK) and des-Arg9-BK induced relaxations of the isolated longitudinal smooth muscles of the rat duodenum. No contractile effects were observed with both peptides at concentrations up to 1 mumol/l. Des-Arg9-BK was about 1000 times less potent than BK. The novel B2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Phe7, Oic8]-BK) potently inhibited the BK-induced relaxations, but did not affect the relaxations induced by des-Arg9-BK. Conversely, the B1 receptor antagonist des-Arg9-[Leu8]-BK only inhibited des-Arg9-BK, but did not affect BK-induced relaxations. The relaxations induced by BK and by des-Arg9-BK were inhibited by apamin (1 mumol/l) demonstrating that apamin-sensitive K+ channels are involved. In contrast, tetraethylammonium (1 mmol/l) did not inhibit the relaxations. BK-induced relaxations were reduced by about 25% in the presence of indomethacin (10 mumol/l) although the concentration-response curve to BK was not shifted to the left. Prostaglandin E1 caused relaxations with a pD2 value of 9.2. It is concluded that both BK and des-Arg9-BK can elicit relaxations of the rat duodenum via pharmacologically distinct kinin receptor subtypes, but via similar effector mechanisms.

Animals↗
PubMed1976

Relaxation of splenic strips during wash out with amine-free solution after an exposure to noradrenaline.

1. Strips were prepared from the spleens of normal or of reserpine-pretreated cats or rabbits. The strips were first exposed to (-)noradrenaline and then washed out with amine-free solution. 2. After inhibition of monoamine oxidase by pargyline "secondary sensitization" was prominent during the incubation with noradrenaline, and the early phase of quick relaxation was followed by a late phase of slow relaxation. The latter was cocaine-sensitive and has to be attributed to a slowly declining efflux of noradrenaline from adrenergic nerve endings. 3. Inhibition of catechol-O-methyl transferase by U-0521 or inhibition of extraneuronal uptake by hydrocortisone (cat) or corticosterone (rabbit) failed to alter relaxation. Apparently, an efflux of noradrenaline from extraneuronal stores plays little or no role in the relaxation of splenic strips. 4. During prolonged exposure to noradrenaline strips become desensitized to noradrenaline; on wash out of the amine, sensitivity is restored. As a consequence of this temporary desensitization the response to noradrenaline is not well maintained during prolonged exposure to this amine (when MAO is intact), and the relaxation curve is distorted (whenever a late phase of slow relaxation is prominent). 5. Indometacin enhances the sensitivity of rabbit (but not of cat) splenic strips to noradrenaline but fails to substantially alter relaxation curves. 6. When the distribution of noradrenaline is restricted to the extracellular space and when the concentration of the amine is varied over a wide range, essentially parallel relaxation curves are obtained on wash out, provided the initial contraction does not exceed 80% of maximum. For higher initial contractions relaxation is slowed during the first minute of wash out, probably because of the sigmoid shape of the dose-response curve.

Animals↗
PubMedDate not supplied

Improvement of relaxation velocity parameters by calcium channel blockers in the aging rabbit myocardium.

Normal aging in man is known to be associated with a reduction in left-ventricular diastolic function, including the rates of relaxation and filling. Calcium channel blockers have been reported to improve left-ventricular diastolic function in patients with various forms of heart disease. Clinically, the action of calcium channel blockers may be related to either a direct myocardial effect or may be secondary to the peripheral or coronary vasodilation effects. The purpose of this study is to investigate a possible direct effect of calcium channel blockers on modulation of the reported age-related reduction in myocardial relaxation. The direct effects on myocardial relaxation of the dihydropyridine calcium channel blocker, nifedipine, were studied in isolated, perfused interventricular septa and left-ventricular wall from eight young (ages 9 to 18 months) and 14 old (ages 3 to 5 years) rabbits. Septa were perfused with oxygenated Ringer's solution and paced at 48 beats/min. Maximum relaxation velocity per unit of developed tension [-dT/dt]/T, and relaxation time per unit of developed tension tR/T were continuously measured before and after infusion of calcium channel blockers. In absence of drugs, the older rabbits demonstrated a mean [-dT/dt]/T which was 32% lower (p < 0.003) and a mean tR/T which was 45% higher (p < 0.005) than the younger rabbits. When nifedipine was introduced at concentrations > 10(-8) M equivalent to doses above the therapeutic free-plasma concentration in humans, all contraction and relaxation parameters were depressed. However, at lower doses, equivalent to doses in the clinical therapeutic range, [-dT/dt]/T was increased in the older rabbit septa by 18% in the presence of nifedipine. tR/T was shortened in the older rabbit septa by 17% in the presence of nifedipine. Myocardial relaxation in older rabbits after drug infusion approximated these parameters in the younger rabbits prior to drug infusion (P = NS). Calcium channel blockers had similar beneficial effects on the relaxation properties of the myocardium in younger rabbits. All beneficial effects were observed at concentrations of calcium channel blockers which were within and below the clinically therapeutic range of plasma free drug concentration, i.e., 5 x 10(-9) to 4 x 10(-8) M. Potential differences in relaxation effects related to different segments of the myocardium and different mechanical recording vectors were evaluated. Isolated left ventricle preparations from aging rabbits demonstrated improvements in tR/T and [-dT/dt]/T similar to those observed in the septum. Furthermore, improvement in mechanical function along the y-axis and x-axis vectors of the septum was similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1983

Stress management training and relaxation imagery in the treatment of essential hypertension.

The present study compared the effectiveness of three procedures in the treatment of 34 individuals with essential hypertension: (1) stress management training plus relaxation imagery, which consisted of an adaptation of existing stress management techniques in conjunction with extensive relaxation training using relaxation imagery; (2) relaxation imagery alone; and (3) weekly blood pressure checks. The relaxation imagery technique involved visualization of a relaxing image along with concentration on suggestions of relaxation, heaviness, and warmth. Treatment was individualized and lasted 8 weeks. Results indicated stress management plus relaxation imagery and relaxation imagery alone were significantly more effective than blood pressure checks in reducing systolic and diastolic blood pressures during treatment and in maintaining diastolic blood pressure reductions during follow-up. However, no significant differences were found between the two treatment procedures. Clinical implications of these findings are discussed.

Adolescent↗
PubMed1988

Feedback delays and relaxation expectancies in EMG biofeedback.

The use of noncontingent feedback controls in studies of the efficacy and process of electromyographic (EMG) biofeedback may yield results confounded by differential expectancies for relaxation. Furthermore, the role of expectancies in producing psychological and physical relaxation as well as reducing muscle activity is unclear. This study investigated the effects of feedback delays and induced relaxation expectancies on EMG activity and experienced relaxation. One hundred four non-clinical subjects participated in one auditory frontal EMG biofeedback training session. Subjects were assigned to one of four computerized feedback delay conditions (0.0037, 0.7493, 2.2481, 6.7444 s) and to one of two relaxation expectancy conditions (positive or negative). During 20 minutes of biofeedback training, all groups decreased frontal activity. Feedback delays interacted with training epochs in affecting EMG; the longest delay group reduced frontal activity more slowly than the shortest delay group during training. Positive relaxation expectancies produced greater experienced relaxation than did negative relaxation expectancies. Instrumental and expectancy factors in EMG biofeedback appear to operate independently of each other by reducing physiological activity and producing psychological relaxation respectively.

Biofeedback, Psychology↗
PubMed2006

Electrically stimulated relaxation is not mediated by GABA in cat lower esophageal sphincter muscle.

This study examined the effect of Gamma-Amino butyric acid (GABA) and selective GABA receptor related drugs on the electrically stimulated relaxation in the lower esophageal sphincter muscle (LES) of a cat. Tetrodotoxin (10(-6) M) suppressed the electrically stimulated (0.5-5 Hz) relaxation of the LES. However, guanethidine (10(-6) M) and atropine (10(-6) M) had no effect indicating that the relaxations were neurally mediated via the nonadrenergic and noncholinergic (NANC) pathways. NG-nitro-L-arginine methyl ester (10(-4) M, L-NAME) also inhibited the relaxant response but did not completely abolish the electrically stimulated relaxation with 60 % inhibition, which suggests the involvement of nitric oxide as an inhibitory transmitter. This study examined the role of GABA, an inhibitory neurotransmitter, on neurally mediated LES relaxation. GABA (10(-3)-10(-5) M, non selective receptor agonist), muscimol (10(-3)-10(-5) M, GABA-A agonist), and baclofen (10(-3)-10(-5) M, GABA-B agonist) had no significant effect on the electrically stimulated relaxation. Moreover, bicuculline (10(-5) M, GABA-A antagonist) and phaclofen (10(-5) M, GABA-B antagonist) had no inhibitory effect on the electrically stimulated relaxation. This suggests that GABA and the GABA receptor are not involved in the electrically stimulated NANC relaxation in the cat LES.

Animals↗
PubMed1997

Halothane inhibition of acetylcholine-induced relaxation in rat mesenteric artery and aorta.

PURPOSE: The effect of halothane was compared on acetylcholine (ACh)-induced relaxation of the mesenteric artery and the aorta in rats. METHODS: The responses of isolated rat aortic and mesenteric arterial ring segments precontracted with phenylephrine to ACh (10(-8)-10(-5) M), in the presence of halothane 0-3%, were compared using isometric force tension recordings. Effects of NG-nitro-l-arginine (L-NOARG, 3 x 10(-5), methylene blue (MB, 5 x 10(-6) M), oxyhaemoglobin in (OxyHB, 10(-7) M), and various potassium channel inhibitors; tetraethylammonium (TEA, 10(-5) M, 10(-3) M), apamin (AP, 10(-7) M), charybdotoxin (ChTx, 10(-7) M) and glibenclamide (GC, 10(-5) M) on ACh-induced relaxation in mesenteric artery were tested. Using radioimmunoassay, ACh (10(-6) M)-induced guanosine 3':5'-cyclic monophosphate (cGMP) accumulation of mesenteric arterial rings pretreated with L-NAORG were also measured. RESULTS: L-NOARG partially inhibited ACh-induced relaxation in mesenteric arterial rings (P < 0.05, maximum relaxation reduced by approximately 50%), whereas it abolished them in aortic rings. The remaining relaxation resistant to L-NOARG in mesenteric arterial rings was insensitive to additional MB or OxyHB, and was not accompanied by increases in cGMP contents of rings. Halothane inhibited endothelium-dependent relaxation in aorta and mesenteric arterial rings. This inhibitory effect was larger in aorta. Halothane also inhibited NO independent EDHF-dependent relaxation in the mesenteric arterial rings, CONCLUSION: Despite a similar inhibitory effect on the EDHF relaxing pathway, halothane has a larger effect on endothelium-dependent relaxation in the aorta (NO dependent mainly) than in the mesenteric rings (NO and EDHF dependent).

Acetylcholine↗
PubMed1998

Inhibitory effects of large Ca2+-activated K+ channel blockers on beta-adrenergic- and NO-donor-mediated relaxations of human and guinea-pig airway smooth muscles.

In human bronchi, relaxations to salbutamol and sodium nitroprusside were performed in the presence or absence of blockers of the large Ca2+-activated K+-channels (BKCa): charybdotoxin (Chtx), iberiotoxin (Ibtx) or tetraethylammonium (TEA). In bronchi under basal tone in presence of indomethacin (1 microM) or precontracted with acetylcholine (in presence or absence of indomethacin), the relaxations to salbutamol or sodium nitroprusside were unaffected or weakly inhibited by pretreatment with the BKca blockers (Chtx (100 nM), Ibtx (100 and 300 nM) and TEA (1 mM)). Significant inhibitions were mainly observed with TEA (1 mM) and iberiotoxin at high concentration (300 nM). These results contrasts with the potent inhibitory effects exerted by Chtx (100 nM) or Ibtx (100 nM) in guinea-pig trachea precontracted with acetylcholine in absence or presence of indomethacin indicating that human airways are less susceptible to BKCa blockade than guinea-pig airways. In addition, the BKCa blockers induced slowly developing contractions of human bronchi at basal tone. The contraction induced by TEA (1 mM) was abolished by verapamil (10 microM) suggesting that BKca blockade promotes an increase in membrane Ca2+-conductance through activation of voltage-gated Ca2+-channels. Verapamil also reversed the effects of TEA on salbutamol-induced relaxations in human bronchi as well as the effects of Ibtx on salbutamol- or sodium nitroprusside-induced relaxations in guinea-pig trachea. These data suggest that BKCa blockers induce activation of voltage-gated Ca2+-channels and therefore influx of Ca2+ which in turn cause a functional antagonism of beta2-adrenoceptor-agonist- and NO-donor-induced relaxations. Moreover, the BKCa opener, NS-1619, induced weak relaxations in human bronchi and guinea-pig trachea which were not blocked by TEA or Ibtx suggesting that BKCa opening is of minor significance for the relaxation of human airway smooth muscles. In conclusion, although a wealth of studies have demonstrated that beta-adrenoceptor agonists or NO-donors activate BKCa, the present study provides evidence that in human bronchi, as recently suggested in guinea-pig trachea, opening of BKCa does not appear to functionally participate in the relaxation to these relaxant agents.

Adrenergic beta-Agonists↗
PubMed1998

The relaxing effect of BDF 9148 on the KCl-contracted aorta isolated from normo- and hyper-tensive rats.

BDF 9148, a positive cardiac inotrope, relaxes the rat isolated portal vein and the KCl-contracted rat aorta. The aims of our study were to determine the mechanism of action of BDF 9148, and to ascertain whether the relaxing effect of BDF 9148 was maintained in the presence of the hypertrophy associated with hypertension, by investigating the effects of BDF 9148 on the contractility and electrophysiology of aortae of Wistar Kyoto normo-tensive rats (WKY) and Spontaneously Hypertensive Rats (SHRs). High concentrations of veratridine contracted the quiescent rat aorta. BDF 9148 had no effect on the quiescent, but relaxed the KCl-contracted WKY and SHR aorta by a tetrodotoxin insensitive mechanism, and these relaxations decreased with age but were not greatly altered by hypertrophy. The verapamil relaxations of the KCl-contracted aorta were not altered by age or hypertrophy. The ability of KCl to depolarise the aorta was reversed by verapamil, but not by BDF 9148. On the contracted rat aorta, the relaxant responses to acetylcholine were abolished by removal of the endothelium but potentiated by IBMX (10[-6] M), and the responses to isoprenaline were inhibited by propranolol (10[-6] M) but potentiated by forskolin (10[-7] M). The relaxation responses of the KCl-contracted aorta to BDF 9148 were not altered by removal of the endothelium, or by propranolol, forskolin and IBMX. In summary, the effects of verapamil and BDF 9148 on the aorta are different, and thus it is unlikely that the relaxant responses to BDF 9148 on the aorta are due to calcium channel blocking activity. The mechanism of the relaxant effect of BDF 9148 on the aorta remains unknown, but we have shown the response is endothelium-independent, and not mediated by sodium channel opening, hyperpolarization, beta-adrenoceptors, or by stimulating adenylate cyclase or guanylate cyclase.

Aging↗
PubMed2002

Relaxation and potentiation of cGMP-mediated response by ibudilast in bovine tracheal smooth muscle.

The effects of ibudilast, an inhibitor of phosphodiesterases (PDEs), on tension, levels of guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) were investigated in bovine tracheal smooth muscle. We especially examined the combined effect of ibudilast with the cGMP-elevating agents on these parameters. Ibudilast was equipotent to attenuate the precontractions induced by both 0.3 microM methacholine and 40 mM K(+). By contrast, the relaxant effects of sodium nitroprusside and salbutamol on 40 mM K(+)-contracted preparations were smaller than those on 0.3 microM methacholine-contracted ones. Neither N(omega)-nitro-L-arginine (100 microM), an inhibitor of nitric oxide synthase, nor ODQ (1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 5 microM), an inhibitor of soluble guanylyl cyclase, affected the ibudilast-induced relaxation. The relaxations induced by ibudilast and diltiazem on 40 mM K(+)-contracted preparations were significantly attenuated when extracellular CaCl(2) was increased from 2.54 mM to 10 mM. Ibudilast (10 microM), which caused only minor effect by itself, significantly ( P<0.05) shifted the concentration-response curves for the relaxant responses to sodium nitroprusside (SNP), atrial natriuretic peptide (ANP) and salbutamol to the left. On the other hand, ibudilast did not change the relaxant responses to diltiazem. Unlike ibudilast, diltiazem (3 microM) failed to affect the SNP- and salbutamol-induced relaxations. Ibudilast significantly ( P<0.05) increased basal levels of cGMP and cAMP. Furthermore, ibudilast enhanced SNP (0.3 microM)- and ANP (0.3 microM)-induced cGMP accumulation and salbutamol (10 nM)-induced cAMP accumulation. Zaprinast (10 microM), a type 5 PDE inhibitor, enhanced both relaxation and cGMP accumulation induced by SNP and ANP without changing salbutamol-induced responses. These findings suggest that blockade of voltage-gated Ca(2+) channels is involved in the relaxing action of ibudilast in bovine tracheal smooth muscle. However, ibudilast potentiates relaxation responses to ANP and SNP by inhibition of PDE 5, not by blockade of Ca(2+) channels. The enhancement of cGMP-mediated response may contribute to the therapeutic effects of ibudilast.

Albuterol↗
PubMed1999

Differential mechanisms of urethral smooth muscle relaxation by several NO donors and nitric oxide.

We have examined the mechanisms of action of a broad spectrum of nitric oxide (NO) donors, including several S-nitrosothiols, sodium nitroprusside (SNP) and nitroglycerine (GTN), in relation to their relaxant activity of urethral smooth muscle. For all the compounds examined, NO release (in solution and in the presence of urethral tissue), relaxation responses, elevations in cGMP levels and the effect of thiol modulators were evaluated and compared with the effect of NO itself. Whilst all NO donors, except GTN, released NO in solution due to photolysis or chemical catalysis, this release was not correlated with their relaxant activity in sheep urethral preparations, which were furthermore not affected by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO; 0.3 mM). A substantial NO-generating activity was found for S-nitroso-L-cysteine (CysNO) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in the presence of urethral cytosolic fractions, suggesting metabolic activation to NO in the cytosol of the target tissue. In contrast, NO generation from S-nitroso-N-acetyl-L-cysteine (N-ac-CysNO), S-nitrosoglutathione (GSNO) and SNP were reduced by the presence of urethral homogenate and/or subcellular fractions, suggesting direct NO transfer to tissue constituents. NO donors and NO gas induced dissimilar degrees of cGMP accumulation in urethral tissue, while they were essentially equipotent as urethral relaxants. Furthermore, 1H-[1,2,4] -oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ; 10 microM) inhibited both relaxation and cGMP accumulations, but with different potency for the different compounds. Oxidation of sarcolemmal thiol groups with 5-5'-dithio-bis[2-nitrobenzoic acid] (DTNB; 0.5 mM) enhanced relaxations to GSNO, an effect that was reversed by dithiotreitol (DTT; 1 mM), suggesting a direct effect through nitrosylation/oxidation reactions at the cell membrane, while relaxations to NO and to all the other compounds were not affected by these treatments. Finally, photodegradation of SNP induced the formation of a stable intermediate that still evoked NO-cGMP-mediated relaxations. This indicates that the assumption that SNP is fully depleted of NO by exposure to light should be revised. It can be concluded that important differences exist in the mechanisms by which distinct NO donors relax urethral smooth muscle and they cannot be regarded simply as NO-releasing prodrugs.

Alkylation↗
PubMed1999

The mechanisms underlying the relaxant effect of methyl and ethyl gallates in the guinea pig trachea in vitro: contribution of potassium channels.

The relaxant response and the possible contribution of K+ channels to the relaxation caused by both methyl and ethyl gallates, two compounds isolated from the Brazilian medicinal plant Phyllanthus urinaria, were investigated in the guinea pig trachea in vitro. Both methyl and ethyl gallate (0.01-30 microM) caused graded and complete relaxation of the guinea pig trachea without epithelium, pre-contracted by histamine, with mean EC50 values of 1.8 (1.2-2.2) microM and 0.7 (0.6-0.8) microM, respectively, and Emax of both 100+/-0%. Response to ethyl, but not methyl gallate, was significantly shifted to the right, with no change in the maximum effect when the epithelium was removed. The increase in K+ concentration in the medium to 80 mM completely abolished the relaxant response caused by both methyl and ethyl gallate. In addition, tetraethylammonium (10 mM) reduced by 50+/-6% and 43+/-4% the relaxation caused by methyl and ethyl gallates. In contrast, glibenclamide (3 microM) shifted (by about two- and fourfold) the concentration-response curves for both methyl and ethyl gallates, with no changes in the maximum effect. Charybdotoxin (100 nM), but not apamin (100 nM), significantly blocked by 54+/-5% and 59+/-4% the relaxation of both methyl and ethyl gallates. In contrast, SQ 22536 (10 microM; a selective adenylyl cyclase inhibitor), methylene blue (10 microM) or ODQ (1 microM; a guanylyl cyclase inhibitor) did not significantly affect the relaxant response caused by either of the compounds. These results provide evidence that the relaxation caused by both methyl and ethyl gallates in the guinea pig trachea in vitro may involve the activation of large-conductance Ca2+-activated K+ channels, and, to a lesser extent, ATP-sensitive K+ channels. Such results extend our previous observations and are consistent with the notion that methyl and ethyl gallates are mainly responsible for the relaxant action previously demonstrated in the extract of this plant.

Animals↗
PubMed2004

Sarcomeric determinants of striated muscle relaxation kinetics.

Ca2+ is the primary regulator of force generation by cross-bridges in striated muscle activation and relaxation. Relaxation is as necessary as contraction and, while the kinetics of Ca2+-induced force development have been investigated extensively, those of force relaxation have been both studied and understood less well. Knowledge of the molecular mechanisms underlying relaxation kinetics is of special importance for understanding diastolic function and dysfunction of the heart. A number of experimental models, from whole muscle organs and intact muscle fibres down to single myofibrils, have been used to explore the cascade of kinetic events leading to mechanical relaxation. By using isolated myofibrils and fast solution switching techniques we can distinguish the sarcomeric mechanisms of relaxation from those of myoplasmic Ca2+ removal. There is strong evidence that cross-bridge mechanics and kinetics are major determinants of the time course of striated muscle relaxation whilst thin filament inactivation kinetics and cooperative activation of thin filament by cycling, force-generating cross-bridges do not significantly limit the relaxation rate. Results in myofibrils can be explained well by a simple two-state model of the cross-bridge cycle in which the apparent rate of the force generating transition is modulated by fast, Ca2+-dependent equilibration between off- and on-states of actin. Inter-sarcomere dynamics during the final rapid phase of full force relaxation are responsible for deviations from this simple model.

Animals↗