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PubMed1988

Comparative pharmacology of endothelium-derived relaxing factor and nitric oxide.

The present study was designed to characterize endothelium-derived relaxing factor (EDRF) and nitric oxide (NO) by employing both biological and chemical methods. EDRF was released by the calcium ionophore A23187 from cultured bovine pulmonary artery endothelium (BPAE) grown on microcarrier beads and then superfused in a cell column. The maximum relaxations induced by EDRF (83%) or NO (79%) on phenylephrine (PE)-contracted rabbit aorta were similar. In contrast, EDRF was only half as potent as NO in relaxing the KCl-contracted rabbit aorta. EDRF induced a concentration-dependent relaxation of both PE-contracted rabbit aorta and histamine-contracted guinea pig aorta that was accompanied by a marked elevation in cyclic GMP levels. However, EDRF was vascular selective and did not relax or increase cyclic GMP levels of the histamine-contracted taenia coli of either species. NO was not vascular selective and relaxed both aorta and taenia coli and also markedly increased cyclic GMP levels in each. NO also relaxed dog femoral artery and gastrointestinal smooth muscle preparation of the lower esophageal sphincter, whereas EDRF only relaxed the femoral artery. Experiments were also performed describing the actions of a series of different resins: anion exchange resins (NH2/NH, AG-1), cation exchange resin (-COOH), reversed phase resin (C18) and hemoglobin-agarose on EDRF- or NO-induced relaxation. NH2/NH, AG-1 and hemoglobin-agarose resins inhibited EDRF-induced relaxation, but -COOH and C18 did not. The inhibition was dependent on the amount of resin employed. NO-induced relaxation was blocked only by hemoglobin-agarose but by none of the other resins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Extracellular calcium dependence of contraction and endothelium-dependent relaxation varies along the length of the aorta and its branches.

Dependence of contraction and endothelium-dependent relaxation of segments of the rabbit aorta and the celiac, superior mesenteric and renal arteries on the presence of calcium in the physiological salt solution in which they were bathed have been studied in vitro. Arteries were tested before and 60 min after removal of Ca++ from the bath solution. Norepinephrine-induced contraction and acetylcholine and A23187-induced relaxation were calcium-dependent in the thoracic and upper abdominal aorta. Contractions were resistant to the effect of calcium removal in segments from the aorta below the origin of the renal artery and from the renal artery itself. The aorta between the superior mesenteric and the renal arteries was intermediate in its dependence. Relaxation of the aorta caudal to the origin of the celiac artery and the renal artery was also resistant. The insertion of an intact everted vessel into an artery whose intima had been inactivated by rubbing restored partially the relaxation to acetylcholine and A23187 in the presence of normal calcium. Vessels that did not relax to acetylcholine after Ca++ exclusion from the bathing solution relaxed when the renal artery was the donor. Donor arteries whose relaxation was sensitive to Ca++ removal did not increase the relaxation response of the renal artery after calcium removal. Diltiazem and D600 reduced the relaxation responses of acetylcholine in the thoracic aorta and enhanced those in the renal artery. It is concluded that there is a transition in the extracellular Ca++ dependence of contraction and endothelium-derived relaxation along the length of the abdominal aorta. Changes in the dependence of contraction occurred more gradually than relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1996

Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats.

The alpha-2 adrenoceptor subtype and its signal transduction pathway mediating vascular relaxation in rats were studied in vitro using rings of superior mesenteric arteries. Removal of endothelium or incubation with NG-nitro-L-arginine completely blocked relaxant responses to UK14,304, suggesting endothelium-derived nitric oxide mediates relaxation. The order of potency for full (F) or partial (P) agonists causing relaxation was guanabenz (P) > UK14,304 (F) > clonidine (P) > epinephrine (F) > norepinephrine (F). Affinities (Ka) of alpha-2 adrenoceptor subtype-selective drugs for blocking relaxation were obtained in side-by-side experiments comparing rat mesenteric arteries with pig coronary arteries. Relaxation of pig coronary arteries is known to be mediated by the alpha-2A adrenoceptor subtype. Ka values in nM for rauwolscine (19), WB-4101 (265), SKF-104078 (197), spiroxatrine (128), and prazosin (1531) for blocking relaxation in rat arteries were consistent with their affinities for binding at the alpha-2D adrenoceptor subtype. Ka values for rauwolscine and WB-4101, drugs distinguishing the alpha-2D from the alpha-2A adrenoceptor subtype, were significantly higher in blocking relaxation of rat arteries compared with pig arteries, suggesting the alpha-2D adrenoceptor subtype mediates NO-induced relaxation in rat arteries. We used forskolin to oppose alpha-2 adrenoceptor-mediated inhibition of cAMP formation by directly stimulating cAMP formation in endothelium. Forskolin did not affect the relaxant response to UK14,304, suggesting that cAMP is not involved in the coupling of alpha-2 adrenoceptors to nitric oxide-induced vascular relaxation.

Adrenergic alpha-Antagonists↗
PubMed1990

Glibenclamide blocks the relaxant action of pinacidil and cromakalim in airway smooth muscle.

Concentration-relaxation curves for pinacidil and cromakalim were obtained in isolated guinea-pig tracheas contracted by histamine. Pinacidil produced complete relaxation with an EC50 value of 2.8 microM. The antidiabetic sulfonylurea, glibenclamide (0.1, 1, 10 microM), caused concentration-dependent rightward shifts (3- to 16-fold) of the concentration-relaxation curve for pinacidil without changing the maximal relaxant response. Cromakalim produced 85% relaxation with an EC50 value of 1.1 microM. Glibenclamide (0.1 microM) displaced the concentration-relaxation curve to the right and at higher concentrations (1-10 microM) caused nearly complete suppression of the maximal relaxant response to cromakalim. Glibenclamide not only prevented the effects of pinacidil and cromakalim but also produced a concentration-dependent and complete reversal of submaximal relaxations produced by these drugs. Glibenclamide was a selective antagonist of the relaxation of airway smooth muscle induced by pinacidil and cromakalim. Concentration-relaxation curves for theophylline, terbutaline and verapamil were unaffected by glibenclamide.

Animals↗
PubMed2006

Effect of hypnotic suggestion on fibromyalgic pain: comparison between hypnosis and relaxation.

The main aims of this experimental study are: (1) to compare the relative effects of analgesia suggestions and relaxation suggestions on clinical pain, and (2) to compare the relative effect of relaxation suggestions when they are presented as "hypnosis" and as "relaxation training". Forty-five patients with fibromyalgia were randomly assigned to one of the following experimental conditions: (a) hypnosis with relaxation suggestions; (b) hypnosis with analgesia suggestions; (c) relaxation. Before and after the experimental session, the pain intensity was measured using a visual analogue scale (VAS) and the sensory and affective dimensions were measured with the McGill Pain Questionnaire. The results showed: (1) that hypnosis followed by analgesia suggestions has a greater effect on the intensity of pain and on the sensory dimension of pain than hypnosis followed by relaxation suggestions; (2) that the effect of hypnosis followed by relaxation suggestions is not greater than relaxation. We discuss the implications of the study on our understanding of the importance of suggestions used in hypnosis and of the differences and similarities between hypnotic relaxation and relaxation training.

Adult↗
PubMed1984

The effects of short term flotation REST on relaxation: a controlled study.

The purpose of this study was to compare the effects of restricted environmental stimulation using a flotation tank (Flotation REST) to the effects of a normal sensory environment on relaxation. All of the subjects were first introduced to a simple relaxation program to be used during the experimental sessions. The program consisted of guided point-to-point relaxation, breathing techniques, and visual imagery techniques. Subjects were then pre-tested on measurements of electromyogram (EMG), galvanic skin response (GSR), peripheral skin temperature, and systolic and diastolic blood pressure. The experimental group experienced ten 45-minute sessions practicing the relaxation program in a Flotation REST environment. The control subjects practiced the same relaxation program in a similar body position for 45 minutes in a normal sensory environment. All subjects answered a five-question Subjective Relaxation Questionnaire on trials five through ten and were then post-tested on EMG, GSR, skin temperature, and blood pressure. The results indicated significant differences between groups from pre-test to post-test on systolic and diastolic blood pressure; the experimental group showed greater reductions. Significant differences also were observed on three of five questions on the Subjective Relaxation Questionnaire; the experimental group reported greater subjective relaxation and trends in a similar direction on the remaining two questions. The results of this study indicate that flotation REST enhances point-to-point relaxation, breathing techniques, and visual imagery techniques and, when combined with these techniques, can be an effective means of teaching normal subjects to lower systolic and diastolic pressure and heighten their subjective perception of relaxation.

Adolescent↗
PubMed1987

[Enhancement of the muscle relaxant action of baclofen by glucocorticoids].

Effects of pretreatment with hydrocortisone or prednisolone on the pharmacological effects of baclofen, particularly on the muscle relaxant action, were studied in young adult rats. Muscle relaxation was determined using an inclined board (50 degrees). A single injection of hydrocortisone (10 mg/kg, s.c.) 15 min prior to the administration of baclofen (5 mg/kg, i.p.) increased significantly the muscle relaxant time by baclofen. Prednisolone pretreatment (2 mg/kg, s.c.) also prolonged baclofen-induced muscle relaxation. Muscle relaxation due to tolperisone (50 mg/kg, i.p.) and mephenesin (80 mg/kg, i.p.) administration was enhanced by the pretreatment of hydrocortisone. Hydrocortisone pretreatment enhanced the muscle relaxant time of diazepam (2 mg/kg, i.p.) but at a lesser extent and only in males. No synergistic effect of hydrocortisone on the muscle relaxation time by suxamethonium (0.01 mg/kg, i.p.) was observed. Seven daily injections of 2 mg/kg hydrocortisone as well as of 0.4 mg/kg prednisolone did not enhance the muscle relaxation by baclofen when tested 24 hr after the last injection of the two steroids. Fifteen min priming with hydrocortisone had no effect on the antinociceptive and hypothermic effects of baclofen. 3H-Baclofen was injected i.v. as a tracer of 1 mg/kg unlabeled baclofen. In hydrocortisone-treated rats, the uptake of 3H-baclofen into the hippocampus, medulla oblongata and cerebellum was significantly higher than that in the vehicle-treated rats, whereas the radioactivity in the cervical, thoracic and lumbar spinal cord tended to decrease. The results indicate that acute priming with hydrocortisone enhances rather selectively the muscle relaxant action of the centrally acting muscle relaxant drugs. It is suggested that the primary site of the synergistic action of hydrocortisone to baclofen could be at the supraspinal level of the CNS.

Animals↗
PubMed1998

Relaxation training and breast milk secretory IgA.

OBJECTIVE: To evaluate the hypothesis that breast-feeding women who participate in relaxation training will have increased secretory IgA (sIgA) levels in their breast milk compared with women not receiving training. DESIGN: Nonrandomized control trial of a convenience sample. SETTING: Women were recruited from the postpartum floor of a university teaching hospital. The intervention took place in the women's homes. PARTICIPANTS: Women in the first 48 hours after delivery who were planning to breast-feed their healthy newborn infants for at least 8 weeks were approached for enrollment. Women were excluded if they had previous experience with relaxation training. At 4 to 6 weeks postpartum, we enrolled 38 women still breast-feeding their infants. INTERVENTIONS: Women were allocated into 3 groups. Women in group 1 were taught relaxation and had breast milk samples collected before and after the teaching. Women in group 2 had conversation with similar breast milk sample collection, and women in group 3 had 1 breast milk sample collected. Women in group 1 were encouraged to practice the relaxation once or twice a day for 2 weeks, and a second visit was made to all mothers with repeated breast milk collections. Women who were still breast-feeding at 6 to 8 weeks after study end had a final breast milk sample collected. Breast milk was analyzed for secretory IgA levels. Stress was assayed using the Symptom Checklist-90-R and open-ended questions. RESULTS: There was no difference in sIgA levels among the 3 groups at any time. Women who reported stress present between visit 1 and visit 2 increased their sIgA levels at the final sample collection (+0.16 g/L) compared with women who reported no stress (-0.09 g/L; P= .03). The ratings of success in relaxation in women in group 1 were related to the following sIgA levels in sample 4: poor relaxation, 0.67 g/L; fair relaxation, 0.41 g/L; good relaxation, 0.35 g/L; and very good, 0.30 g/L (P= .006). CONCLUSIONS: Self-reported stress appears to increase breast milk sIgA levels. Success at relaxation was inversely related to sIgA levels in the group learning relaxation.

Adult↗
PubMed2001

The relaxation of isolated rabbit corpus cavernosum by the herbal medicine Catuama and its constituents.

The effects of the Brazilian herbal medicine Catuama and each of its plant constituents (Paullinia cupana, Trichilia catigua, Zingiber officinalis and Ptychopetalum olacoides) were investigated on rabbit corpus cavernosum (RbCC) using a bioassay cascade. Catuama caused short-lived and dose-dependent relaxations (11% +/- 7%, 26% +/- 5% and 82% +/- 9%, at doses of 1, 3 and 10 mg, respectively). Neither the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 10 microM) nor the soluble guanylate cyclase inhibitor ODQ (10 microM) significantly affected the Catuama-induced relaxations. Similarly, the selective ATP-dependent K(+) channel (K(ATP)) blocker glibenclamide (10 microM), the muscarinic receptor antagonist atropine (1 microM) and the voltage-dependent Na(+) channel blocker tetrodotoxin (1 microM) all failed to affect significantly the Catuama-induced relaxations. These results indicate that the relaxations induced by Catuama involve neither nitric oxide release nor K(ATP) channel activation. The extracts of P. cupana, Z. officinalis and P. olacoides caused short-lived and dose-dependent RbCC relaxations, whereas T. catigua evoked long-lasting relaxations which were occasionally preceded by a brief contractile effect. The extract of P. cupana was the most active in relaxing RbCC strips. The relaxations induced by all extracts were not significantly affected by L-NAME (10 microM). The infusion of ODQ (10 microM) had no significant effect on the P. cupana- and Z. officinalis-induced relaxations but reduced by >50% (p < 0.05) those evoked by P. olacoides and T. catigua. Incubations of RbCC with Catuama(10 mg/mL for 0.25 to 5 min) caused increases of cAMP levels (143% increase at 5 min of incubation). Incubations of RbCC with P. cupana extract (1 mg/mL) increased the cAMP levels by 200% whereas higher doses (10 and 100 mg/mL) caused smaller increases in the nucleotide levels (150% and 89%, respectively). The extracts of Z. officinalis and P. olacoides (same doses) caused smaller increases of the cAMP levels compared with the P. cupana extract, whereas T. catigua (1-100 mg) did not increase the levels of this nucleotide above the basal values. Our results show that of the four extracts assayed, P. cupana was the most effective, indicating that it is the main extract responsible for the relaxing effect of Catuama on rabbit cavernosal tissue.

Animals↗
PubMed1996

Arginine vasotocin relaxation of gar (Lepisosteous spp.) hepatic vein in vitro.

The effects of arginine vasotocin (AVT) were examined in isolated gar arteries (afferent branchial, ABA; conus arteriosus, CA; ventral aorta, VA) and veins (hepatic, HV; intestinal; ovarian). AVT (10(-11) - 10(-7) M) had no effect in CA, produced contraction in ABA and VA and stimulated relaxation in veins. In precontracted HV, AVT relaxation was dose-dependent, long-lived (> 30 min) and reduced total tension by 49.0 +/- 10.7%. EC50s for AVT, arginine vasopressin, oxytocin, desmopressin, and isotocin in gar HV were 1.4 +/- 0.3, 3.6 +/- 0.2, 5.3 +/- 1.7, 11.0 +/- 6.5, and 19.0 +/- 0.4 nM, respectively. AVT was more potent compared with isotocin. Strength of relaxation (percentage decrease in total tension) of AVT and structural analogs was similar (range = 32.5 to 55%). Endothelium removal did not alter percentage relaxation or sensitivity to AVT in HV. AVT relaxation was not inhibited by nitric oxide synthase inhibitors or propranolol or reversed by addition of methylene blue but it was significantly enhanced by indomethacin (10(-5) M). Arginine vasopressin-receptor antagonists (V1- or V2-type selectivity; 10(-6) M) were equally effective inhibitors, each blocked 99% of AVT relaxation. Forskolin (10(-6) M) and papaverine (10(-4) M) relaxed precontracted gar arteries and veins. The adenylyl cyclase inhibitors SQ 22536 and MDL 12,330A (10(-5) M) produced transient contraction and stable relaxation, respectively, but did not inhibit AVT-induced relaxation in HV. Atrial natriuretic peptide (3 x 10(-8) M) and sodium nitroprusside (10(-4) M) had no effect in precontracted HV. AVT acts directly on gar venous smooth muscle cells via a nonclassical AVP receptor, possibly by increasing [cAMP]. AVT is a potent vasoconstrictor in vertebrate vasculature but produces a novel relaxation in gar veins.

Adrenergic beta-Antagonists↗
PubMed1993

Role of NO in vagally-mediated relaxations of guinea-pig stomach.

Vagal stimulation of the stomach induces a relaxation mediated via non-adrenergic, non-cholinergic (NANC) nerves. The neurotransmitter which is responsible for this relaxation is still unknown. To determine whether nitric oxide (NO) or a NO related substance mediates this relaxation, an intact guinea-pig stomach was mounted in an organ bath, with electrodes surrounding the vagal nerves. Electrical stimulation of the vagal nerves, in the presence of atropine, induced frequency dependent, tetrodotoxin-(TTX) sensitive relaxations of the stomach quantified as changes in volume. These relaxations were not affected by alpha- or beta-adrenoceptor antagonists or guanethidine. Thus they were evoked by non-adrenergic, non-cholinergic (NANC) inhibitory nerves. The relaxant responses could be inhibited in a concentration-dependent manner by NG-nitro-L-arginine (L-NNA) a substance that inhibits the formation of nitric oxide (NO). Addition of L-arginine, the substrate for NO-synthase, reversed the L-NNA-induced-inhibition of the relaxation. Addition of nitroglycerin (a NO-donor) to a non-stimulated stomach mimicked the relaxations observed after vagal stimulation in a concentration dependent manner. These relaxations were insensitive to TTX. Relaxation of the stomach by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions. These data indicate that NO or a substance releasing NO plays an important role in NANC-neurotransmission after vagal stimulation of the guinea-pig stomach.

Adrenergic Fibers↗
PubMed1987

A relaxing factor released by phospholipase A2 in the absence of endothelium.

Phospholipase A2 (PLA2) produced slow dose dependent relaxation in intact and endothelium-deprived precontracted rabbit aortic strips. In endothelium-deprived preparations, relaxation induced by PLA2 is inhibited by hemoglobin, methylene blue and parabromophenacylbromide (PBPB), and is potentiated by superoxide dismutase (SOD). Indomethacin has no effect. Relaxation is accompanied by a rise in c-GMP. Phospholipase C causes a significant increase in tension, while Phospholipase D has no effects. In intact aortic strips PLA2 causes a biphasic response with no elevation in c-GMP. The results indicate several common features of the PLA2 released factor with endothelium-derived relaxing factor (EDRF). However, PLA2 induced relaxation is not dependent on endothelial cells. Apparently in addition to nitric oxide which may be the endothelium-derived relaxing factor, a second smooth muscle relaxing factor exists which is initiated by PLA2 and is independent of endothelium. The production of the PLA2 produced relaxation is dependent on its specific hydrolytic activity. We call this relaxing factor the phospholipid-derived relaxing factor (PDRF).

Animals↗
PubMed2002

Involvement of peptide histidine isoleucine in non-adrenergic non-cholinergic relaxation of the rat gastric fundus induced by high-frequency neuronal firing.

The role of peptide histidine isoleucine (PHI) as a neurotransmitter of the inhibitory motor neurones, the physiological role of PHI and vasoactive intestinal polypeptide (VIP) in the non-adrenergic non-cholinergic (NANC) relaxation and the relative amounts of VIP- and PHI-like immunoreactivity (LI) co-released by neuronal activation were investigated in the rat gastric fundus. Longitudinal muscle strips from the rat gastric fundus precontracted by the thromboxane receptor agonist U46619 (0.1 micro M) were studied in organ baths under conditions of muscarinic receptor blockade by atropine (1 micro M) and adrenergic neurone blockade by guanethidine (5 micro M) ("NANC conditions"). Concentration-response curves were plotted for both amplitude and area under the curve (AUC) of the relaxant responses induced by VIP (0.3 nM-0.3 micro M), PHI (0.3 nM-1 micro M) and peptide histidine valine [PHV(1-42); 0.3 nM-1 micro M]. All three peptides were more potent in the curve based on amplitude than in that based on the AUC of relaxation. In addition, VIP was 5.3 and 7 times more potent than PHI and PHV(1-42), respectively, in producing relaxation expressed as amplitude, and 2.7 and 2.8 times, respectively, in producing relaxation expressed as AUC. PHI and PHV(1-42) behaved as partial agonists with respect to VIP in producing relaxation expressed as AUC. Electrical field stimulation (EFS; 120 mA, 1 ms, 4-32 Hz, pulse trains of 2 min) evoked frequency-dependent relaxant responses. Alpha-chymotrypsin (1 u/ml or 3 u/ml), an anti-VIP serum (1:100 or 1:50) and an anti-PHI serum (1:25), slightly reduced the amplitude, but greatly inhibited the AUC of the NANC relaxation induced by EFS (13 Hz) [approximately 72%, 47% and 28% less than that seen in time controls or with normal rabbit serum (1:100 or 1:25), respectively]. EFS (8-32 Hz) caused significant, frequency-dependent increases in the outflow of VIP- and PHI-LI from the strips. The EFS-induced release of VIP-LI was approximately 20% of the PHI-LI release. These findings indicate that PHI is involved in EFS-induced NANC relaxation of the rat gastric fundus, the major physiological role of VIP and PHI is the maintenance of smooth muscle relaxation and VIP is co-released in equimolar amounts mainly with PHI.

Action Potentials↗
PubMed2003

Evidence for a significant role of a Gs-triggered mechanism unrelated to the activation of adenylyl cyclase in the cyclic AMP-independent relaxant response of guinea-pig tracheal smooth muscle.

Cyclic AMP is a key molecule in the regulation of airway smooth muscle tone. Increased cyclic AMP leads to relaxation of this smooth muscle and its inhibition results in the muscle contraction. A constitutive role for cyclic AMP in the contraction and relaxation of airway muscle is supported by the observations that direct activators of adenylyl cyclase, such as forskolin and membrane-permeable cyclic AMP analogues, relax this smooth muscle potently. This traditional view of the role for cyclic AMP is the basis for the idea that relaxation of airway smooth muscle mediated through adenylyl cyclase-linked, G(s)-coupled receptors, including the beta(2)-adrenoceptor, is achieved mainly by the elevation of cyclic AMP content [cyclic AMP-dependent mechanism(s)]. However, recent pharmacological and biochemical evidence raises a fundamental question concerning the role of cyclic AMP; can G(s)-coupled receptor-mediated relaxation of tracheal smooth muscle be attributed exclusively to cyclic AMP-dependent mechanism(s)? In the present study, we show that cholera toxin (CTX, 5 microg/ml), an activator of the heterotrimeric guanine-nucleotide-binding protein G(s), relaxes guinea-pig tracheal smooth muscle. CTX also elevates tissue cyclic AMP content by about 30-fold and this is practically abolished by an adenylyl cyclase inhibitor, SQ 22,536 (100 microM). However, unexpectedly, the relaxant response to CTX is not affected by SQ 22,536. These results firstly show that activation of G(s) is able to produce a relaxation in tracheal smooth muscle independently of the elevation of cyclic AMP. G(s)-triggered, cyclic AMP-unrelated cellular mechanism(s) seem(s) to play a substantial role in smooth muscle relaxation mediated through adenylyl cyclase-linked receptors. This mechanism may account in part for the cyclic AMP-independent relaxant response of tracheal smooth muscle.

Adenylyl Cyclases↗
PubMed2004

Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs.

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F(2alpha) (PGF(2alpha))-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1-10 nM) was abolished by mechanical removal of the endothelium or after the addition of L: -NAME (200 microM), and was inhibited by the 5-HT(2B/2C) receptor antagonist SB 206553 (1 microM), but not the 5-HT(2C) receptor antagonist SB 242084 (0.1 microM). Endothelium-intact arteries were also relaxed by the selective 5-HT(2B) receptor agonist BW 723C86 (pD(2) 7.7). The relaxant response to BW 723C86 was inhibited by 1 microM SB 206553 (pK(B) 6.8). The low affinity component of relaxation to 5-HT (>/=30 nM) remained unaffected after mechanical removal of the endothelium or the addition of L: -NAME. In endothelium-denuded arterial rings, 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), and frovatriptan produced monophasic relaxations with pD(2) values of 6.5, 7.5, 5.9, and 4.7 respectively. Relaxant responses to the agonists were antagonized by the selective 5-HT(7) receptor antagonist SB 269970 (pK(B) 8.2-8.9). The relaxant response to the potent 5-HT(7) receptor agonist 5-CT was also antagonized by methiothepin (pK(B) 9.6), pimozide (pK(B) 8.2), mesulergine (pK(B) 7.7), methysergide (pK(B) 7.4), clozapine (pK(B) 7.6), and spiperone (pK(B) 7.4). The estimated pK(B) values argue in favor of an involvement of 5-HT(7) receptors in the direct vasorelaxant action of 5-HT in the pulmonary arteries of weaned pigs. The relaxant response to 5-CT was associated with an increase in cAMP that was surmountably antagonized by SB 269970 (pK(B) 8.6). The present in vitro bioassay can be used to characterize new drugs with potential agonist or antagonist properties at functional 5-HT(7) receptors.

Algorithms↗
PubMed2001

Nitrergic relaxation in urethral smooth muscle: involvement of potassium channels and alternative redox forms of NO.

We examined the contribution of K+ channels to the relaxation responses induced by different redox forms of nitric oxide (NO., NO- and NO+) in comparison with those evoked by electrical field stimulation (EFS) of nitrergic nerves in the sheep urethra. K+ channel blockers with different selectivity profile were used. Sodium nitroprusside (SNP) and different S-nitrosothiols were used as NO+ donors, Angeli's salt as an NO- donor and nitroglycerin (GTN) was chosen as a representative compound known to require metabolic activation in the target tissue. Pure NO gas was used to prepare NO. solutions. Relaxation evoked by EFS of nitrergic nerves or by exogenous NO was not inhibited by any of the K+ channel blockers, but was enhanced by 4-aminopyridine [inhibitor of voltage-dependent K+ (KV) channels]. This suggests that, whereas K+ channel activation and hyperpolarization of the postsynaptic membrane do not contribute to relaxation, prejunctional modulation of the nitrergic neurotransmission by Kv channels may be relevant. Relaxation induced by NO+ or NO- donors was not affected by K+ channel blockade with the following exceptions: glybenclamide, a blocker of ATP-sensitive K+ channels (KATP), enhanced responses to SNP and Angeli's salt, 4-aminopyridine inhibited relaxation evoked by Angeli's salt and GTN, and charybdotoxin, a blocker of large-conductance, Ca2+-activated K+ channels (BKCa) inhibited those induced by the S-nitrosothiol S-nitrosoglutathione. These results do not suggest the existence of a general mechanism of action on K+ channels for compounds releasing either NO+ or NO- in the sheep urethra. None of the K+ channel blockers affected relaxation induced by the membrane-permeable analogue of cGMP, 8-bromo-cGMP. However, the fact that the addition of the phosphodiesterase inhibitor zaprinast (0.1 mM) enhanced the relaxation to Angeli's salt, while preventing the inhibition induced by 4-aminopyridine, suggests that involvement of guanylate cyclase activation in the action of NO donors on K+ channels can not be excluded. Accordingly, the guanylate cyclase inhibitors 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ, 10 microM) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS 2028, 10 microM) almost abolished relaxations to EFS and Angeli's salt. In contrast, ODQ only moderately inhibited relaxations to NO.. In addition, the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) effectively inhibited responses to NO. whilst not affecting those to EFS or NO-, suggesting a close similarity between the nitrergic transmitter and nitroxyl ion. We conclude that nitrergic relaxation induced either by the endogenous transmitter or by exogenous NO donors in the ovine urethra is not mediated by postsynaptic alterations in the K+ conductance; only a prejunctional modulation through Kv channels seems to be significant. In addition, the production and/or release of alternative redox forms of NO, such as NO-, may be involved in neurotransmission processes in the urethra.

Animals↗
PubMed1999

Evidence for a contribution of store-operated Ca2+ channels to NO-mediated endothelium-dependent relaxation of guinea-pig aorta in response to a Ca2+ ionophore, A23187.

A23187 (6S-[6alpha,8beta,9beta,11alpha]-5-(methylamino) -2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7- dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid, calcimycin), an antibiotic Ca2+ ionophore, produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features were functionally characterized of endothelium-dependent relaxant response of guinea-pig aorta to A23187, especially focusing on the possible Ca2+ source and Ca2+ mobilization mechanisms in endothelial cells responsible for the vasorelaxant response to the Ca2+ ionophore. A23187-induced endothelium-dependent relaxation was suppressed profoundly by N(G)-nitro-L-arginine (L-NNA; 3 x 10(-4) M) or calmidazolium (3 x 10(-5) M), suggesting that nitric oxide (NO) produced by the enhanced activation of Ca2+/calmodulin-dependent endothelial NO synthase (eNOS) is largely responsible for the relaxant response of this artery to A23187. In the Ca2+-free solution without EGTA, NO-mediated endothelium-dependent relaxation induced by A23187 was almost abolished, which suggests that Ca2+ entry from extracellular space into endothelial cells plays the key role in the A23187-induced functional vasorelaxation. On the other hand, SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole; 5 x 10(-5) M) and Ni2+ (3 x 10(-4) M), both of which inhibit capacitative Ca2+ influx through store-operated Ca2+ channels (SOCCs), attenuated significantly NO-mediated endothelium-dependent relaxation by A23187. Furthermore, A23187-induced endothelium-dependent relaxation was suppressed more strongly than endothelium-independent relaxation induced by SIN-1 (3-morpholino-sydnonimine), an NO donor, when aortic preparation was preconstricted with high KCl instead of agonistic stimulation (prostaglandin F2alpha). These findings suggest that NO-mediated endothelium-dependent relaxant response of guinea-pig aorta to A23187 is preceded by the increase in endothelial cytosolic free Ca2+ concentration ([Ca2+]cyt) due to the enhanced Ca2+ influx from extracellular space. In the enhanced Ca2+ entry leading to the stimulation of eNOS and NO-mediated functional relaxant response of guinea-pig aorta to A23187, activation of SOCCs but not the Ca2+ entry through plasma membrane Ca2+-specific routes made by A23187 seems to play the predominant role. It is most likely that A23187 acts primarily at the Ca2+ store sites in endothelial cells, which subsequently depletes stored Ca2+ to activate SOCCs via unidentified mechanisms.

Animals↗
PubMed2003

EMG and MMG of synergists and antagonists during relaxation at three joint angles.

The aim of the study was to estimate the influence of force changes during relaxation from maximal voluntary contraction (MVC) of elbow flexors on electrical (EMG) and mechanical (MMG) activity of synergists and antagonists at different joint angles. Repeated studies were conducted on 22 young female students to estimate the EMG and MMG activity of the biceps brachii (BB), brachioradialis (BR), and triceps brachii (TB) muscles during relaxation from MVC at an optimal angle (the angle at which a subject achieved MVC=Lo), as well as at angles that were smaller (Ls=Lo-30 degrees ) and bigger (Ll=Lo+30 degrees ). Four testing sessions consisted of 2-s or 3-s MVC at each angle with simultaneous recording of EMG and MMG signals from BB, BR, and TB muscles. The EMG/MMG probes were used to record EMG and MMG signals. The results showed that the slow relaxation rate was related to a percentage decrease of the EMG amplitude (as measured by root mean square; EMG RMS) of the synergists, while the fast relaxation was related to the EMG RMS of the antagonist, independent of the joint angle. The MMG amplitude (MMG RMS) increased gradually during slow and fast relaxation (compared to the MMG RMS at MVC), indicating a bigger muscle oscillation during relaxation; the changes were related to the muscle tested and joint angle. It was found that, during the slow relaxation, the MMG RMS reflects the force amplitude changes in the BB muscle and the velocity of force changes in the BB and TB muscle (but not in the BR). During the fast relaxation, the MMG amplitude reflects a change in muscle force in the TB and BB muscles (but not in the BR), and the velocity of force changes in the synergists (not in the antagonist). The different contribution of the force and velocity of force changes during slow and fast relaxation to the MMG signal in the three muscle tested can be related to the different deactivation time of each muscle. In conclusion, the present results indicate that MMG recordings might be useful to measure the fast relaxation of individual muscle during voluntary contraction, but this needs be tested on isolated muscle.

Adult↗