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PubMed2006

Relaxant effect of Crocus sativus (saffron) on guinea-pig tracheal chains and its possible mechanisms.

As indicated in ancient Iranian medical books, Crocus sativus has therapeutic effects on respiratory diseases. The relaxant effect of this plant has been observed also on smooth muscles in previous studies. Therefore, in this study the relaxant effects of aqueous-ethanolic extracts of C. sativus and one of its main constituents, safranal, were examined on guinea-pig tracheal chains. The relaxant effects of four cumulative concentrations of aqueous-ethanolic extract (0.15, 0.3, 0.45, and 0.60 g %) and safranal (0.15, 0.30, 0.45, and 0.60 mL 0.2 mg mL(-1) solution) in comparison with saline, as negative control, and four cumulative concentrations of theophylline (0.15, 0.30, 0.45, and 0.60 mM), as positive control, were examined using guinea-pig precontracted tracheal chains. The tracheal chains had been precontracted by three different methods. Group 1 had been precontracted using 10 microM methacholine. The other two groups had been precontracted using 60 mM KCl at two different conditions: non-incubated tissues (group 2) and tissues incubated with 1 microM propranolol, 1 microM chlorpheniramine and 1 microM atropine (group 3) (for each group, n = 6). In group 1 all concentrations of theophylline, extract and safranal showed significant relaxant effects compared with saline (P < 0.05 to P < 0.001). In group 2 theophylline, extract and safranal showed concentration-dependent relaxant effects also compared with saline (P < 0.05 to P < 0.001 for different concentrations except two low concentrations of safranal). However, in group 3 the extracts of C. sativus showed a weak relaxant effect (P < 0.05 only for the highest concentration). The effects of the last concentration of safranal (0.60 mL 0.2 mg mL(-1) solution) in group 1, and all its concentrations in group 2 were significantly lower than those of theophylline (P < 0.05 to P < 0.001). In addition, the effects of safranal 0.45 and 0.60 mL 0.2 mg mL(-1) solution in groups 1 and 2 were significantly lower than that of C. sativus extract. There were significant correlations between the relaxant effects and concentrations for extract, safranal and theophylline in all experimental groups (P < 0.001 for all cases). These results showed a potent relaxant effect of C. sativus on tracheal chains of guinea-pigs that was comparable to or even higher than that of theophylline at the concentrations used. The results indicated that safranal was, at least in part, responsible for the relaxant effect of C. sativus.

Animals↗
PubMed2003

Comparative analysis of nitric oxide and SALMFamide neuropeptides as general muscle relaxants in starfish.

Previous studies have established that the gaseous signalling molecule nitric oxide (NO) and the SALMFamide neuropeptides S1 and S2 cause cardiac stomach relaxation in the starfish Asterias rubens. Here we show that S1, S2 and the NO donor SNAP also cause relaxation of two other preparations from Asterias - tube feet and the apical muscle of the body wall. The rank order of effectiveness as muscle relaxants when tested at a concentration of 10 micro mol l(-1) was SNAP>S2>S1 for both tube feet and apical muscle whereas for cardiac stomach it was S2>S1>SNAP. Significantly, these data indicate that NO and SALMFamide neuropeptides function as general muscle relaxants in starfish but vary in their relative importance in different organ systems. The molecular mechanisms by which NO and SALMFamides cause muscle relaxation in starfish are not known, but previous pharmacological studies on the cardiac stomach using the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazol[4,3-a]quinoxalin-1-one (ODQ) indicate that the cyclic nucleotide second messenger cGMP may mediate effects of NO. Consistent with this hypothesis, here we report that ODQ also causes partial inhibition of the relaxing effect of SNAP on tube foot and apical muscle preparations. To further investigate the involvement of cyclic nucleotides as mediators of the effects of NO and SALMFamides on starfish muscle, we have measured both cGMP and cAMP in cardiac stomach and in apical muscle after treatment with S1, S2 or SNAP. However, no significant changes in cyclic nucleotide content were observed compared with controls. Further experiments were performed on apical muscle tissue in the presence of the cyclic-nucleotide-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), a drug that also causes cardiac stomach relaxation in starfish. Treatment with IBMX caused a 2-3-fold increase above basal levels for cGMP and cAMP, but co-treatment with IBMX and S1 or S2 or SNAP resulted in no significant further increase above the level observed with IBMX alone. We conclude from these data that the relaxing action of NO on starfish muscle may be mediated by both cGMP-dependent and cGMP-independent pathways. However, the mechanisms by which SALMFamides cause muscle relaxation in starfish remain unknown and, although our results do not rule out the involvement of cGMP or cAMP, other signalling pathways may now need to be investigated.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Participation of ATP in nonadrenergic, noncholinergic relaxation of longitudinal muscle of wistar rat jejunum.

A role of ATP in nonadrenergic, noncholinergic (NANC) relaxations was examined in the Wistar rat jejunum. Electrical field stimulation (EFS) induced NANC relaxation of longitudinal muscle of the jejunal segments in a frequency-dependent manner. A purinoceptor antagonist, adenosine 3'-phosphate 5'-phosphosulfate (A3P5PS, 100 muM) inhibited the relaxation: relaxations induced by EFS at lower or higher frequencies were either completely or partially inhibited, respectively. After the jejunal segments had been desensitized to ATP, the relaxations were decreased to the same extent as those inhibited by A3P5PS. An inhibitor of small conductance Ca(2+)-activated K(+) channels (SK channels), apamin (100 nM), completely inhibited EFS-induced relaxations. Treatment of the segments with an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin (1 muM), significantly inhibited the relaxations. The exogenous ATP-induced relaxation of longitudinal muscle occurred with a concomitant decrease in intracellular Ca(2+) levels. Apamin and thapsigargin abolished these ATP-induced responses. A3P5PS significantly inhibited the inhibitory junction potentials which were induced in the longitudinal muscle cells. In addition, apamin significantly inhibited the hyperpolarization that was induced by exogenous ATP in the cells. These findings in the Wistar rat jejunum suggest that ATP participates in the NANC relaxation via activation of SK channels induced by Ca(2+) ions that are released from the thapsigargin-sensitive store site.

Adenosine Phosphosulfate↗
PubMed2002

Relaxed conditions can provide memory cues in both undergraduates and primary school children.

BACKGROUND: Memory can be impaired by changes between the contexts of learning and retrieval (context-dependent memory, CDM). However, the reminder properties of context have usually been investigated by experimental manipulation of cues in isolation, underestimating CDM that results from interactions between cues. AIMS: To test whether CDM can be demonstrated using multiple contextual cues combined to create relaxing versus neutral contexts at separate learning and memory testing stages of the experiments. SAMPLE: Forty university undergraduates (in Experiment 1), and forty 9-10 year-olds (in Experiment 2). METHODS: All participants were given age-appropriate tasks under either relaxing or neutral conditions. The next day they were tested for retrieval or practice effects, under the same or different (relaxing versus neutral) conditions. RESULTS: For both age groups, there was a (mostly asymmetric) CDM effect with performance generally best in the relaxing-relaxing condition. There was also some overall benefit of having learned under relaxed conditions. CONCLUSION: A relaxed learning environment can provide effective retrieval cues, as well as improve learning. COMMENT: For both primary school children and university students, the educational implication of these findings is that learning can be improved in a relaxed state. For this benefit to be fully manifest, the assessment of learning should also take place under relaxed conditions.

Adult↗
PubMedDate not supplied

Essential role of newly synthesized ATP for cyclic GMP-induced relaxation in alpha-toxin permeabilized smooth muscle of rat proximal colon.

The role of newly synthesized ATP in cyclic GMP-induced relaxation was studied in membrane permeabilized longitudinal muscle preparations of the rat proximal colon. Cyclic GMP and 8 bromo cGMP induced concentration-dependent relaxation of alpha-toxin permeabilized preparations which were precontracted by 3 microM Ca2+ in the presence of 4 mM ATP and 5 mM phosphocreatine (PC). The relaxation by 8 bromo cGMP was inhibited by Rp-8-pCPT cGMPS, an inhibitor of cyclic GMP dependent protein kinase. The relaxation was inhibited by removal of PC from the bathing solution, in spite of the presence of ATP. The relaxation was also inhibited by dinitrofluorobenzene (DNFB), a selective inhibitor of creatine kinase. The removal of PC or treatment with DNFB is known to produce accumulation of ADP within smooth muscle cell, however, ADPbetaS did not affect the relaxation. After irreversible inhibition of endogenous creatine kinase by DNFB in beta-escin permeabilized preparations, treatment of the preparations with exogenous creatine kinase restored the relaxation. In the presence of ADP and PC but without ATP, 8-bromo cGMP induced the relaxation to the similar extent to that in the presence of ATP and PC. These results suggest that ATP newly synthesized from ADP and PC by creatine kinase is essential for cyclic GMP-induced relaxation of the smooth muscle preparations obtained from the proximal colon of rats.

Adenosine Triphosphate↗
PubMed2004

Beta1-adrenoceptor-mediated relaxation with isoprenaline and the role of MaxiK channels in guinea-pig esophageal smooth muscle.

The possible functional coupling between beta1-adrenoceptor and MaxiK channels which results in smooth muscle relaxation was examined in the guinea-pig esophageal muscularis mucosae. Isoprenaline-elicited relaxation of esophageal smooth muscle was confirmed to be mediated through beta1-adrenoceptors as the response was competitively antagonized by a beta1-selective antagonist atenolol with a pA2 value of 7.01. Iberiotoxin (IbTx, 10(-7) M), a selective MaxiK channel inhibitor, substantially diminished the relaxant response to isoprenaline. The extent of the MaxiK channel contribution to the relaxant response was 15-40% of the control response when estimated as the E50%-Emax responses to isoprenaline. The relaxation to isoprenaline was also attenuated by high-KCl (80 mM) to the same degree as the relaxant response generated in the presence of IbTx, and thus the estimated extent of the K+ channel contribution was 10-40%. These findings indicate that beta1-adrenoceptors are substantially coupled with MaxiK channels to produce relaxation of esophageal smooth muscle in the guinea-pig. Although MaxiK channels account for the contribution of K+ channels to the beta1-adrenoceptor-mediated relaxation in this smooth muscle preparation, their contribution seems to be less when compared to the beta2-adrenoceptor-mediated relaxation of tracheal smooth muscle.

Adrenergic beta-Agonists↗
PubMed2005

Effects of dual-action genistein derivatives on relaxation in rat aorta.

Protein tyrosine kinases and nitric oxide (NO) play important roles in several cardiovascular diseases. In this study, we examined the actions of two compounds, each has structure of genistein (a tyrosine kinase inhibitor) and an NO donor, on endothelium-independent relaxation responses in the isolated rat aorta. By rational drug design, genistein was modified to acquire an NO donor, and we synthesized two such compounds (G-II, G-VI). These compounds and genistein induced dose-dependent relaxation responses in endothelium-denuded aortic strips, the rank order of potencies being G-VI > G-II > genistein. Incubation of endothelium-denuded strips with 1H-[1,2,4] oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10 microM), a guanylyl cyclase inhibitor, inhibited both the G-II- and G-VI-induced relaxations, but not the genistein-induced relaxation. The residual relaxations induced by these two compounds were similar to the genistein-induced relaxation. Incubation of endothelium-denuded strips with lysophosphatidylcholine (LPC, 20 microM)-which is a major atherogenic lysophospholipid component of oxidized low-density lipoprotein and is known to activate tyrosine kinase-caused a significant rightward shift in the dose-response curve for genistein. LPC also shifted the G-II- and G-VI-induced relaxation curves to the right; however, these relaxations in the presence of LPC were greater than that induced by genistein. The sodium nitroprusside-induced relaxation in endothelium-denuded strips was similar between in the absence and presence of LPC. These results suggest that each of our newly developed G-II and G-VI compounds has a dual action, as an NO donor and a tyrosine kinase inhibitor. These compounds may be useful against certain cardiovascular diseases.

Animals↗
PubMed2006

Effect of L-arginine on the relaxation caused by sodium nitroprusside on isolated rat renal artery.

In the present study we investigated the mechanism of nitric oxide induced relaxation of renal arteries, with or without endothelium, taken from normotensive and spontaneously hypertensive (SH) rats. With this purpose in mind, the effects of the nitric oxide donor, sodium nitroprusside (SNP), with and without L-arg in the medium, on isolated rat renal artery relaxation were studied. Relaxing effect of SNP was higher in normotensive (10(-5) M of SNP caused 220% of relaxation in the cases with endothelium and 240% without endothelium), in comparison with SH rats (100% of relaxation with endothelium and 150% without). L-arg antagonized the relaxing effect of SNP in the examined renal arteries, more in normotensive (100-160% with endothelium and 110-195% without) than in hypertensive ones (0-10% with endothelium and 35-75% without) at SNP concentrations 10(-7) - 10(-5) M, respectively (*P < 0.05; **P < 0.001). L-arg did not significantly change relaxing effect of SNP in the isolated renal arteries with endothelium taken from SH rats, which show that L-arg, by modifying the chemical versatility of NO into redox active forms -nitrosonium (NO+) and -nitroxyl (NO-), produces different relaxing effects in normotensive and hypertensive isolated arteries of rats, with or without endothelium, potentiating the role of nitroxyl induced relaxation in SH rats.

Animals↗
PubMed2003

Evaluation of beta3-adrenoceptor-mediated relaxation in intact and endotoxin-treated equine digital veins.

OBJECTIVE: To investigate the functional expression of beta3-adrenoceptors (beta3-ARs) in equine digital veins (EDVs) and to examine whether beta3-AR relaxation was altered in EDVs incubated with endotoxin. SAMPLE POPULATION: Forelimbs obtained from 30 horses. PROCEDURE: Forelimbs were obtained from horses in an abattoir. Equine digital veins were carefully removed from distal portions of the forelimbs. Rings of dissected EDVs were mounted in 5-mL organ baths to record isometric tension in the presence of various beta3-AR agonists (SR 58611A, ZD 2079, and ZM 215001). RESULTS: In intact EDVs, isoprenaline, SR 58611A, ZD 2079, and ZM 215001 induced concentration-dependent relaxation. Isoprenaline and SR 58611A-induced relaxations were reduced or unaffected by nadolol, respectively. In intact EDVs, SR 58611A-induced relaxation was significantly reduced in the presence of 2 microM ZM 215001 (used as a beta3-AR antagonist). In endothelium-denuded EDVs or intact EDVs in the presence of a nitric oxide synthase inhibitor, isoprenaline and SR 58611A-induced relaxations were significantly decreased. The endothelium-independent relaxation to SR 58611A was significantly inhibited in the presence of ZM 215001. In endotoxin-treated EDV, isoprenaline- and SR 58611A-induced relaxations were significantly reduced. In these conditions, cycloheximide (a protein synthesis inhibitor) and ibuprofen (a cyclooxygenase inhibitor) restored the relaxant response to SR 58611A. CONCLUSIONS AND CLINICAL RELEVANCE: Beta3-adrenoceptors are functionally expressed in EDVs. Incubation in the presence of endotoxin, used as an in vitro model of laminitis, induced an alteration of beta-AR-mediated relaxations in EDVs, which could be the consequence of cyclooxygenase induction and subsequent prostanoid production.

Adrenergic beta-3 Receptor Agonists↗
PubMed1994

Experimental evidence for endothelium dependent relaxation and neuronal nitric oxide in corpus cavernosum.

It is known that penile erection is mediated primarily through the release of a nonadrenergic noncholinergic (NANC) neurotransmitter which has been recently identified as nitric oxide (NO). To evaluate whether the endothelium is involved in neurally mediated relaxation in corpus cavernosum, we determined electrical field stimulation (EFS) induced relaxation in both the presence and absence of endothelium, and we tested the effect of an inhibitor of NO synthase, NG-nitro-L-arginine (NOARG), in the absence of endothelium to examine if de-endothelialized tissue can still generate NO. Isolated corpus cavernosal strips from New Zealand White rabbits were used for isometric tension study using organ chambers. The endothelium was removed through denuding tissue. After the tissue was contracted with norepinephrine, EFS was performed at frequencies of 5, 15 and 40 Hz in the presence of guanethidine and atropine to evaluate NANC-selective nerural relaxation. The relaxation induced by EFS was observed after preincubation with NOARG(10(-4) M) for 30 minutes. L-arginine (10(-3) M) was then added for 30 minutes in the presence of NOARG before a second set of EFS studies were performed. Following norepinephrine precontraction, EFS relaxed corporal strips in both the intact and de-endothelialized strips. However, deendothelialization significantly impaired EFS induced relaxation (p < 0.05). NOARG attenuated relaxation induced by EFS and the addition of L-arginine reversed the inhibitory effect of NOARG in the strips with endothelium. In the strips without endothelium, NOARG still inhibited EFS induced relaxation. This relaxation was reversed by the addition of L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Stimulation of P2y purinoceptors induces, via nitric oxide production, endothelium-dependent relaxation of human isolated corpus cavernosum.

PURPOSE: Endothelial P2y purinoceptor stimulation is known to induce vasodilatation mediated by NO release from endothelial cells. We examined the effect of a potent P2y agonist, adenosine-5'-O-(2-thiodiphosphate) (ADPbetaS), on human corporal cavernosal strips and its dependence on a functional endothelial lining. MATERIALS AND METHODS: The preparations mounted in isometric conditions were precontracted by noradrenaline (NA) at a concentration of 0.1 microM. Increasing concentrations of ADPbetaS from 1 microM to 100 microM were added in the presence and absence of a functional endothelium or in the presence and absence of an NO synthase inhibitor and a selective P2y antagonist. Acetylcholine (Ach)-induced relaxation was used in each experiment for control. RESULTS: In human precontracted corporal cavernosal strips with a functional endothelium (relaxed by acetylcholine) ADPbetaS induces a dose-dependent relaxation with maximal relaxation of 45.5+/-5.0% and an EC50 of 11.7 microM. The relaxant effect of ADPbetaS was reduced by 77.1+/-7.0% by reactive blue 2 (20 microM)(a P2y antagonist). L-NAME (L-Nitro Arginin Methyl Ester), an NO synthase inhibitor (100 microM), reduced Ach- and ADPbetaS- induced relaxations by 86.59+/-3.24% and 86.83+/-0.5% respectively. Ach- and ADPbetaS- induced relaxations were significantly inhibited after dislodging of the endothelial lining of the corporal cavernosal strips, 90.11+/-6.2% and 87.1+/-5% respectively. CONCLUSIONS: Human corporal cavernosal strips can be relaxed by stimulation of P2y purinoceptors via NO release. This relaxation is an endothelium-dependent mechanism. Purines may be implicated in physiological erection in man.

Adenosine Diphosphate↗
PubMedDate not supplied

Relaxation kinetics of the aorta in N omega-nitro-L-arginine methyl ester-treated pregnant rats.

OBJECTIVE: To test the hypothesis that vascular relaxation kinetics are prolonged in pregnant rats treated chronically with N omega-nitro-L-arginine methyl ester (L-NAME). METHODS: Timed pregnant rats (on day 15 of a 22-day gestation) were implanted with infusion pumps containing vehicle (controls) or L-NAME (50 mg/d). L-NAME pumps were retained until day 22 (group 1), or removed on day 20 (group 2). All rats were killed at term. Aortic rings were mounted in organ chambers containing physiologic salt solution (PSS) for isometric tension recording, contracted with high-K+ PSS (60 mM), and allowed to relax in normal-K+ PSS. Relaxation kinetics were quantified as time for 50% and 80% relaxation. After contraction with phenylephrine, responses to cumulative concentrations of methacholine were studied in the absence and presence of L-arginine (L-Arg) (10(-3) M). RESULTS: Responses to methacholine were inhibited completely in group 1 and partially in group 2 (P < .05). The inhibition in both groups was reversed by L-Arg. The rate of relaxation was significantly slower in groups 1 and 2 (P < .05) as compared with controls. Mechanical removal of the endothelium caused prolongation of relaxation in controls and group 2 (P < .05), but not in group 1. Preincubation of aortic rings from untreated controls with L-NAME (in vitro, 10(-4) M) did not affect relaxation. CONCLUSION: The endothelium modulates the rate of vascular relaxation by a factor other than nitric oxide. N omega-nitro-L-arginine methyl ester (L-NAME) prolongs vasorelaxation by endothelium-dependent and -independent mechanisms. Prolongation of vascular relaxation kinetics may be a mechanism to elevate blood pressure and peripheral vascular resistance in preeclampsia.

Animals↗
PubMed1999

Glycyrrhetinic acid-sensitive mechanism does not make a major contribution to non-prostanoid, non-nitric oxide mediated endothelium-dependent relaxation of rat mesenteric artery in response to acetylcholine.

Pharmacological characteristics of non-prostanoid (PGI2), non-NO mediated endothelium-dependent relaxation in response to acetylcholine (ACh) were examined in the isolated rat mesenteric artery, especially focusing on the possible contribution of the gap junctional communication in the response. ACh produced an endothelium-dependent relaxation of the isolated rat mesenteric artery with functional endothelium in the presence of both indomethacin (3 x 10(-6) M) and N(G)-nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide synthase (NOS). ACh-induced relaxation of the rat mesenteric artery in the presence of indomethacin and L-NAME was strongly attenuated in the solution containing high (80 mM) KCl, tetraethylammonium (TEA) (10(-2) M), which suggests the involvement of endothelium-derived relaxing factor(s) (EDHF(s)) in the response. Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not profoundly affected by glibenclamide (10(-6) M), 4-aminopyridine (4-AP) (10(-4) M), iberiotoxin (10(-7) M), agitoxin-2 (10(-8) M), or apamin (10(-7) M), but was abolished by the treatment with apamin (10(-7) M) plus charybdotoxin (10(-7) M). Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not substantially affected by arachidonic acid (AA) (10(-4) M) or ONO-RS-082 (10(-5) M), an inhibitor of phospholipase A2, which rules out the involvement of AA metabolites in the vascular response. Furthermore, a gap junction inhibitor, 18alpha-glycyrrhetinic acid (18alpha-GA) did not show dramatic inhibitory effect on non-PGI2, non-NO mediated endothelium-dependent relaxation induced by ACh. These findings suggest that 1) metabolites of AA are not involved in non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh in the isolated rat mesenteric artery; 2) Heterocellular gap junctional communication does not mainly account for non-PGI2, non-NO mediated endothelium-dependent relaxation evoked by ACh in this artery.

Acetylcholine↗
PubMed1992

Prostanoid-induced relaxation of precontracted cat ciliary muscle is mediated by EP2 and DP receptors.

The pharmacology of prostanoid-induced relaxation of the precontracted cat ciliary smooth muscle was characterized using synthetic prostaglandin (PG) analogues that are selective for specific prostanoid receptors. Relaxation was studied using carbachol to precontract the isolated longitudinal ciliary muscle, followed by application of the PG agonist. Of the compounds studied, PGE2 was the most potent relaxant (concentration that produced 50% of maximum relaxation, 10(-7) mol/l), and its maximal effect in each preparation was used as a standard for comparison. Both PGD2 and PGF2 alpha produced relaxations that were approximately 30- and 100-fold weaker, respectively, than those produced by PGE2. Prostanoids with activity at the EP2 (19-(R)-hydroxy PGE2 and 11-deoxy PGE1) and DP (BW 245C) receptors potently relaxed the ciliary muscle. Other EP receptor subtypes and the TP receptor were not involved as indicated by the lack of relaxant activity of sulprostone (EP3 > EP1), MB 28767 (EP3 > TP), and U-46619 (TP). Although 17-phenyl trinor PGE2 (EP1 and EP3) and PGI2 (IP) had some activity, it occurred at a nonselective dose (10(-4) mol/l). The presence of DP receptors in the cat ciliary muscle was confirmed by using BW A868C, a selective DP-receptor antagonist. This drug (concentration, 1 mumol/l) displaced the relaxant effects of PGD2 but had no effect on the activities of PGE2 and 11-deoxy PGE1. In addition, 17-phenyl trinor PGF2 alpha (FP) was inactive, indicating that the FP receptor was not involved in ciliary muscle relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

[beta-adrenoceptor subtypes involved in relaxations of guinea-pig gastrointestinal smooth muscles: distribution and signaling pathway of beta 3-adrenoceptors].

The distribution and signaling pathway of beta 3-adrenoceptors involved in relaxations were examined in guinea-pig gastrointestinal smooth muscles. In esophagus, beta 1-adrenoceptors participate in isoprenaline-induced relaxations. However, both beta 2- and beta 3-adrenoceptors contribute to the relaxations in taenia caecum. In gastric fundus, duodenum, and ileum, beta 3-adrenoceptors were responsible for the relaxant responses. These results suggest that functional beta 3-adrenoceptors are present in four smooth muscles except esophagus. This was strongly supported by molecular analyses with RT-PCR, showing the expression of beta 3-adrenoceptor mRNA in the four tissues. beta 3-Adrenoceptor-mediated relaxations were unaffected by both an adenylyl cyclase inhibitor, SQ-22,536 (100 microM), and a PKA inhibitor, H-89 (10 microM), in guinea-pig gastric fundus smooth muscle. Furthermore, in the presence of SQ-22,536 (100 microM), the stimulation of beta 3-adrenoceptors elicited relaxations without an elevation of cAMP, indicating the involvement of cAMP-independent mechanism(s). beta 3-Adrenoceptor-mediated, cAMP-independent relaxations were significantly diminished by a Kv channel blocker, 4-aminopyridine (3 mM). These results indicate that beta 3-adrenoceptors play a primary role in relaxations of guinea-pig gastrointestinal smooth muscles and 4-aminopyridine-sensitive Kv channels participate in cAMP-independent smooth muscle relaxations in response to the activation of beta 3-adrenoceptors.

Animals↗
PubMed1992

Functional innervation of pig tracheal smooth muscle: neural and non-neural mechanisms of relaxation.

In pig tracheal smooth muscle (TSM), the isometric tension responses to electrical field stimulation (EFS) were compared to exogenous peptides, vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP), as well as to the nicotinic agonist dimethylphenyl piperazinium chloride (DMPP). The objectives of this study were to understand the mechanisms of nonadrenergic, noncholinergic relaxations of pig TSM and identify some putative candidate substances mediating the neural inhibitory response. In strips of TSM obtained from 6- to 12-week-old pigs set up in vitro in organ baths in Kreb's solution, EFS resulted in frequency-dependent contractions that were abolished by 1 microM atropine or 0.1 microM tetrodotoxin (TTX). Addition of DMPP (20-100 microM) resulted in a transient, atropine-sensitive contraction, which quickly desensitized. EFS failed to elicit any further contractions, but the tissues responded to carbachol. In tissues exposed to DMPP and contracted with carbachol, EFS elicited frequency-dependent relaxations that were unaffected by 1 microM propranolol, abolished by TTX and partially inhibited by omega-conotoxin. At the peak of carbachol-induced contraction, addition of DMPP resulted in rapid relaxation reversing spontaneously to base line, with no significant relaxation to further addition of DMPP. DMPP-induced relaxations were unaffected by TTX or omega-conotoxin. These tissues readily relaxed to 10(-8) M VIP. In carbachol precontracted tissues, VIP elicited concentration-dependent relaxations that quickly desensitized. However, these tissues readily relaxed to DMPP. CGRP produced only weak relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Relationship between bolus transit and LES-relaxation studied with concurrent impedance and manometry.

BACKGROUND/AIMS: Neuromuscular mechanisms regulating esophageal bolus transport are well studied. However, detailed data about the relationship between bolus transit and lower esophageal sphincter (LES)-relaxation during conventional motility testing are still lacking. METHODOLOGY: We performed systematic studies in 25 normal subjects, employing a catheter that integrates the two techniques impedancometry and manometry in a single instrument for simultaneous recording and analysis of the relationship between bolus transit and LES relaxation after swallowing saline or yogurt. RESULTS: 195 swallows were analyzed. LES relaxation occurred frequently later than UES relaxation. The mean latency between bolus entry into the esophagus and LES relaxation was 3.6 +0.2 sec. Two types of swallow-induced LES relaxation were observed: (a) LES relaxation preceding bolus transit (46 cases or 24%) and (b) LES relaxation occurring during bolus transit (149 cases or 76%). In the later case, during 114 (76%) cases of this deglutition, the position of the bolus was very close to the LES. CONCLUSIONS: During deglutition, LES relaxation seems to be modulated by bolus transit and occurs predominantly upon arrival of the bolus in the distal esophagus.

Adult↗
PubMed1991

Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters.

Nicorandil increases cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. However, high concentrations are required to activate guanylate cyclase (GC). We examined the relationship between activation of GC, increases in cGMP and relaxation in canine mesenteric artery and vein, renal and coronary artery and thoracic aorta. Nicorandil (10-100 microM) relaxed in each of the blood vessels. Relaxation was associated with elevations of cGMP but independent of release of endothelium-derived relaxing factor, and inhibited by methylene blue and hemoglobin. The organic nitrate esters nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, 2-isosorbide mononitrate, and 5-isosorbide mononitrate each behaved in a similar manner. In each blood vessel pentaerythritol tetranitrate was the most potent and 5-isosorbide mononitrate the least potent relaxant and stimulant of cGMP. Each of the organic nitrate esters (1 microM to 1 mM) except nicorandil stimulated soluble GC activity in the presence of 10 mM cysteine. Nicorandil (EC50 38 mM) increased GC activity. Moreover, nicorandil (0.1 microM to 30 microM) did not inhibit cGMP phosphodiesterase. The EC50 for vascular relaxation was directly correlated with the EC50 for elevation of cGMP for each of the agonists in each blood vessel type. The EC50 for activation of GC was directly related to the reciprocal of the rate constant for nitric oxide formation for each of the organic nitrate esters. However, a direct correlation existed between the EC50 for activation of GC and the EC50 for 1) elevation of cGMP and 2) relaxation, for each of the organic nitrate esters except nicorandil. Thus, the high concentrations of nicorandil required to activate GC cannot account for the low concentrations required to elevate cGMP or relax smooth muscle. We postulate that nicorandil may interact with a membrane receptor or release a second messenger, distinct from nitric oxide or endothelium-derived relaxing factor, which then activates GC. This may represent a physiologic mechanism for regulation of GC activity in smooth muscle.

3',5'-Cyclic-GMP Phosphodiesterases↗