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PubMed1997

Characterization of endothelium-derived relaxing factors released by bradykinin in human resistance arteries.

1. Relaxing factors released by the endothelium and their relative contribution to the endothelium-dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries. 2. BK produced an endothelium-dependent relaxation of arteries pre-contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 microM), produced a parallel shift to the right of the concentration-response curve to BK with a pA2 of 7.75. 3. Neither the cyclo-oxygenase inhibitor, indomethacin (10 microM) alone, the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 300 microM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 microM) alone, nor the combination of L-NAME plus Hb affected the concentration-response curve to BK. Conversely, the combination of indomethacin with either L-NAME or Hb attenuated but did not abolish the BK-induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L-NAME. Also, the presence of indomethacin plus L-NAME produced contraction of arteries with functional endothelium. 4. The indomethacin plus L-NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L-NAME did not affect the nitric oxide donor, S-N-acetylpenicillamine-induced relaxation. 5. The indomethacin plus L-NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 microM), 4-aminopyridine (100 microM), glibenclamide (10 microM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). 6. In the presence of indomethacin plus L-NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 microM) or by the inhibitor of cytochrome P450, SKF 525a (10 microM). Another cytochrome P450 inhibitor, clotrimazole (10 microM) which also inhibits K+ channels, inhibited the relaxation to BK. 7. These results show that BK induces endothelium-dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo-oxygenase derived prostanoid(s) and another factor (probably an endothelium-derived hyperpolarizing factor). They indicate that nitric oxide and cyclo-oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P-450 pathway, in these arteries.

Arteries↗
PubMed2002

Divergent effects of vitamin C on relaxations of rabbit aortic rings to acetylcholine and NO-donors.

1. Vitamin C may influence NO-dependent relaxation independently of effects on oxidant stress. 2. We investigated effects of vitamin C (0.1 -- 10 mmol l(-1)) on relaxation of pre-constricted rabbit aortic rings to acetylcholine (ACh), authentic NO and the NO-donors glyceryl trinitrate (GTN), nitroprusside (NP) and S-nitroso-N-acetyl-penicillamine (SNAP). DETCA (2 -- 6 mmol l(-1)), a cell permeable inhibitor of endogenous Cu-Zn superoxide dismutase (SOD) was used to increase intracellular superoxide anion (O(2)(-)). 3. Vitamin C reduced the response to ACh (71 +/- 7% inhibition of maximum relaxation at 10 mmol l(-1)) and inhibited relaxation to authentic NO. Vitamin C inhibited relaxation to GTN but potentiated relaxations to NP and SNAP, causing a parallel shift to a lower concentration range of the log dose-response curve by approximately one log unit at the highest dose. 4. Vitamin C increased the concentration of NO in bath solution (plus EDTA, 1.0 mmol l(-1)) following the addition of SNAP from 53 +/- 14 to 771 +/- 101 nmol l(-1) over the range 0.1-3.0 mmol l(-1). 5. DETCA inhibited relaxation to ACh (71 +/- 9% inhibition of maximum relaxation). This inhibition was abolished by a cell permeable SOD mimetic, but not by vitamin C. DETCA inhibited relaxation to SNAP but not that to NP nor to GTN. 6. Vitamin C inhibits endothelium-dependent relaxations of rabbit aortic rings to ACh and authentic NO and does not reverse impaired relaxation resulting from increased intracellular oxidant stress. Vitamin C potentiates relaxation to the NO-donors NP and SNAP by a mechanism that could involve release of NO from nitrosothiols.

Acetylcholine↗
PubMed2006

Study on the cyclic GMP-dependency of relaxations to endogenous and exogenous nitric oxide in the mouse gastrointestinal tract.

BACKGROUND AND PURPOSE: cGMP mediates nitrergic relaxations of intestinal smooth muscle, but several studies have indicated that cGMP-independent mechanisms may also be involved. We addressed this contention by studying the effect of ODQ and ns2028, specific inhibitors of soluble guanylate cyclase, on nitrergic relaxations of the mouse gut. EXPERIMENTAL APPROACH: Mouse gastric fundus and small intestinal muscle preparations were mounted in organ baths to study relaxations to exogenous NO, NO donors and electrical field stimulation (EFS) of enteric nerves. KEY RESULTS: In gastric fundus longitudinal muscle strips, ODQ and NS2028 abolished the L-nitroarginine-sensitive relaxations to EFS and the relaxations to NO and NO donors, glyceryl trinitrate (GTN), SIN-1 and sodium nitroprusside (SNP). EFS of intestinal segments and muscle strips showed L-nitroarginine-resistant relaxations, which were abolished by the purinoceptor blocker suramin. In the presence of suramin, ODQ and NS2028 abolished all relaxations to EFS in intestinal segments and strips. ODQ and NS2028 abolished the relaxations to exogenous NO and to the NO donors GTN, SIN-1 and SNP in circular and longitudinal intestinal muscle strips. Intestinal segments showed residual relaxations to NO and GTN. CONCLUSIONS AND IMPLICATIONS: Our results indicate that relaxations to endogenous NO in the mouse gastric fundus and small intestine are completely dependent on cGMP. ODQ and NS2028 incompletely blocked nitrergic relaxations to exogenous NO in intact intestinal segments. However, it is unlikely that this is due to the involvement of cGMP-independent pathways because ODQ and NS2028 abolished all relaxations to endogenous and exogenous NO in intestinal muscle strips.

Animals↗
PubMed1998

Relaxation for the relief of chronic pain: a systematic review.

The effectiveness of relaxation techniques in the management of chronic pain was determined in this systematic review of published randomized controlled trials. Reports were sought by searching MEDLINE, psycLIT, CINAHL, EMBASE and the Oxford Pain Relief Database. Studies were included in this review if they were randomized controlled trials of relaxation techniques in chronic pain. Studies which investigated the effects of relaxation in combination with other interventions were not considered. Nine studies involving 414 patients met the predefined inclusion criteria and are critically appraised in this review. Meta-analysis was not possible, due to lack of quantitative data in the primary studies. Studies involved patients with a range of chronic pain conditions. The McGill Pain Questionnaire was the most common pain outcome used. Whilst four studies were able to show a significant difference for the pain outcomes in favour of relaxation for the pre- and post-treatment assessments, few statistically significant differences were reported in favour of relaxation when between treatment comparisons were used. Only three studies reported statistically significant differences in favour of relaxation (judged as a significant difference for at least 1 of the pain outcomes) compared to the other treatment groups. In rheumatoid arthritis the McGill Pain Questionnaire scores were significantly lower for patients receiving relaxation compared to those who were in the routine treatment control group. In ulcerative colitis significant differences were reported for six of seven different pain outcome measures in favour of progressive muscle relaxation compared to patients in the waiting list control group. In one of the two cancer pain studies, relaxation taught by nurses produced significantly lower pain sensation scores compared to the control group. Two studies reported significant differences in favour of the experimental control groups rather than for relaxation. There is insufficient evidence to confirm that relaxation can reduce chronic pain. Many of the studies both positive and negative suffer methodological inadequacies. Recommendations for future research into the effectiveness of relaxation techniques for chronic pain are made.

Humans↗
PubMed2003

NO/cyclic GMP pathway mediates the relaxation of feline lower oesophageal sphincter.

1. We examined the role of the NO/cyclic GMP (cyclic GMP) pathway in nitric oxide (NO)- and vasoactive intestinal peptide (VIP)-induced relaxation of feline lower oesophageal sphincter (LES). Furthermore, it was studied whether methylene blue, LY83583 and ODQ, which are soluble guanylate cyclase (sGC) inhibitors, could inhibit NO-induced relaxation. 2. The nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine (L-NNA) had no effect in sodium nitropruside (SNP)-induced relaxation, but 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1)-induced relaxation was decreased by the pretreatment of L-NNA, which showed that SIN-1, not SNP, could activate NOS to cause relaxation. Methylene blue and LY83583 did not inhibit the relaxation by SNP and SIN-1. However, the more specific sGC inhibitor ODQ blocked the relaxation induced by NO donors. 3. To identify the relationship of NOS, sGC and adenylate cyclase in VIP-induced relaxation, tissue were pretreated with L-NNA and ODQ and SQ22536. These inhibitors produced significant inhibition of this response to VIP. The adenylyl cyclase inhibitor SQ 22536 also inhibited relaxation by VIP. 4. In conclusion, our data showed that SNP- and SIN-1-induced relaxation was mediated by sGC. Of sGC inhibitors, methylene blue and LY83583 were not adequate for the examination of NO donor-induced feline LES smooth muscle relaxation. VIP also caused relaxation by the pathway involving NO and cGMP and cAMP.

Aminoquinolines↗
PubMed1997

Loss of acetylcholine-induced relaxation by M3-receptor activation in mesenteric arteries of spontaneously hypertensive rats.

This study investigated which subtype of muscarinic receptor in mesenteric arteries from SHRs mediates the loss of the release of nitric oxide (NO) or endothelium-derived hyperpolarizing factor (EDHF) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. After SHRs and WKY rats were killed, their superior mesenteric arteries were isolated to perform the vascular relaxation study. Acetylcholine (ACh, 1 nM-1 microM)-induced relaxation was in a concentration-dependent manner and was impaired in mesenteric arterial rings obtained from the SHR group, whereas nitroglycerin (10 nM-1 microM)-induced relaxation was not affected in endothelium-denuded rings obtained from the hypertensive rat. In the presence of N(omega)-nitro-L-arginine (L-NNA; 0.1 mM) or methylene blue (10 microM), the ACh-induced relaxation was partially attenuated in both SHRs and WKY rats. The relaxation of ACh was partially inhibited by 4-aminopyridine (4-AP; 1 mM), apamin (APM; 1 microM), or charybdotoxin (CTX; 0.1 microM) in WKY rats, whereas that relaxation was not affected by 4-AP, APM, or CTX in SHRs. However, the L-NNA-resistant relaxation of ACh was further inhibited by APM or CTX in WKY rats but not in SHRs. When arterial rings were precontracted by 60 mM K+, the ACh-induced relaxation was not significantly different in SHRs and WKY rats. However, this relaxation was abolished by L-NNA (0.1 mM) in both strains. In addition, the M3 muscarinic antagonist, 4-diphenylacetoxy-N-methylpiperidine was the most potent in inhibiting the relaxation of ACh, being more potent than pirenzepine and methoctramine, which preferentially block M1 and M2 receptors in the mesenteric artery of WKY rats, respectively. 2-Nitro-4-carboxyphenyl-N,N-diphenylcarbamate (1 microM) almost abolished the relaxation of ACh, but not of A23187, in SHRs and WKY rats. These results suggest that NO and EDHF are released from the endothelium of rat mesenteric artery on the activation of muscarinic M3-receptor by ACh, and the loss of ACh-induced relaxation in small arteries of SHRs is mainly through reducing the release or activity or both of EDHF.

Acetylcholine↗
PubMed1999

In vitro simultaneous measurements of relaxation and nitric oxide concentration in rat superior mesenteric artery.

1. The relationship between nitric oxide (NO) concentration measured with an NO-specific microelectrode and endothelium-dependent relaxation was investigated in isolated rat superior mesenteric artery contracted with 1 microM noradrenaline. 2. Acetylcholine (10 microM) induced endothelium-dependent simultaneous increases in luminal NO concentration of 21 +/- 6 nM, and relaxations with pD2 values and maximum of 6.95 +/- 0.32 and 97.5 +/- 0.7 % (n = 7), respectively. An inhibitor of NO synthase, N G-nitro-L-arginine (L-NOARG, 100 microM) inhibited the relaxations and increases in NO concentration induced by acetylcholine. 3. Oxyhaemoglobin (10 microM) reversed the relaxations and increases in NO concentrations induced by acetylcholine, S-nitroso-N-acetylpenicillamine (SNAP) and S-morpholino-sydnonimine (SIN-1), but not the relaxations induced with forskolin. Oxyhaemoglobin also decreased the NO concentration below baseline level. 4. In the presence of L-NOARG (100 microM), a small relaxation to acetylcholine (10 microM) of noradrenaline-contracted segments was still seen; oxyhaemogobin inhibited this relaxation and decreased the NO concentration by 14 +/- 4 nM (n = 4). 5. The NO concentration-relaxation relationship for acetylcholine resembled that for SNAP and SIN-1 more than for authentic NO. Thus while 7-17 nM NO induced half-maximal relaxations in response to SNAP or SIN-1, 378 +/- 129 nM NO (n = 4) was needed for half-maximal relaxation to authentic NO. 6. The present study provides direct evidence that the relaxation of the rat superior mesenteric artery with the endothelium-dependent vasodilator acetylcholine is correlated to the endogeneous release of NO. The study also suggests that NO mediates the L-NOARG-resistant relaxations in this artery, and that there is a basal NO release.

Acetylcholine↗
PubMed1984

Bronchodilator-mediated relaxation of normal and ovalbumin-sensitized guinea-pig airways: lack of correlation with lung adenylate cyclase activation.

Isoprenaline, vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and forskolin caused a dose-dependent relaxation of normal and ovalbumin-sensitized guinea-pig tracheal spirals and lung parenchymal strips in vitro. There was no difference in magnitude of relaxation or sensitivity to these relaxants between normal and sensitized tissues. The rank order of potency (concentration of each drug at which 50% of the maximum is obtained) for these relaxants on both trachea and parenchyma was VIP greater than isoprenaline greater than PGE2 greater than forskolin, although the parenchyma was more sensitive than the trachea. The rank order of efficacy of the drugs used in relaxing both the trachea and lung parenchyma was isoprenaline (10 microM) greater than forskolin (30 microM) greater than VIP (0.1 microM) greater than PGE2 (10 microM). PGE2 at concentrations greater than 1 microM sometimes contracted the lung strip. Pretreatment with indomethacin (8.5 microM), a cyclo-oxygenase inhibitor, reduced the resting tone of tracheal spirals, but did not significantly affect the tone of lung strips. Indomethacin-pretreatment did not affect drug-induced relaxations of either normal or sensitized tracheal spirals. However, both normal and sensitized indomethacin-pretreated lung strips relaxed significantly less (P less than 0.05) to isoprenaline, PGE2 and forskolin. Indomethacin-pretreatment did not affect sensitivity of normal and sensitized trachea or parenchyma to the relaxant drugs. All the relaxant drugs used stimulated adenylate cyclase activity in normal or sensitized lung parenchyma membrane preparations. The rank order of efficacy (maximal activation) was forskolin greater than isoprenaline = VIP greater than PGE2. There was no difference in response between normal and sensitized lungs. Adenylate cyclase activity of normal lung was stimulated as follows: forskolin (100 microM), 500.0 +/- 50.0%; isoprenaline (100 microM), 186.0 +/- 29.0%; VIP (10 microM), 213.0 +/- 19.0% and PGE2 (100 microM), 155.0 +/- 23.0% of basal activity. Similar values were obtained for sensitized lung parenchyma. Indomethacin-pretreatment did not significantly affect normal or sensitized lung adenylate cyclase stimulation by isoprenaline, VIP, forskolin or PGE2. It was concluded that: Immunological sensitization to ovalbumin does not induce hypoactivity of relaxant drug receptors and/or the adenylate cyclase system of the airway tissues of the guinea-pig. (b) There is an apparent lack of correlation between tissue relaxation in vitro and adenylate cyclase activity since the rank order of the efficacy of a range of relaxants was different for the two effects and furthermore indomethacin-treatment of airway tissues yielded differential results.

Adenylyl Cyclases↗
PubMed1994

Effects of P1 and P2Y purinoceptor antagonists on endothelium-dependent and -independent relaxations of rat mesenteric artery to GTP and guanosine.

1. Guanosine 5'-triphosphate (GTP) and guanosine can relax both endothelium-intact and -denuded arterial preparations. In the present work the P1 and P2Y purinoceptor antagonists, 8-phenyltheophylline and reactive blue 2, respectively, were used to study the mechanisms of relaxation responses induced by GTP, guanosine, adenosine 5'-triphosphate (ATP) and adenosine in noradrenaline-precontracted rat mesenteric artery rings. 2. GTP (10 microM-1mM) dose-dependently relaxed endothelium-intact mesenteric artery rings and also induced moderate relaxation responses in endothelium-denuded preparations. Pretreatment of the rings with 8-phenyltheophylline (10 microM) or reactive blue 2 (10 microM) did not attenuate the relaxant effect of GTP. 3. Guanosine (10 microM-1mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The presence of 8-phenyltheophylline or reactive blue 2 had no effects on guanosine-induced relaxations. 4. ATP-induced (0.1 microM-0.1 mM) relaxation of endothelium-intact artery rings was attenuated by reactive blue 2 while 8-phenyltheophylline was ineffective. ATP also relaxed endothelium-denuded artery rings and this relaxation was inhibited by 8-phenyltheophylline, but not by reactive blue 2. 5. Adenosine-induced (10 microM-1 mM) relaxation of endothelium-intact and -denuded artery rings was attenuated by the presence of 8-phenyltheophylline, but not of reactive blue 2. 6. In conclusion, the endothelium-dependent and -independent relaxations of rat mesenteric arteries to GTP and guanosine are not mediated via P1 and P2Y purinoceptors. Therefore, these results support our previous suggestion on the presence of a novel guanine nucleotide-specific receptor, a putative PG receptor, on both endothelial and smooth muscle cells, which may participate in the regulation of arterial tone.

Adenosine↗
PubMed1994

Pilocarpine-induced relaxation of rat tail artery by a non-cholinergic mechanism and in the absence of an intact endothelium.

1. The partial muscarinic agonist, pilocarpine, evoked concentration-dependent relaxation with an EC50 of 2.4 x 10(-3) M in isolated segments of rat tail artery that were constricted with phenylephrine (10(-8) to 2 x 10(-7) M). Acetylcholine also evoked concentration-dependent relaxation but was more potent than pilocarpine (EC50, 6.5 x 10(-7) M). 2. The concentration-relaxation curves for pilocarpine were not affected by the muscarinic antagonists, atropine (10(-9) M) or pirenzepine (5 x 10(-7) M), while the concentration-relaxation curves for acetylcholine-evoked relaxation of the same tissues were shifted some 10 fold to the right by these concentrations of atropine and pirenzepine. 3. Acetylcholine failed to evoke relaxation following removal of the endothelium. The smooth muscle of the rat tail artery was some 10 fold more sensitive to the relaxing action of pilocarpine following denudation of the endothelium. 4. The effects of pilocarpine and acetylcholine on membrane potential were studied in tissues that were depolarized to -39 +/- 1 mV with phenylephrine (5 x 10(-8) to 2 x 10(-7) M). In intact tissues, pilocarpine caused hyperpolarization, an effect that persisted in the presence of muscarinic antagonists. Acetylcholine also evoked hyperpolarization. 5. Following removal of the endothelium, pilocarpine (10(-5) to 10(-3) M) evoked hyperpolarization in 6 of 15 preparations and a decrease in the frequency of action potentials in the remainder. Both of these responses were associated with relaxation. 6. The effects of pilocarpine were compared with other agents that evoke endothelium-independent relaxation. The concentration-relaxation curves in response to pilocarpine and nitroprusside were shifted to the right by ferricyanide (10-5 M) and methylene blue (10-5 M). Glibenclamide (10-6 M) was without effect on the hyperpolarization and relaxation evoked by pilocarpine (10' to 10- M).7. Thus, pilocarpine evokes relaxation of rat tail artery independently of the cholinergic system and it is suggested that this is achieved by decreasing the frequency of action potentials in the smooth muscle.

Acetylcholine↗
PubMed1994

Mechanism underlying substance P-induced relaxation in dog isolated superficial temporal arteries.

1. In helical strips of dog superficial temporal arteries with intact endothelium, substance P elicited a concentration-related relaxation with an EC50 of 2.8 (2.4-3.2) x 10(-10) M. 2. The relaxant response to the peptide in low concentrations (1-4 x 10(-10) M) sufficient to produce approximately half maximal relaxation was not inhibited by indomethacin, but was markedly suppressed by NG-nitro-L-arginine (L-NOARG), a nitric oxide (NO) synthase inhibitor, and by endothelium denudation. 3. High concentration (10(-7) M) of substance P produced marked relaxations in endothelium-intact strips. Removal of the endothelium attenuated the relaxation, and indomethacin or tranylcypromine suppressed the endothelium-independent relaxation. In indomethacin-treated strips with intact endothelium, L-NOARG attenuated but did not abolish the relaxation. The residual, L-NOARG-resistant relaxation was not significantly inhibited by ouabain, glibenclamide or tetraethylammonium. 4. Substance P (10(-7) M) increased the levels of cyclic GMP and cyclic AMP. The increase in cyclic GMP was abolished by endothelium denudation and treatment with L-NOARG, whereas the cyclic AMP increment was abolished by indomethacin. 5. Three different mechanisms may be involved in the substance P-induced relaxation: (1) an endothelium-dependent relaxation mediated by the release of NO from the endothelium, resulting in an increase of cyclic GMP (low and high concentrations of the peptide); (2) an endothelium-independent relaxation in association with cyclic AMP increment caused by prostaglandin I2 released from subendothelial tissues (high concentration), and (3) another endothelium-dependent relaxation possibly mediated by unidentified mediator(s) released from the endothelium (high concentration).

Analysis of Variance↗
PubMed1995

Endothelium-dependent relaxation to acetylcholine in bovine oviductal arteries: mediation by nitric oxide and changes in apamin-sensitive K+ conductance.

1. Mechanisms underlying the relaxant response to acetylcholine (ACh) were examined in bovine oviductal arteries (o.d. 300-500 microns and i.d. 150-300 microns) in vitro. Vascular rings were treated with indomethacin (10 microM) to prevent the effects of prostaglandins. 2. ACh elicited a concentration-related relaxation in ring segments precontracted with noradrenaline (NA), which was abolished by endothelium denudation. 3. The ACh-induced relaxation was attenuated but not abolished by NG-nitro-L-arginine (L-NOARG, 1 microM-1 mM), an inhibitor of nitric oxide (NO) formation. The inhibition caused by L-NOARG (10 microM) was reversed by addition of excess of L-arginine but not D-arginine (1 mM). 4. In high K+ (40-60 mM)-contracted rings, ACh was a much less effective vasodilator and its relaxant response was completely abolished by L-NOARG (100 microM). 5. In NA (10 microM)-contracted rings, ACh induced sustained and concentration-dependent increases in cyclic GMP, which were reduced below basal values by L-NOARG (100 microM), while potent relaxation persisted. Similar increases in cyclic GMP were evoked by ACh in high K+ (50 mM)-treated arteries and under these conditions, both cyclic GMP accumulation and relaxation were L-NOARG-sensitive. 6. S-nitroso-L-cysteine (NC), a proposed endogenous precursor of endothelial NO, also induced cyclic GMP accumulation in NA-contracted oviductal arteries. 7. Methylene blue (MB, 10 microM), a proposed inhibitor of soluble guanylate cyclase, inhibited both endothelium-dependent relaxation to ACh and endothelium-independent response to exogenous NO, whereas relaxation to NC remained unaffected. 8. The L-NOARG-resistant response to ACh was not affected by either ouabain (0.5 mM), glibenclamide (3 microM), tetraethylammonium (TEA, 1 mM) or charybdotoxin (50 nM), but was selectively blocked by apamin (0.1-1 microM). However, apamin did not inhibit either relaxation to ACh in high K(+)-contracted rings or endothelium-independent relaxation to either NO or NC. 9. Apamin and MB inhibited ACh-induced relaxation in an additive fashion, suggesting the involvement of two separate modulating mechanisms. 10. These results suggest that ACh relaxes bovine oviductal arteries by the release of two distinct endothelial factors: a NO-like substance derived from L-arginine, which induces cyclic GMP accumulation in smooth muscle, and another non-prostanoid factor acting by hyperpolarization mechanisms through alterations in apamin-sensitive K+ conductance.

Acetylcholine↗
PubMed1995

Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation.

1. Non-adrenergic, non-cholinergic (NANC) relaxations induced by electrical field stimulation (EFS) were studied in pig isolated urethra. The mechanism for relaxation was characterized by measurement of cyclic nucleotides and by study of involvement of different subsets of voltage-operated calcium channels (VOCCs). 2. EFS evoked frequency-dependent and tetrodotoxin-sensitive relaxations in the presence of propranolol (1 microM), phentolamine (1 microM) and scopolamine (1 microM). At low frequencies (< 12 Hz), relaxations were rapid, whereas at high (> 12 Hz) frequencies distinct biphasic relaxations were evoked. The latter consisted of a rapidly developing first phase followed by a more long-lasting second phase. 3. Treatment with the NO-synthesis inhibitor NG-nitro-L-arginine (L-NOARG; 0.3 mM) inhibited relaxations at low frequencies of stimulation. At high frequencies (> 12 Hz) only the first relaxation phase was affected. 4. Measurement of cyclic nucleotides in preparations subjected to continuous nerve-stimulation, revealed an increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels from 1.3 +/- 0.3 to 3.0 +/- 0.4 pmol mg-1 protein (P < 0.01). In the presence of L-NOARG, there was a significant decrease in cyclic GMP content to control. However, there was no increase in cyclic GMP content in response to EFS. Levels of cyclic AMP remained unchanged following EFS. 5. Treatment with the N-type VOCC-inhibitor, omega-conotoxin GVIA (0.1 microM) reduced NO-dependent relaxations, the effect being most pronounced at low frequencies (1-4 Hz) of stimulation. The NO independent second phase of the relaxation, studied in the presence of L-NOARG (0.3 mM) at 16-30 Hz, was however markedly reduced or abolished by omega-conotoxin GVIA. omega-Conotoxin MVIIC (1 microM)or omega-agatoxin IVA (30 nM) had no effect on electrically evoked relaxations.6. These results suggest that NANC-nerve derived urethral relaxation in the pig consists of two apparently independent components. One is mediated by NO and associated with an increase in cyclic GMP content. The other mediator is unknown and produces relaxations not associated with changes in levels of cyclic nucleotides. The release of this mediator seems to involve the N-type VOCC, since the relaxation was markedly reduced or abolished by omega-conotoxin GVIA.

Animals↗
PubMed1996

Effects of cytochrome P450 inhibitors on EDHF-mediated relaxation in the rat hepatic artery.

1. The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors N omega-nitro-L-arginine (L-NOARG) and indomethacin, respectively. 2. 17-Octadecynoic acid (17-ODYA, 50 microM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acids (EETs), had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 microM). Furthermore, 5,6-, 8,9-, 11,12- and 14,15- EETs failed to relax arteries without endothelium in the presence of L-NOARG plus indomethacin. 3. Proadifen and clotrimazole, which are inhibitors of several isoforms of cytochrome P450 mono-oxygenases, inhibited acetylcholine-induced relaxations in the presence of L-NOARG plus indomethacin. The concentration of acetylcholine which caused half-maximal relaxation was about 3 and 30 times higher in the presence than in the absence of clotrimazole (3 microM) and proadifen (10 microM), respectively. The maximal relaxation was reduced by proadifen but not by clotrimazole. Proadifen (10 microM) also inhibited acetylcholine-induced hyperpolarization in the presence of L-NOARG plus indomethacin. 4. In the presence of 30 mM K+ plus indomethacin (10 microM), acetylcholine induced an L-NOARG-sensitive relaxation mediated via release of NO. Under these conditions, proadifen (10 microM) shifted the acetylcholine concentration-response curve 6 fold to the right without affecting the maximal relaxation. Clotrimazole (3 microM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 microM). 5. The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 microM) and strongly attenuated by clotrimazole (3 microM). Proadifen (10 microM) also abolished the hyperpolarization induced by levcromakalim (1 microM). 6. The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

Acetylcholine↗
PubMed1996

The inhibitory effects of iberiotoxin and 4-aminopyridine on the relaxation induced by beta 1- and beta 2-adrenoceptor activation in rat aortic rings.

1. In rat aortic rings contracted by phenylephrine, the relaxation induced by isoprenaline was partly inhibited by iberiotoxin, (ibTX), tetraethylammonium, 4-aminopyridine (4-AP) and 1,9-dideoxyforskolin, but not by glibenclamide. 2. In the presence of 4-AP, 1,9-dideoxyforskolin failed to inhibit further the relaxant response to isoprenaline. Cromakalim-induced relaxation was inhibited by glibenclamide. 3. In the absence of endothelium, ibTX and 4-AP still inhibited the relaxant response to isoprenaline. 4. The inhibitory effect of ibTX on the relaxant response to isoprenaline was eliminated by pretreatment with ICI-118,551, a beta 2-adrenoceptor antagonist, but not by atenolol, a beta 1-adrenoceptor antagonist. 5. The inhibitory effect of 4-AP on the relaxation induced by isoprenaline was abolished by atenolol, but not by ICI-118,551. 6. The inhibitory effect of ibTX on the isoprenaline-induced relaxation in the presence of atenolol was completely abolished by MDL 12,330A, an adenylate cyclase inhibitor. Further, the inhibitory effect of 4-AP on the isoprenaline-induced relaxation in the presence of ICI-118,551 was markedly reduced by MDL 12,330A. 7. The relaxation induced by dibutyryl cyclic AMP was partly inhibited by 4-AP but not by ibTX. However, in the presence of KT5720, an inhibitor of cyclic AMP-dependent protein kinase, ibTX failed to inhibit further the relaxation induced by isoprenaline. 8. These results suggest that, in rat aortic rings, KCa channels are involved in the relaxation induced by isoprenaline. In addition, KCa channels are mainly activated by beta 2-adrenoceptors through cyclic AMP-dependent pathways. Further, the inhibition of isoprenaline-relaxation by 4-AP may be related to the activation of beta 1-adrenoceptors and cyclic AMP formation.

4-Aminopyridine↗
PubMed1996

Effect of thiol modulators and Cu/Zn superoxide dismutase inhibition on nitrergic relaxations in the rat gastric fundus.

1. The effects of superoxide anion generators before and after treatment with inhibitors of Cu/Zn superoxide dismutase (Cu/Zn SOD) and the effects of thiol-modulating agents were investigated on nitrergic relaxations to electrical stimulation of non-adrenergic non-cholinergic (NANC) nerves of the rat gastric fundus and on relaxations to authentic nitric oxide (NO) and nitroglycerin. 2. The superoxide anion generators, pyrogallol (30 microM) and duroquinone (30-60 microM), significantly inhibited the relaxations to NO (0.03-3 microM) but not nitrergic relaxations to NANC nerve stimulation (0.5-8 Hz) or those to ATP (10 microM). Treatment of the rat gastric fundus with the inhibitors of Cu/Zn SOD, diethyldithiocarbamate (DETC, 1 mM for 2 h) or triethylenetetramine (TETA, 100 microM for 2 h) had no effect on the relaxations to NANC nerve stimulation (1-8 Hz), NO (0.03-3 microM) or on those to ATP (10 microM). 3. After treatment of the rat gastric fundus with DETC (1 mM) but not after treatment with TETA (100 microM), pyrogallol (30 microM) and duroquinone (30-60 microM) significantly inhibited the nitrergic relaxations to electrical stimulation (0.5-8 Hz) and those to NO (0.03-3 microM). This inhibitory effect of pyrogallol and duroquinone was prevented by addition of exogenous SOD (250 units ml-1). Pyrogallol but not duroquinone also inhibited the NO-independent relaxations to ATP (10 microM). 4. The thiol modulators, buthionine sulphoximine (1 mM for 2 h) and ethacrynic acid (30 microM for 2 h), significantly inhibited the relaxations to nitroglycerin (0.03-3 microM) but had no effect on the nitrergic relaxations to electrical stimulation (0.5-8 Hz) or on those to NO (0.03-10 microM) and ATP (10 microM). The thiol modulators, sulphobromophthalein (100 microM for 2 h) and diamide (30-100 microM for 2 h) did not affect the relaxations to nitroglycerin, or those to NANC nerve stimulation and NO. 5. In summary, thiol modulators significantly inhibited the thiol-dependent relaxations to nitroglycerin but not those to NANC nerve stimulation or NO. Relaxations to nitrergic stimulation were decreased by superoxide anion generators only after inhibition of Cu/Zn SOD. These results suggest that the nitrergic NANC neurotransmitter in the rat gastric fundus is not a nitrosothiol but more likely free NO, which is protected from breakdown by tissue SOD.

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PubMed1998

Lower esophageal sphincter relaxation characteristics using a sleeve sensor in clinical manometry.

OBJECTIVE: We undertook this study to determine the characteristics of swallow-induced lower esophageal sphincter (LES) relaxation in the setting of clinical manometry using a standardized methodology. METHODS: We reviewed 170 manometric recordings performed using a perfused manometric assembly with a sleeve sensor and a computer polygraph. Patients were categorized as patient controls, gastroesophageal reflux disease (GERD), diffuse esophageal spasm (DES), or achalasia. Tracing were semiautomatically analyzed for basal LES pressure, LES pressure during deglutitive relaxation (relaxation LES pressure), duration of LES relaxation, timing of LES relaxation, and the success rate of primary peristalsis. RESULTS: Forty-six patient controls, 93 with GERD, five with DES, and 26 with achalasia were identified. GERD and achalasia patients had lower or higher basal LES pressures than patient controls, respectively. Compared with patient controls, achalasia patients had higher relaxation LES pressures, lower percent LES relaxation, and shorter durations of LES relaxation. The best single measure for distinguishing achalasia was the relaxation LES pressure; using the 95th percentile value of patient controls (12 mm Hg) as the upper limit of normal, its sensitivity and positive predictive value for the diagnosis of achalasia were 92% and 88%, respectively. Coupled with the finding of aperistalsis, a relaxation LES pressure > or = 10 mm Hg achieved 100% sensitivity and positive predictive value among these patients. CONCLUSIONS: Sleeve sensor recording is a practical method for clinical manometry that reliably records LES relaxation characteristics and is amenable to both a standardized manometry protocol and a semiautomated analysis routine. Relaxation LES pressure has a high diagnostic value for achalasia.

Deglutition↗
PubMed1996

Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries.

1. The effects of the sodium salt of the weak acid lactate on tension and intracellular pH (pH1) were studied in rat mesenteric small arteries mounted on a wire myograph. Sodium lactate was substituted iso-osmotically for sodium chloride. 2. At a concentration of 50 mM, both L- and D-stereoisomers of lactate markedly relaxed arteries preconstricted with noradrenaline (NA) within 10 min. The concentration-response relationship for L-lactate showed that the NA contracture was relaxed by 50% at approximately 26 mM. L-Lactate did not, however, relax arteries preconstricted with high-K+(45 mM) solution. 3. L-Lactate did not alter extracellular pH (pHo) but caused a small but significant decrease in pH1, measured using the pH-sensitive fluorochrome, 2',7'-bis(carboxyethyl)-5-(6)-carboxyfluorescein (BCECF). Relaxation to L-lactate was unaffected when this change in pHi was offset by the simultaneous addition of NH4Cl to the solution. 4. Sodium pyruvate (50 mM) caused a significant intracellular acidosis but did not relax arteries preconstricted with NA. 5. L-Lactate-induced relaxations were unaffected by removal of the endothelium or when the synthesis of nitric oxide (NO) was inhibited by 10(-4) M N omega-nitro-L-arginine methyl ester (L-NAME). 6. The potassium channel blockers glibenclamide (10 microM), 4-aminopyridine (3 mM) and tetraethylammonium chloride (10 mM) did not affect L-lactate-induced relaxation in arteries preconstricted with NA. Inhibition of guanylate cyclase with Methylene Blue, or cyclooxgenase with indomethacin, also did not affect relaxation to L-lactate. 7. The Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), an analogue of cAMP which inhibits competitively stimulation of protein kinase A, reduced significantly L-lactate-induced relaxation at a concentration of 25 microM. Rp-cAMPS also significantly reduced forskolin-induced relaxation of the NA contracture. 8. It is concluded that L-lactate-induced relaxation in this vascular bed is pHi-1 endothelium-, and nitric oxide-independent. It is not mediated by inhibition of voltage-gated Ca2+ channels, opening of K+ channels, prostacylin or cyclic GMP. cAMP may however play a role in L-lactate-induced relaxation.

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