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PubMed2000

Nitric oxide, prostanoid and non-NO, non-prostanoid involvement in acetylcholine relaxation of isolated human small arteries.

The main purpose of the study was to clarify to which extent nitric oxide (NO) contributes to acetylcholine (ACh) induced relaxation of human subcutaneous small arteries. Arterial segments were mounted in myographs for recording of isometric tension, NO concentration and smooth muscle membrane potential. In noradrenaline-contracted arteries, ACh induced endothelium-dependent relaxations. The NO synthase inhibitor, N(G)-nitro-L-arginine (L-NOARG) had a small significant effect on the concentration-response curves for ACh, and in the presence of L-NOARG, indomethacin only caused a small additional rightward shift in the ACh relaxation. The NO scavenger, oxyhaemoglobin attenuated relaxations for ACh and for the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Inhibition of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), and inhibition of protein kinase G with beta-phenyl-1, N2-etheno-8-bromoguanosine- 3', 5'- cyclic monophosphorothioate, Rp-isomer, slightly attenuated ACh relaxation, but abolished SNAP induced relaxation. ACh induced relaxation without increases in the free NO concentration. In contrast, for equivalent relaxation, SNAP increased the NO concentration 32+/-8 nM. ACh hyperpolarized the arterial smooth muscle cells with 11.4+/-1.3 mV and 10.5+/-1.3 mV in the absence and presence of L-NOARG, respectively. SNAP only elicited a hyperpolarization of 1.6+/-0.9 mV. In the presence of indomethacin and L-NOARG, ACh relaxation was almost unaffected by lipoxygenase inhibition with nordihydroguaiaretic acid, or cytochrome P450 inhibition with 17-octadecynoic acid or econazole. ACh relaxation was strongly reduced by the combination of charybdotoxin and apamin, but small increments in the extracellular potassium concentration induced no relaxations. The study demonstrates that the NO/L-arginine pathway is present in human subcutaneous small arteries and to a limited extent is involved in ACh induced relaxation. The study also suggests a small contribution of arachidonic acid metabolites. However, ACh relaxation is mainly dependent on a non-NO, non-prostanoid endothelium dependent hyperpolarization. British Journal of Pharmacology (2000) 129, 184 - 192

Acetylcholine↗
PubMed2001

Blockade of chloride channels reveals relaxations of rat small mesenteric arteries to raised potassium.

1. Raised extracellular K(+) relaxes some arteries, and has been proposed as Endothelium-Derived Hyperpolarizing Factor (EDHF). However, relaxation of rat small mesenteric arteries to K(+) is highly variable. We have investigated the mechanism of K(+)-induced dilatation and relaxation of pressurized arteries and arteries mounted for measurement of isometric force. 2. Raising [K(+)](o) from 5.88 - 10.58 mM did not dilate or relax pressurized or isometric arteries. Relaxation to raised [K(+)](o) was revealed in the presence of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB); this effect of NPPB was concentration-dependent (IC(50): 1.16 microM). 3. Relaxations to raised [K(+)](o) in the presence of NPPB, were abolished by 30 microM Ba(2+) or endothelial-denudation. Acetycholine (10 microM) relaxed endothelium-intact arteries in presence of raised [K(+)](o) NPPB and Ba(2+). 4. Relaxations to raised [K(+)](o) were revealed in hyperosmotic superfusate (+60 mM sucrose). These relaxations were abolished by 30 microM Ba(2+). In the presence of raised [K(+)](o), 60 mM sucrose and 30 microM Ba(2+), 10 microM acetycholine still relaxed all arteries. 5. Fifty microM 18 alpha-glycyrrhetinic acid (18 alpha-GA), a gap junction inhibitor, depressed relaxations to both 10 microM acetylcholine and raised [K(+)](o), in the presence of 10 microM NPPB. 6. In summary, blockade of a volume-sensitive Cl(-) conductance in small rat mesenteric arteries, using NPPB or hyperosmotic superfusion, reveals a endothelium-dependent, Ba(2+) sensitive dilatation or relaxation of rat mesenteric arteries to raised [K(+)](o). We conclude that inwardly rectifying potassium channels on the endothelium underlie relaxations to raised [K(+)](o) in rat small mesenteric arteries.

Acetylcholine↗
PubMedDate not supplied

Histamine receptor type coupled to nitric oxide-induced relaxation of guinea-pig nasal mucosa.

1 The aim of this study was to characterize the histamine receptor type mediating relaxation of the vascular bed of the nasal mucosa from the guinea-pig, and to determine the role of cyclo-oxygenase products and nitric oxide in this relaxant response to histamine. These studies were performed in isolated nasal mucosae examined in vitro to obtain potencies of histamine receptor-type selective agonists in causing vasorelaxation and to determine affinities of histamine receptor antagonists for inhibiting histamine-induced relaxation. 2 After contraction of nasal mucosae with noradrenaline, histamine caused a maximal relaxation response that was 75 +/- 6% of the contraction caused by noradrenaline with a mean EC50 value of 4.3 +/- 0.5 microM. Neither dimaprit (H2-receptor selective) nor R-alpha-methylhistamine (H3-receptor selective) caused significant relaxation of nasal mucosae. In contrast, betahistine (H1-receptor selective) caused an 81 +/- 7% relaxation of noradrenaline-induced tone with an EC50 value of 15 +/- 1 microM. 3 pA2 experiments were performed to obtain KB values of chlorpheniramine (H1-receptor selective) and diphenhydramine (H1-receptor selective) for blocking histamine-stimulated relaxation of nasal mucosae. KB values for chlorpheniramine (0.87 nM) and diphenhydramine (7.4 nM) were consistent with their interaction at the H1-receptor type. Additionally, neither 10 microM cimetidine (H2-receptor selective) nor 1 microM thioperamide (H3-receptor selective) had any effect on the relaxation curve for histamine. 4 In the presence of 10 microM indomethacin (cyclo-oxygenase inhibitor), histamine caused a maximal relaxation response of 73 +/- 5% of the noradrenaline-induced tone with an EC50 value of 2.9 +/- 0.2 microM, which was not different from control values (EC50 = 5.0 +/- 0.4 microM; maximal relaxation = 71 +/- 6%). In contrast, 200 microM NG-nitro-L-arginine (nitric oxide synthase inhibitor) completely inhibited histamine-induced relaxation of nasal mucosae. 5 In conclusion, data from the present study suggest only the H1-receptor type mediates relaxation of nasal mucosal blood vessels to histamine, and histamine-induced relaxation of nasal mucosae is entirely dependent on nitric oxide production.

Adrenergic alpha-Agonists↗
PubMed2001

Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats.

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.

Adrenergic beta-Antagonists↗
PubMed1998

Mechanisms of ischemia-induced cavernosal smooth muscle relaxation impairment in a rabbit model of vasculogenic erectile dysfunction.

PURPOSE: To determine the effects of hypercholesterolemia and atherosclerosis-induced chronic cavernosal arterial insufficiency on cavernosal smooth muscle tone, nitric oxide synthase (NOS) activity and cavernosal tissue synthesis of constrictor eicosanoids. To study whether inhibition of the cyclooxygenase pathway by indomethacin and tissue treatment with nitric oxide (NO) precursor L-arginine improve hypercholesterolemia and ischemia-induced impaired endothelium-dependent and neurogenic relaxation of cavernosal tissue. MATERIALS AND METHODS: New Zealand White rabbits were divided into control (n = 10, fed a regular diet), hypercholesterolemia (Hch, n = 13, fed a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 14) groups. The CCI group underwent balloon deendothelialization of iliac arteries and received a diet containing 0.5% cholesterol. After 16 weeks, we examined the effects of Hch and balloon de-endothelialization induced arterial occlusive disease on iliac arterial blood flow, reactivity of cavernosal tissue, cavernosal NOS activity and cavernosal tissue synthesis of constrictor eicosanoids. RESULTS: Histology revealed significant atherosclerotic arterial occlusive disease in the CCI group. Iliac artery blood flow in the CCI group was significantly reduced compared with the control and Hch groups. In the Hch and CCI groups, endothelium-dependent relaxation of cavernosal tissue to acetylcholine was significantly reduced compared with the control group. Electrical field stimulation-induced neurogenic relaxation and cavernosal NOS activity were significantly reduced in the CCI group but not in the Hch group. The basal release of cavernosal constrictor eicosanoids, prostaglandin F2alpha (PGF2alpha) and thromboxane A2 (TXA2) was significantly increased in the CCI group. Indomethacin increased endothelium-dependent relaxation in all groups and neurogenic relaxation in the CCI group, but failed to normalize the differences in relaxation between treated and control groups. In the presence of indomethacin, L-arginine improved endothelium-dependent relaxation of cavernosal tissue in the Hch group but did not normalize endothelium-dependent or neurogenic relaxations in the CCI group. Relaxation to NO donor sodium nitroprusside and papaverine was similar in cavernosal tissue from all groups. CONCLUSIONS: Impairment of endothelium-dependent relaxation by Hch occurs secondary to disruption of the NO formation in cavernosal endothelium. Improvement of endothelium-dependent relaxation by L-arginine may suggest lack of availability of L-arginine in cavernosal tissue from the Hch animals. Impairment of endothelium-dependent and neurogenic relaxation by CCI occurs secondary to disruption of the NO formation due to an alteration in the expression or activity of NOS and increased output of constrictor eicosanoids in cavernosal tissue. These studies show that Hch and atherosclerosis-induced chronic cavernosal arterial insufficiency, beyond decreasing cavernosal perfusion pressure, also adversely affect smooth muscle relaxation mechanisms in cavernosal tissue.

Animals↗
PubMed1992

Endothelium-dependent and -independent relaxation by dopamine in the rabbit pulmonary artery.

1. The relaxing response of dopamine (DA) was studied in the rabbit pulmonary artery. DA caused concentration-related relaxation in helically cut strips of the artery contracted with prostaglandin F2 alpha in the presence of prazosin. 2. The DA-induced relaxation in endothelium-denuded strips was reduced to about 40% compared with that in endothelium-intact strips. 3. Methylene blue and haemoglobin, inhibitors of endothelium-dependent relaxation, reduced the DA-induced relaxations in endothelium-intact strips to the level of endothelium-denuded strips. These results indicate that the DA-induced relaxation is partially mediated or modified by the release of endothelium-derived relaxing factor (EDRF). 4. Apomorphine, as a DA agonist, caused concentration-dependent relaxation in endothelium-intact strips. Bromocriptine, a DA2 agonist, produced only a little relaxation at higher concentration. 5. In endothelium-intact strips, haloperidol, a DA antagonist, and the DA1 antagonists, fluphenazine and SCH 23390 inhibited DA-induced relaxations. On the other hand spiperone and domperidone, DA2 antagonists, were inactive. 6. In endothelium-denuded strips, fluphenazine and SCH 23390 inhibited DA-induced relaxations, but domperidone was inactive. 7. These results indicate that the DA-induced relaxation is mediated by DA receptors, and that DA1 receptors are involved in both endothelium-dependent and -independent relaxation in the rabbit pulmonary artery.

Animals↗
PubMed1998

Role of endothelium and K+ channels in dobutamine-induced relaxation in rat mesenteric artery.

1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a beta 1-adrenoceptor agonist, in rat isolated mesenteric arteries, the effects of inhibitors of nitric oxide (NO) activity, blockers of K+ channels and high extracellular K+ were studied by measuring isometric tension in both endothelium-intact and -denuded arteries. 2. Dobutamine inhibited the phenylephrine (PE)-induced sustained tension with a pEC50 of 7.40 +/- 0.08 in endothelium-intact arteries. Removal of functional endothelium attenuated the effect of dobutamine. The relaxation induced by dobutamine was inhibited by the beta 1-adrenoceptor antagonist CGP 20712A (3 mumol/L) but not by the beta 2-adrenoceptor antagonist ICI 118,551 (3 mumol/L) in endothelium-denuded arteries. 3. Pretreatment with NG-nitro-L-arginine (L-NNA; 100 mumol/L) or methylene blue (3 mumol/L) induced a similar degree of inhibition of the dobutamine-induced relaxation in endothelium-intact arteries, while NG-nitro-D-arginine (100 mumol/L) and indomethacin (10 mumol/L) had no effect. In contrast, pretreatment with L-NNA (100 mumol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3 mumol/L) inhibited the relaxant response to SNP. 4. Charybdotoxin (CTX; 100 nmol/L), iberiotoxin (IBX; 100 nmol/L) and tetraethylammonium ions (TEA+; 3 mmol/L) significantly reduced the dobutamine-induced relaxation. Tetrapentylammonium ions (TPA+; 5 mumol/L) markedly inhibited the relaxant effect of dobutamine. The pEC50 values for control and in the presence of TPA+ in endothelium-intact arteries were 7.35 +/- 0.11 and 6.14 +/- 0.17, respectively, and 6.35 +/- 0.09 and 5.87 +/- 0.17 for control and in the presence of TPA+ in endothelium-denuded arteries, respectively. In contrast, glibenclamide (3 mumol/L) was ineffective. At 5 mumol/L, TPA+ also inhibited the relaxation induced by forskolin. 5. The maximal relaxation of PE-contracted arteries induced by 3 mumol/L dobutamine was completely abolished in the 60 mmol/L K(+)-contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 mumol/L induced inhibition of the high-K+ response. 6. The present results indicate that endothelium, probably NO but not prostacyclin, was involved in the dobutamine-induced relaxation in rat mesenteric arteries. Activation of CTX-, IBX- and TPA(+)-sensitive K+ channels contributed towards the observed relaxation. Loss of the ability to relax the 60 mmol/L K(+)-contracted arteries suggests that endothelium-derived vasoactive factors affected by concentrations of dobutamine less than 3 mumol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium-independent relaxant effect.

Adrenergic beta-Agonists↗
PubMed1999

Influence of fluoxetine and litoxetine on 5-HT4 receptor-mediated relaxation in the rat isolated oesophagus.

The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant antagonism of litoxetine response (P = 0.037: ANOVA for continuous-by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 microM) increased the relaxant effects of 5-HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5-HT, without changing its potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4 receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that blockade of 5-HT reuptake can participate in the action of litoxetine, since fluoxetine, a 5-HT reuptake inhibitor equipotent to litoxetine, was ineffective in the same range of concentrations. The antimuscarinic activity of litoxetine, previously demonstrated in the isolated guinea-pig intestine, played a role at concentrations greater than 1 microM. The 5-HT-releasing action of litoxetine could account for the potentation by litoxetine of 5-HT-induced relaxation in tissues from untreated rats, which was reversed by pCPA treatment. Under these conditions, litoxetine depressed relaxations to high 5-HT concentrations only. In tissues from untreated rats, fluoxetine slightly but unsurmountably antagonized 5-HT-induced relaxations, thus confirming previous observations in the guinea-pig small intestine.

Animals↗
PubMed1990

Atropine-resistant relaxation induced by high K+ in iris dilator muscle of the rat and pig.

1. The effects of high K+ ion concentration on the isometric tension in dilator muscle strips of the rat and porcine iris were examined. A high K+ solution, prepared by the replacement of Na+ in the medium with equimolar K+, was applied in the presence of 1 microM phentolamine, 1 microM propranolol and 1 or 10 microM atropine. High K+ (greater than 20 mM) induced a biphasic response; an initial phasic contraction followed by relaxation rather than tonic contraction. 2. An additional application of a Ca2+ antagonist, 1 microM nifedipine or nicardipine, almost completely blocked the K(+)-induced initial contraction and enhanced the following relaxation. The effect of K+ under these conditions was concentration-dependent in the range 20 to 80 mM. The maximum amplitude of the atropine-resistant relaxation induced by high K+ corresponds to 50-75% of that produced by acetylcholine in the absence of atropine. A similar K(+)-induced relaxation was observed in the porcine iris dilator. 3. The atropine-resistant relaxation in the rat iris dilator was not affected by pretreatment with 10 microM ouabain. The relaxation induced by 40 or 80 mM K+ in the porcine dilator was slightly enhanced or not affected, respectively, in the presence of 1 microM ouabain. Application of 10 microM ouabain per se induced relaxation in the porcine iris dilator. 4. The low Na+ ion concentration present in high K+ solutions was not responsible for the K(+)-induced relaxation since the complete replacement of Na in the medium with Tris did not affect significantly the relaxation produced by high K(+)-containing solutions. 5. Neither 1 microM tetrodotoxin, 10 microM indomethacin, 10 JM nordihydroguaiaretic acid nor hypoxic conditions affected the high K+-induced relaxation. 6. The inherent tone of the rat iris dilator was not affected by either 8-bromo cyclic GMP, dibutyryl cyclic GMP (0.1-0.3 mM) or nitroprusside (1-100 microM). 7. These results may suggest that the atropine-resistant relaxation induced by high K+ is not due to either activation of the Na-K pump or release of a relaxing factor produced by oxidative metabolism. Although the relaxation mechanism has not been elucidated, it is probably not mediated by an increase in cellular cyclic GMP levels.

Animals↗
PubMed1996

VIP-induced relaxation of guinea-pig intestinal smooth muscle cells: sequential involvement of cyclic AMP and nitric oxide.

1. A possible interaction between cyclic AMP and nitric oxide (NO) in mediating the relaxant effect of vasoactive intestinal polypeptide (VIP) on intestinal smooth muscle cells has been investigated. The effects of the inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME), have been studied on VIP-, forskolin-, and 8 bromo-cyclic AMP- induced relaxation of cells, dispersed by enzymatic digestion of muscle strips from the circular layer of guinea-pig ileum. 2. VIP alone did not modify the length of isolated muscle cells. By contrast, when the cells were contracted by cholecystokinin octapeptide, CCK8 (10 nM), VIP inhibited this contraction, inducing a concentration-dependent relaxation of the cells. Maximal relaxation was induced by 1 microM VIP (EC50 = 408.2 +/- 16.7 pM). 3. N-ethylmaleimide, inhibitors of adenylate cyclase or somatostatin, abolished the relaxing effect of VIP. (R)-p-cAMPs, an antagonist of cyclic AMP on protein kinase A also inhibited the VIP-induced relaxation by 92.1 +/- 6.3%. Inhibitors of nitric oxide synthase (NOS), L-NAME and L-NMMA, partially inhibited VIP-induced relaxation. The effect of L-NAME was reversed by L-arginine but not by D-arginine. 4. (R)-p-cAMPS and L-NAME also inhibited the cell relaxation induced either by forskolin which directly stimulates adenylate cyclase activity or 8-bromo-cyclic AMP, an analogue of cyclic AMP. 5. When cells were incubated for 30 min with dexamethasone 10 microM, a glucocorticoid known to decrease the synthesis of iNOS, the relaxing effect of a maximal concentration of VIP was decreased by 52 +/- 4% and L-NMMA had no further effect on this residual VIP-induced relaxation. Milrinone, a phosphodiesterase type III inhibitor, potentiated the relaxant effect of VIP. 6. These data demonstrate that the intracellular pathway mediating the relaxant effect of VIP in intestinal smooth muscle cells includes the sequential activation of adenylate cyclase, protein kinase A, activation of NOS and finally production of NO and cyclic GMP. NO could in turn regulate the cyclic AMP-dependent pathway of cell relaxation.

Animals↗
PubMed1996

Analysis of relaxation and repolarization mechanisms of nicorandil in rat mesenteric artery.

1. The mechanisms by which nicorandil causes relaxation of rat isolated small mesenteric arteries mounted on a Mulvany myograph was investigated by use of a combination of putatively mechanism-specific antagonists. 2. In arteries precontracted by the thromboxane-mimetic, U46619, the EC50 for cromakalim and levcromakalim-induced relaxation curves were raised by 36 and 17 fold by glibenclamide (3 microM) while the EC50 for nicorandil-induced relaxation was unaffected by either glibenclamide or methylene blue (10 microM). A combination of these antagonists raised the EC50 for nicorandil by 8 fold. 3. In U46619-contracted arteries, nifedipine (100 nM) did not affect the cromakalim relaxation curve but it raised the EC50 for nicorandil by 5 fold. The combination of methylene blue, glibenclamide and nifedipine further inhibited the maximum relaxation to nicorandil. 4. In separate experiments, membrane potential (Em) and force responses were measured simultaneously. In arteries depolarized and contracted by U46619 both nicorandil and cromakalim repolarized (delta Em, 35 mV) and relaxed (100%) the vessels. Glibenclamide (3 microM) did not alter the relaxation-concentration curve to nicorandil but reduced the maximum repolarization to delta 10.8 mV. In contrast to Em and relaxation-response curves to cromakalim were shifted to the right by glibenclamide by 30-100 fold. 5. In unstimulated arteries, nicorandil (but not cromakalim) -induced hyperpolarization was significantly antagonized by methylene blue (10 microM) (6.6 fold rightward shift) or nifedipine (100 nM) (2.6 fold). In depolarized arteries (U46619), nifedipine but not methylene blue inhibited the nicorandil-induced hyperpolarization. 6. In arteries precontracted to 50% tissue maximum by either KCl or U46619, nifedipine (100 nM) relaxed the artery but failed to repolarize the Em. Presumably voltage-operated calcium channels (VOCC) were blocked preventing contraction but the artery remained depolarized, presumably through non VOCC mechanisms. 7. These data suggest that nicorandil may relax small arteries through 3 parallel pathways, (i) NO-donor mediated stimulation of guanylate cyclase and increase in cyclic GMP, (ii) K+ATP channel opening, and (iii) nifedipine-sensitive VOCC inhibition. Em data suggest that nicorandil-induced repolarization is caused principally through opening K+ATP channels. Blockade of this hyperpolarization by glibenclamide is not sufficient to alter the relaxation, indicating dissociation of nicorandil-induced changes in membrane potential and relaxation. 8. These results highlight the 'chameleon' actions of nicorandil where there is no apparent association of Em repolarization with relaxation, in contrast to the parallel responses for cromakalim.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Role of membrane potential in endothelium-dependent relaxation of guinea-pig coronary arterial smooth muscle.

1. Membrane potential and tension were measured simultaneously in ring segments of main coronary artery of guinea-pigs. The synthetic thromboxane A2 analogue U46619 depolarized the tissues from -58 +/- 2 to -40 +/- 1 mV and increased tension by 12 +/- 1 mN mm-1. Nitric oxide (NO) and Iloprost, the stable analogue of prostacyclin, evoked hyperpolarization and relaxation. 2. The concentration of NO required to evoke half-maximal hyperpolarization (EC50 of 2 x 10(-5) M) was 40-fold higher than that which was required to induce relaxation (EC50 of 5 x 10(-7) M). The EC50 for Iloprost-induced hyperpolarization (3 x 10(-8) M) was similar to that for relaxation (4 x 10(-8) M). 3. Glibenclamide (10(-6) M) abolished the hyperpolarization in response to both NO and Iloprost but was without effect on the amplitudes of the relaxations over the complete concentration-response curves. 4. Acetylcholine evoked concentration-dependent hyperpolarization and relaxation in the presence of N omega-nitro-L-arginine methyl ester (NAME; 10(-5) M) and indomethacin (10(-6) M), and these responses were attributed to endothelium-derived hyperpolarizing factor (EDHF). The hyperpolarization produced by EDHF always preceded relaxation, and relaxation never occurred at concentrations of acetylcholine that were insufficient to evoke hyperpolarization. 5. The concentration-hyperpolarization and concentration-relaxation curves in response to acetylcholine were not affected by glibenclamide or barium (1-3 mM) but were shifted to the right 4- and 5-fold, respectively, by 1 mM tetraethylammonium. The hyperpolarization and relaxation evoked by acetylcholine were also reduced in a parallel manner when the potassium concentration in the superfusate was increased. 6. Hyperpolarizing current steps, applied to spiral strips of coronary artery denuded of endothelium and depolarized and constricted with U46619, caused relaxation. The relationship between hyperpolarization and relaxation evoked electronically was similar to that which was due to EDHF in intact tissues stimulated with acetylcholine. 7. It is concluded that the ability of NO or Iloprost to relax guinea-pig coronary artery does not depend upon hyperpolarization of the smooth muscle. In contrast, hyperpolarization is likely to play a major, if not the only, role in the relaxation in response to EDHF in this tissue.

Acetylcholine↗
PubMed1985

Mechanics of caudal artery relaxation in control and hypertensive rats.

Alterations of smooth muscle function can just as easily stem from mechanical alterations in its ability to relax as from alteration in contraction. Since a failure of arterial smooth muscle to relax may contribute to the development of hypertension, we felt it necessary to study the relaxation process in greater depth. The effect of load on the time course of relaxation of rat caudal artery smooth muscle was analyzed either by comparing afterloaded contractions against various loads or by imposing abrupt alterations in load. Unlike mammalian striated muscles in which relaxation was reported sensitive to loading conditions, relaxation in the smooth muscle of the rat caudal artery (n = 17) was found to be largely independent of loading conditions. This type of relaxation has been termed "inactivation-dependent" relaxation; it is typical of muscle tissue in which the calcium sequestering apparatus is poorly developed. Our results suggest that calcium resequestration, or some biochemical process downstream to it, is the rate-limiting step during relaxation in arterial smooth muscle and that this is not qualitatively different for hypertensive arterial smooth muscle. These analytic techniques were used in the study of relaxation of hypertensive vessels. Quantitative analysis of the relaxation curves showed that both isometric and isotonic relaxation time was prolonged in hypertensive arterial smooth muscle. Prolonged isotonic relaxation indicates that hypertensive arteries remain narrowed for prolonged periods compared with normotensive vessels. Such narrowed vessels may be a factor in the increased total peripheral resistance seen in genetic hypertension.

Animals↗
PubMed2000

Complete lower esophageal sphincter relaxation observed in some achalasia patients is functionally inadequate.

Generally accepted manometric criteria for the diagnosis of achalasia are absent peristalsis and incomplete lower esophageal sphincter (LES) relaxation. However, in some patients with otherwise typical features of achalasia, esophageal manometry shows complete LES relaxation during swallowing. To establish whether such apparently complete LES relaxations are functionally adequate, we quantified changes in resistance to flow at the esophagogastric junction (EGJ) during wet swallowing. We studied seven achalasia patients with manometrically complete (>80%) LES relaxation, eight achalasia patients with incomplete (<40%) LES relaxation, and eight healthy volunteers. Complete LES relaxation on standard manometry (open-tip catheters) was confirmed in five of the seven achalasia patients by a Dentsleeve. Changes in EGJ resistance to flow were quantified using a pneumatic resistometer. Manometrically, the relaxation time span was significantly longer in patients with complete LES relaxation than in those with incomplete relaxation (7. 3 +/- 0.5 vs. 4.4 +/- 0.7 s; P < 0.05). The fall in EGJ resistance from basal values during swallowing was markedly reduced in both achalasia groups (21 +/- 8% in those with manometrically complete relaxation and 4 +/- 2% in those with incomplete relaxation) by comparison with healthy individuals, in whom resistance fell by 90 +/- 3% (P < 0.05 vs. both achalasia groups). The duration of EGJ resistance drop was also much shorter in achalasia with (0.7 +/- 0.2 s) and without (0.2 +/- 0.1 s) complete LES relaxation compared with healthy control values (6.6 +/- 1.2 s). Our results reveal that the apparently complete LES relaxation observed manometrically in some patients with achalasia is functionally inadequate since it is not associated with the normal profound fall in EGJ resistance to flow.

Adult↗
PubMed1997

Involvement of capsaicin-sensitive sensory nerves in gastric adaptive relaxation in isolated guinea-pig stomachs.

We investigated the role of capsaicin-sensitive sensory nerves (CPSNs), nitric oxide (NO), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) in gastric adaptive and receptive relaxation in isolated guineapig stomachs. Changes in intragastric volume and pressure were recorded simultaneously in isolated stomachs in baths containing atropine and guanethidine. Adaptive relaxation was induced by luminal distention, and receptive relaxation was induced by electrical vagal stimulation. We found that desensitization to capsaicin inhibited adaptive relaxation, but not vagally induced relaxation. Extraluminal capsaicin induced gastric relaxation. Adaptive relaxation and capsaicin-induced relaxation were reduced by both tetrodotoxin and NG-nitro-L-arginine (LNNA), but not by hexamethonium. The effect of LNNA was partially reversed by co-incubation with L-arginine. Neither CGRP(8-37) nor VIP(10-28) inhibited all responses of adaptive relaxation, vagally induced and capsaicin-induced relaxation. These findings suggest that activation of CPSNs may be involved in adaptive relaxation, and that NO, but not CGRP or VIP, may be involved in the mechanisms of adaptive relaxation and receptive relaxation.

Adaptation, Physiological↗
PubMed1986

Experimental induction of isolated lower esophageal sphincter relaxation in anesthetized opossums.

Isolated lower esophageal sphincter (LES) relaxation, defined as a transient sphincteric relaxation unaccompanied by esophageal peristalsis, has been shown to precede most episodes of gastroesophageal reflux in humans. We studied the genesis of isolated LES relaxation in anesthetized opossums by observing the response of four components of the deglutition reflex (mylohyoid electrical activity, pharyngeal contraction, esophageal peristalsis, and LES relaxation) to pharyngeal tactile stimulation, electrical stimulation of superior laryngeal nerve (SLN) afferents or cervical vagal efferents, and to balloon distention of the esophageal body. A single pharyngeal stroking evoked isolated LES relaxation in 56% of 160 instances. The proportion of isolated relaxations in response to SLN electrical stimulation varied inversely with the stimulus frequency, occurring in 64% of the responses at 5 Hz and 4% of the responses at 30 Hz. A full four-component deglutition sequence was most likely to occur at the higher frequencies of SLN electrical stimulation. Esophageal balloon distention elicited isolated LES relaxations or no response at low distending volumes, whereas at higher volumes LES relaxation and esophageal contraction predominated. Isolated LES relaxation had significantly less magnitude than relaxations accompanied by esophageal contractions. Bilateral cervical vagotomy abolished all LES and esophageal body responses induced by pharyngeal stroking and SLN stimulation, and rendered the esophageal body and LES less responsive to small volumes of distention. Vagal efferent stimulation produced isolated LES relaxation at lower frequency stimulation and LES relaxation with esophageal contractions at higher frequency stimulation. These studies show that isolated LES relaxation represents incomplete expression of either the deglutitive reflex or the peripheral reflex mediating secondary peristalsis.

Anesthesia↗
PubMed2004

Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) are major factors in gastritis and peptic ulcer However, the role of NSAIDs and H. pylori infection in dyspepsia remains unclear. Gastric adaptive relaxation may be related to the pathogenesis of functional dyspepsia because the response is often disturbed in dyspeptic patients. In this study, we investigated the effects of indomethacin or H. pylori water extracts on gastric adaptive relaxation. This experiment was performed using the modified method of Desai et al. Isolated guinea-pig stomach in an organ bath was monitored for intragastric pressure and volume. Adaptive relaxation was induced by gastric luminal distention. The effects of indomethacin and H. pylori on gastric relaxation were tested in this system. Indomethacin (> 1 x 10(-5) M) significantly inhibited adaptive relaxation. Indomethacin (> 3 x 10(-6) M) induced gastric relaxation in a dose-dependent fashion. However, aspirin at a concentration sufficient for cyclooxygenase (COX)-1 inhibition did not induce gastric relaxation. Preincubation with N-nitro-L-arginine methyl ester, a nitric oxide (NO)-synthase inhibitor, inhibited indomethacin-induced gastric relaxation. Adaptive relaxation was not affected by H. pylori water extracts. In conclusion, indomethacin inhibited adaptive relaxation via prior gastric relaxation. NO production, but not COX-1 inhibition, may be involved in this effect of indomethacin. H. pylori water extracts may not have direct effects on adaptive relaxation. Inhibition of adaptive relaxation may be one of the major mechanisms underlying NSAID-induced dyspepsia.

Animals↗
PubMed1981

Relaxation of vascular smooth muscle by isoproterenol, dibutyryl-cyclic AMP and theophylline.

There is evidence that the relaxation of vascular smooth muscle produced by isoproterenol or cyclic AMP is mediated by membrane hyperpolarization. The current study investigates the possibility that this hyperpolarization, and hence the relaxation, may be produced by activation of the electrogenic sodium pump. Rat and pig tail artery strips were placed in a 1.0-mM potassium solution for 15 min. This procedure results in a decrease in the activity of the sodium pump. The strips were then made to contract in response to norepinephrine. Two minutes later, the concentration of potassium was increased to 6.0 mM and a relaxation occurred. The amplitude of this relaxation reflects the activity of the sodium pump. Either isoproterenol or dibutyryl-cyclic AMP causes an enhancement (time or degree) of potassium-induced relaxation. Theophylline potentiated potassium-induced relaxation in pig arteries but not in rat arteries. The relaxant action of isoproterenol on 1.0 mM barium contractures of rat arteries was inhibited by treatment with ouabain or with potassium-free solution. Ouabain inhibited the relaxant action of isoproterenol in pig arteries contracted with depolarizing potassium solution but not in rat tail arteries. Dibutyryl-cyclic AMP, theophylline and nitroprusside caused relaxation of serotonin-induced contractions; however, in rat arteries these responses were not inhibited by ouabain or by the absence of potassium. Similar studies on tail arteries from baboons, dogs, pigs and cats showed that relaxation by dibutyryl-cyclic AMP or by theophylline had some dependency on the activity of the sodium pump. These observations are consistent with the following conclusions: 1) isoproterenol and cyclic AMP potentiate the electrogenic pumping of sodium and potassium responsible for potassium-induced relaxation; 2) the relaxing action of isoproterenol, dibutyryl-cyclic AMP and theophylline are dependent upon experimental conditions and the species from which the vascular tissue is obtained; and 3) there is a component of isoproterenol- and cyclic AMP-induced relaxation which is not altered by inhibition of the electrogenic sodium pump in the rat.

Animals↗