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PubMed2000

Tetanus relaxation of fast skeletal muscles of the mouse made parvalbumin deficient by gene inactivation.

The effects of tetanus duration on the relaxation rate of extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles were studied in normal (wild-type, WT) and parvalbumin-deficient (PVKO) mice, at 20 C. In EDL of PVKO, the relaxation rate was low and unaffected by tetanus duration (< 3.2 s). In contrast, the relaxation rate of WT muscles decreased when tetanus duration increased from 0.2 to 3.2 s. In WT muscles, fast relaxation recovered as the rest interval increased. Specific effect of parvalbumin was asserted by calculating the difference in relaxation rate between WT and PVKO muscles. For EDL, the rate constant of relaxation slowing was 1.10 s-1 of tetanization; the rate constant of relaxation recovery was 0.05 s-1 of rest. In FDB, the effects of tetanus duration on WT and PVKO muscles were qualitatively similar to those observed in EDL. Relaxation slowing as tetanus duration increases, reflects the progressive saturation of parvalbumin by Ca2+, while recovery as rest interval increases reflects the return to Ca2+-free parvalbumin. At all tetanus durations, relaxation rate still remained slightly faster in WT muscles. This suggested that parvalbumin facilitates calcium traffic from myofibrils to the SR. No difference was found between WT and PVKO muscles for: (i) the expression of the fast isoforms of myosin heavy chains, (ii) the force-velocity relationship and maximal shortening velocity and (iii) the Ca2+-activated ATPase activity from isolated preparations of the sarcoplasmic reticulum (SR).

Animals↗
PubMed1996

Smooth muscle relaxant activity of A1- and A2-selective adenosine receptor agonists in guinea pig trachea: involvement of potassium channels.

The relaxant activities of N6-cyclopentyladenosine (CPA), an A1-selective agonist, and of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), a potent A2-receptor agonist, in the carbachol-contracted guinea pig isolated trachea have been evaluated. Both CPA and CPCA induced concentration-dependent relaxations of the guinea pig trachea, CPCA demonstrating a more potent but less efficient activity. 8-Cyclopentyl-1,3-dimethylxanthine (CPT) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (10 microM), both selective and potent A1-adenosine receptor antagonists, induced only a weak inhibition of CPA while 3,7-dimethyl-1-propargylxanthine (DMPX) (10 microM), a selective A2-adenosine receptor antagonist, failed to antagonize the relaxant activity of CPA. These results indicate that a major component of the tracheal relaxant activity of CPA occurred by a mechanism which is insensitive to the antagonist potency of A1- and A1-xanthine adenosine antagonists and therefore was not mediated by A1- or A1-adenosine receptors activation. The relaxant activity of CPCA was inhibited by DMPX, which supported the involvement of A2-adenosine receptors. Glibenclamide (10 microM), an inhibitor of KATP-channels, inhibited the relaxant activity of CPCA, whereas it was without effect on CPA. Iberiotoxin (180 nM), an inhibitor of the large-conductance CA2(+)-activated K+ channel, inhibited the relaxant action of CPA and CPCA. However, verapamil can offset the inhibition of CPA provided by iberiotoxin which suggests that such an antagonism does not represent an interaction between the toxin and CPA at the level of the large-conductance CA2(+)-activated K(+)-channel gating but rather functional antagonism attributable to the promotion of CA2+ influx by the toxin. In contrast, verapamil only partially reversed the inhibition of CPCA relaxant activity provided by iberiotoxin. Taken together, these results suggest that A2-adenosine receptor subtypes are coupled to KATP-channels and large-conductance CA2(+)-activated K(+)-channels in the guinea pig trachea whereas the unidentified adenosine receptor subtype, involved in CPA relaxant activity, is not.

Adenosine↗
PubMed1996

Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea.

The ability of low concentrations of salbutamol to potentiate the relaxant effects of the phosphodiesterase (PDE) inhibitors, rolipram, Ro 20-1724 (PDE type IV inhibitor), siguazodan and milrinone (PDE type III inhibitor) was studied on guinea pig isolated trachea. These PDE inhibitors were strong relaxants of guinea pig trachealis under basal tone, but had only a weak activity on tissues precontracted with histamine (10(-5) M). In both cases, PDE type IV inhibitors showed a relaxant effect composed of two phases. The first phase represented 20 and 40% and the second, 90 and 140%, respectively, of relaxation of basal tone and histamine-induced tone. A second characteristic of PDE type IV inhibitors was the very fast and partially reversible relaxation observed at concentrations greater than 3 x 10(-8) M (for histamine-induced tone) at the first addition of inhibitor, followed by a residual relaxant activity. The latter relaxant effect was stable at concentrations of 3 x 10(-8)-10(-5) M and was equivalent to a 20% relaxation (for histamine-induced tone). In the presence of low concentrations (10(-9) and 10(-8) M) of salbutamol, there was a significant concentration-dependent potentiation of the effects of PDE inhibitors on trachea precontracted with histamine. Salbutamol, at a concentration of 10(-9) M, potentiated the effects of PDE inhibitors between 1.4- and 3.6-fold. In the presence of salbutamol 10(-8) M, the potentiation was more marked for siguazodan (37.9-fold), milrinone (11.0-fold) and Ro 20-1724 (14.5-fold) than for rolipram (4.3-fold). These results suggest that low concentrations of salbutamol can potentiate the relaxant effects of both PDE type III and PDE type IV inhibitors. Thus, PDE type IV inhibitors, which have antiinflammatory properties, could also provide adequate bronchodilation when used in combination with lower than usual doses of beta 2-agonists.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1986

The relaxant action of nicorandil in guinea-pig isolated trachealis.

Nicorandil (1-1000 mumol l-1) caused concentration-dependent relaxation of guinea-pig isolated trachealis. Propranolol (1 mumol l-1) did not modify the relaxant action of nicorandil but antagonized isoprenaline. Among K+-channel inhibitors tested, apamin (0.1 mumol l-1) and procaine (5 mmol l-1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol l-1) caused five fold antagonism. Trachealis exposed to K+-rich (120 mmol l-1) Krebs solution developed near-maximal tension. Nicorandil relaxed the K+-depolarized tissue though its concentration-effect curve was shifted markedly to the right. In tissues in which tone was induced by histamine, methylene blue (100 mumol l-1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. Intracellular electrophysiological recording showed that nicorandil (1 mumol l-1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10-1000 mumol l-1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. TEA (8 mmol l-1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. Procaine (5 mmol l-1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, nicorandil (1000 mumol l-1) increased the efflux rate constant, whereas isoprenaline (1 mumol l-1) was without effect. It is concluded that nicorandil-induced relaxation does not involve the activation of beta-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.

Aminophylline↗
PubMed1986

A comparison of the action of the endothelium-derived relaxant factor and the inhibitory factor from the bovine retractor penis on rabbit aortic smooth muscle.

The dependence of relaxation of rabbit aortic strips by carbachol and by the inhibitory factor from the bovine retractor penis (BRP) on the presence of endothelium has been compared. Carbachol-induced relaxation is abolished by removing the endothelium, inhibitory factor-induced relaxation is unimpaired. The inhibitory factor, therefore, does not act by releasing an endothelium-derived relaxing factor (EDRF). The effect of inhibitors of eicosanoid metabolism on relaxation was examined. Quinacrine and nordihydroguaiaretic acid abolished the relaxant effect of carbachol and flurbiprofen had no effect. The relaxation produced by the inhibitory factor was unaffected by quinacrine and flurbiprofen while nordihydroguaiaretic acid potentiated the response. No eicosanoid appears, therefore, to be involved in the relaxant effect of the inhibitory factor from the BRP. Methylene blue, a drug reported to inhibit guanylate cyclase, in a concentration of 10 microM selectively abolished the relaxation produced by carbachol. However, at the higher concentration of 30 microM it abolished almost completely the response to inhibitory factor from the BRP and reduced inhibition by sodium nitroprusside. It is not possible from these results to exclude the possibility that the EDRF and the inhibitory factor from the BRP are chemically related.

Animals↗
PubMed1986

Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle.

In helical strips cut from the small mesenteric artery of guinea-pig (GPSMA) (0.3-0.6 mm o.d.) relaxations induced by substance P were more susceptible to damage of the endothelium by rubbing than were relaxations evoked by carbachol. Relaxations induced by 2-nicotin-amidoethyl nitrate (SG75) were unaffected by this procedure. Relaxations evoked by the calcium ionophore A23187 persisted when those to substance P had been abolished by rubbing the endothelium in GPSMA, rabbit mesenteric and rabbit ear arteries. In guinea-pig pulmonary artery and aorta relaxations to A23187 were lost after this treatment. Carbachol and SG75 were more effective in inhibiting phasic than tonic tension induced by noradrenaline in GPSMA, but substance P was more effective against tonic tension. In the GPSMA, carbachol and substance P inhibited tension produced by noradrenaline to similar extents. However, carbachol was less, and substance P much less effective in inhibiting tension evoked by high-potassium solution than by noradrenaline. Susceptibility of relaxations to blockade by haemoglobin in GPSMA was: substance P greater than carbachol greater than ATP greater than SG75. The membrane potential of smooth muscle cells in the media of the GPSMA was recorded by microelectrode. Carbachol, but not substance P, hyperpolarized the cells both in the presence and absence of noradrenaline at concentrations which relaxed the muscle. These results suggest a heterogeneity in the mechanisms of endothelial-dependent relaxations induced by various vascular relaxants.

Animals↗
PubMed1988

Prostacyclin releases endothelium-derived relaxing factor and potentiates its action in coronary arteries of the pig.

1. The possible interactions between prostacyclin and endothelium-derived relaxing factor were examined, in isolated coronary arteries of the pig treated with indomethacin (10(-5) M). 2. In organ chamber experiments, prostacyclin caused relaxations, which were potentiated in the presence of the endothelium; the potentiation was abolished by oxyhaemoglobin. 3. In bioassay experiments, prostacyclin caused minimal relaxations of bioassay rings without endothelium; these relaxations were potentiated when the bioassay ring was exposed to basally-released endothelium-derived relaxing factor (interaction between prostacyclin and basal endothelium-derived relaxing factor) and further augmented when the endothelial cells were exposed to the prostanoid (stimulated release of endothelium-derived relaxing factor). The endothelium-dependent, but not the direct effects of prostacyclin were augmented by superoxide dismutase plus catalase and abolished by oxyhaemoglobin. 4. Forskolin, a direct activator of adenylate cyclase, caused relaxations of rings without endothelium, which were augmented by the presence of the endothelium. 5. The relaxations induced by prostacyclin or forskolin also had an endothelium-dependent component in basilar and femoral arteries and in jugular veins of the pig. 6. The endothelium-dependent actions of prostacyclin probably reflect activation of adenylate cyclase.

Animals↗
PubMed1989

Factors inducing endothelium-dependent relaxation in the guinea-pig basilar artery as estimated from the actions of haemoglobin.

1. Factors inducing dilatation of guinea-pig basilar artery were investigated in intact and endothelium-denuded tissues by measurement of isometric tension and by electrophysiological methods. 2. The amplitudes of contractions induced by 9,11,epithio-11,12-methanothromboxane A2 (STA2) and by high K+ were enhanced by haemoglobin (oxyhaemoglobin, Hb) in a concentration-dependent fashion (above 1 microM). For the high K+-induced contraction, the initial tonic component was enhanced to a greater extent than the secondary phasic component. Mechanical responses evoked by STA2 and by high K+ were greater in endothelium-denuded tissues, but Hb (below 10 microM) had no effect on them. 3. Hb (10 microM) had no effect on the contractile proteins as estimated from the actions of Hb on Ca2+-induced contractions in skinned muscle tissues. Further, Hb had no effect on the release of Ca2+ from intracellular stores but it accelerated the Ca2+ accumulation into the sarcoplasmic reticulum as judged from the caffeine- or STA2-induced contraction generated in intact tissues. 4. Acetylcholine (ACh) relaxed tissues that were precontracted by STA2 but Hb prevented this relaxation, in a concentration-dependent fashion. The ACh-induced relaxation was sustained for over 10 min in the absence of Hb, but following application of Hb, ACh caused only a transient relaxation. 5. STA2 (up to 100 nM) did not modify the resting membrane potential of smooth muscle cells of the basilar artery. ACh (10 microM) caused transient hyperpolarization which was only slightly inhibited by Hb (10 microM) whether or not STA2 was present. The hyperpolarization induced by ACh required the presence of endothelial cells. 6. A23187 (0.01-1 microM) relaxed tissues which were precontracted by STA2, in a concentration-dependent fashion but had no effect on the membrane potential. 7. These results suggest that in guinea-pig basilar artery, ACh induces relaxation of tissues that were precontracted by STA2 by causing release of both endothelium-derived relaxing (EDRF) and endothelial dependent hyperpolarizing factor (EDHF) (sustained and initial transient relaxation, respectively), but via different mechanisms. Hb inhibits the former and to a lesser extent, the latter. Since A23187 produced relaxation of pre-contracted tissue but caused no detectable change in the membrane potential, this agent may release EDRF but not EDHF.

Acetylcholine↗
PubMed1992

Calmidazolium, a calmodulin inhibitor, inhibits endothelium-dependent relaxations resistant to nitro-L-arginine in the canine coronary artery.

1. The role of calmodulin in endothelium-dependent relaxations in the canine coronary artery, was investigated by use of the inhibitor of calmodulin, calmidazolium. 2. The endothelium-dependent relaxations to adenosine diphosphate (ADP) and nebivolol, a beta-adrenoceptor antagonist, in control solution, and to bradykinin in high potassium solution (to inhibit endothelium-dependent hyperpolarization), were abolished by nitro-L-arginine (30 microM), an inhibitor of nitro oxide-synthase. Calmidazolium (10 microM) did not inhibit these relaxations. 3. Calmidazolium did not affect the endothelium-independent relaxations to SIN-1, an exogenous donor of nitric oxide (NO). 4. The relaxations to bradykinin and to the calcium ionophore A23187 in control solution were inhibited to a small extent by calmidazolium (10 microM). 5. Bradykinin and A23187 induced relaxations in the presence of nitro-L-arginine (30 microM) that were abolished by calmidazolium (10 microM) but not affected by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels. 6. The endothelium-independent relaxations to lemakalim, an ATP-sensitive K+ channel opener, were not affected by calmidazolium (10 microM) but were inhibited by glibenclamide (10 microM). 7. These results suggest that calmidazolium does not inhibit the endothelium-dependent relaxations due to endothelium-derived NO in the canine coronary artery but inhibits either the production of endothelium-derived hyperpolarizing factor (EDHF) from endothelial cells or its effects on vascular smooth muscle cells. Furthermore these results suggest that EDHF contributes to endothelium-dependent relaxations in the canine coronary artery.

Adenosine Diphosphate↗
PubMed1992

Thimerosal blocks stimulated but not basal release of endothelium-derived relaxing factor (EDRF) in dog isolated coronary artery.

1. The effect of an acetly-coA lysolecithin acyltransferase inhibitor, thimerosal, on the release of endothelium-derived relaxing factor (EDRF) was examined in the greyhound isolated coronary artery. 2. Thimerosal (1-10 microM) relaxed fully, ring segments of coronary artery which were contracted with the thromboxane A2-mimetic, U46619 (30 nM). The response was endothelium-dependent, slow in both onset and time to reach maximum. The maximum relaxation to the highest concentration of thimerosal (10 microM) was maintained for 10-20 min before the tissue slowly regained active force (1-2 h) to the same or higher level as that prior to the addition of thimerosal. At this time the endothelium-dependent relaxation responses to acetylcholine (ACh), substance P (SP), bradykinin (BK) and the calcium ionophores, ionomycin and A23187 were abolished. The endothelium-dependent contractions to the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NNA; 10-100 microM) and NG-monomethyl-L-arginine (L-NMMA: 10-100 microM), however, were unaffected. 3. Thimerosal (10 microM) did not affect the relaxation curve to sodium nitroprusside (SNP) nor the contraction curve to the thromboxane A2-mimetic, U46619. 4. Both the relaxation response to thimerosal and the selective block of the relaxation responses to stimulated EDRF release were unaffected by either indomethacin (10 microM) or superoxide dismutase (150 u ml-1). 5. L-NNA (100 microM) significantly blocked the relaxation curves to thimerosal and A23187 but not that to SNP.6. Abolition of stimulated EDRF-mediated responses with thimerosal was unlikely to result from maximal and maintained stimulation of EDRF release even when active U46619-induced force had returned to pre-thimerosal levels, since the relaxation curves to glyceryl trinitrate (GTN) and SNP were markedly attenuated in the presence of SNP and GTN respectively when active force was restored with endothelin-1 (ET-1).7. Melittin (1 microM), ionomycin (1 microM) and A23187 (1 microM) each had selective effects on stimulated but not basal EDRF responses, similar to those of thimerosal.8. We propose that stimulated but not 'basal' release of EDRF is dependent on the release of arachidonic acid or one of its non-cyclo-oxygenase metabolites, possibly by Ca2'-dependent activation of phospholipase A2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

5-Hydroxytryptamine (5-HT) mediates potent relaxation in the sheep isolated pulmonary vein via activation of 5-HT4 receptors.

1. We investigated the potent 5-hydroxytryptamine (5-HT)-mediated vasorelaxation of the sheep pulmonary vein. Here we present evidence that this response is due to activation of 5-HT4 receptors. 2. 5-HT (1-1000 nM) caused concentration-dependent, maintained relaxations (pEC50 = 8.4 +/- 0.1) of isolated rings of sheep pulmonary vein pre-contracted with endothelin-1 (3 nM). 3. The relaxation response to 5-HT was unaffected by either removal of the endothelium or by inhibition of NO-synthase by NG-nitro-L-arginine (100 microM). 4. Ketanserin, methiothepin, methysergide and MDL 72222 at concentrations that selectively block 5-HT2, 5-HT1-like and 5-HT3 receptors respectively, had no effect on the concentration-relaxation curve to 5-HT. 5. ICS 205-930 (1-10 microM) competitively antagonized the concentration-relaxation curve to 5-HT with a pA2 of approximately 6.7. 6. Increasing the concentration of ICS 205-930 from 10 to 30 microM did not cause a further rightward shift of the 5-HT concentration-relaxation curve. The pEC50 of 6.50 for 5-HT in the presence of ICS 205-930 (30 microM) was taken as an estimate of the affinity of 5-HT for 5-HT1-like receptors since methiothepin (10 nM) unmasked further competitive inhibition of 5-HT in the presence of this concentration of ICS 205-930. 7. Other 5-HT agonists including 5-carboxamidotryptamine (5-CT), alpha-methyl-5-HT and BIMU 8 (but not 2-methyl-5-HT) also relaxed the pulmonary vein.The response to 5-CT was inhibited by methiothepin (10 nM) and methysergide (100 nM) but unaffected by ICS 205-930 (30 microM), whilst that toa-methyl-5-HT and BIMU 8 was unaffected by methiothepin (10 nM) but blocked by ICS 205-930(estimated pKB values of 6.4 and 6.9 respectively). Relaxation curves to both 5-HT and BIMU 8 were unaffected by cocaine (6 microM).8. In conclusion, these results indicate that the sheep pulmonary vein possesses 5-HT4 receptors that mediate potent endothelium-independent relaxation. 5-HT,-like relaxant receptors are also present in this tissue but 5-HT has a lower affinity at these receptors. This preparation may thus provide a robust and sensitive bioassay for future development of selective 5-HT4 receptor agonists and antagonists.

Animals↗
PubMed1992

Endothelium-dependent relaxation to acetylcholine in the rabbit basilar artery: importance of membrane hyperpolarization.

1. Muscarinic stimulation of isolated, preconstricted segments of the basilar artery, with either acetylcholine or carbachol, was followed by endothelium-dependent smooth muscle relaxation and membrane hyperpolarization. 2. Smooth muscle relaxation to acetylcholine was stimulated in the presence of lower concentrations than the associated hyperpolarization (EC50 values 3.2 microM and 31.6 microM, respectively), and was sustained during agonist application, while the hyperpolarization was relatively transient. 3. Repeated exposure to acetylcholine was associated with loss of membrane hyperpolarization, while smooth muscle relaxation was unaltered. Following a second exposure to 100 microM acetylcholine, mean hyperpolarization was markedly depressed from 8.5 to 2 mV, and subsequent exposures failed to induce any hyperpolarization. Relaxations with a similar amplitude and rate of development, were recorded with each subsequent addition of acetylcholine. 4. The competitive substrate inhibitors for nitric oxide synthase, L-NG-monomethyl arginine (100 microM L-NMMA) or L-NG-nitro arginine methyl ester (100 microM L-NAME), modified the form and amplitude of both the relaxation and the hyperpolarization to acetylcholine. In the majority of experiments, both the hyperpolarization and the relaxation were almost totally abolished. 5. Neither nitric oxide, applied directly in physiological salt solution, nor sodium nitroprusside, produced smooth muscle hyperpolarization except in high concentrations. Reproducible, small amplitude (around 2 mV) hyperpolarization followed the application of either NO gas (15 microM) or sodium nitroprusside (100 microM), both of which induced almost maximal smooth muscle relaxation. 6. These data show that muscarinic stimulation of endothelial cells in the rabbit basilar artery is followed by both smooth muscle hyperpolarization and relaxation. They indicate that nitric oxide is involved in both of these responses, but that the smooth muscle hyperpolarization is not an essential component of the relaxation.

Acetylcholine↗
PubMed1992

Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.

1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.We also confirmed that 5-HT induces these relaxations via (a) 5-HT, receptor subtype(s), located on neurones.

Animals↗
PubMed1995

Pertussis toxin-sensitive muscarinic relaxation in the rat iris dilator muscle.

1. The effects of pertussis toxin (PTX) on contraction and/or relaxation induced by agonists or transmural nerve stimulation (TNS) were examined in the rat iris dilator and sphincter muscles. 2. TNS in the presence of phentolamine induced an atropine-sensitive biphasic response: initial contraction followed by relaxation in dilator muscles. Exogenously applied acetylcholine (ACh) elicited a large relaxation at low doses (3 microM or less) and a concentration at high doses. 3. Only the ACh-induced relaxation was affected by injection of PTX (10 ng) into the anterior eye chamber. Relaxation was decreased 12 h after injection and had completely disappeared after 24 h. Relaxation recovered in part 3 weeks and almost completely 8 weeks after PTX treatment. A gradual decrease in muscarinic relaxation in a dilator muscle was also observed in vitro after addition of PTX to the bathing solution. 4. The pA2 values of muscarinic blockers, pirenzepine, AF-DX 116, 4-DAMP, and himbacine for competitive antagonism to ACh-induced contraction were 7.14, 6.53, 9.03, and 6.80, respectively, in PTX-pretreated dilator muscles. These values are comparable to those obtained in parasympathectomized dilator muscles and may indicate involvement of M3 or M3-like receptors in muscle contraction. 5. Pretreatment with PTX did not significantly affect contraction induced by noradrenaline or 5-hydroxytryptamine or the relaxation induced by isoprenaline in dilator muscles. 6. In conclusion, among several agonist-induced responses in the rat iris dilator and sphincter muscles, only muscarinic relaxation in dilator muscle occurs via activation of PTX-sensitive GTP binding proteins.

Acetylcholine↗
PubMed1995

Impairment of nitrergic-mediated relaxation of rat isolated duodenum by experimental diabetes.

1. Diabetes mellitus is associated with changes in gastrointestinal motility. The effects of experimental diabetes, induced by streptozotocin administration to rats 3-4 weeks previously, on the nitric oxide (NO)-mediated (nitrergic) relaxation of the duodenum have now been investigated. 2. The non-adrenergic, non-cholinergic (NANC) relaxation of the isolated duodenum induced by nicotine (0.3-10 microM) or the nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP; 10 microM) was inhibited by the NO synthase inhibitor, NG-nitro-L-arginine (3-100 microM). 3. This nitrergic relaxation induced by nicotine or DMPP of the duodenum from diabetic rats was substantially smaller than that of the tissue from control rats. 4. By contrast, the relaxation of the duodenum from diabetic rats to the NO donor, nitroprusside (0.3-10 microM) was similar to that of control tissue, whereas the relaxation to ATP (0.1-3 microM) was enhanced to a small but significant degree. 5. Incubation of duodenal tissue from control rats at 4 degrees C for 72 h, which leads to neuronal disruption, significantly attenuated the relaxation to nicotine or DMPP whereas the relaxation induced by nitroprusside or ATP was not affected. Comparable cold-storage did not affect the endothelium-dependent relaxation of rat aortic rings induced by acetylcholine (0.01-2 microM). 6. The calcium-dependent NO synthase activity in duodenal tissue, determined by the conversion of radiolabelled L-arginine to citrulline, was significantly reduced in cold-stored tissue and in tissue obtained from diabetic rats. 7. These findings in the rat duodenum indicate that a reduction in intestinal NO synthase activity is associated with an impairment of the NANC relaxation. A defect in the intestinal nitrergic innervation could thus contribute to the motility dysfunction observed in diabetes.

Adenosine Triphosphate↗
PubMed1995

Adenosine receptor-mediated relaxation of guinea-pig precontracted, isolated trachea.

1. We have investigated the pharmacological profile of the adenosine receptor mediating relaxation of the carbachol pre-contracted guinea-pig trachea. 2. 5'-N-Ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine elicited concentration-dependent relaxations with pD2 (-log10 half-maximal values) of 6.37 +/- 0.04 and 5.25 +/- 0.09, with maximal relaxations of 73 +/- 7 and 208 +/- 38%, respectively. In the presence of 10 microM NECA, 2-chloroadenosine was able to relax the tissue further with a pD2 value of 4.74 +/- 0.11 and a maximal response of 252 +/- 68%. 3. CGS 21680, APEC and adenosine failed to elicit significant relaxations of precontracted tracheal rings at concentrations below 10 microM. At 10 microM, adenosine analogues elicited relaxations with the following order of magnitude (% relaxation): 2-chloroadenosine (75 +/- 16%) = NECA (69 +/- 16%) > APEC (25 +/- 8%) > CGS 21680 (11 +/- 2%) > adenosine (6 +/- 4%). 4. NECA-induced relaxation of precontracted trachea was antagonized by adenosine receptor antagonists with the rank order of apparent affinity (Ki, nM): PD 115,199 (27 +/- 8) = XAC (43 +/- 11) > CP 66,713(285 +/- 89) = DPCPX (316 +/- 114). 5. We conclude that the adenosine analogue-induced relaxation of guinea-pig tracheal rings fails to fit into the current classification of A2 adenosine receptors.

Adenosine↗
PubMed1995

Endothelium-dependent relaxations in sheep pulmonary arteries and veins: resistance to block by NG-nitro-L-arginine in pulmonary hypertension.

1. The effect of the nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG), on endothelium-dependent relaxation to a receptor-independent agent, ionomycin, was examined in isolated pulmonary arteries and veins from control, short-term and chronic pulmonary hypertensive sheep. All vessel segments were contracted to optimal levels of active force with endothelin-1 to record endothelium-dependent relaxation. 2. Pulmonary hypertension was induced by continuous pulmonary artery air embolization for 1 day (short-term) and 14 days (chronic) and was associated with a 2 and 3 fold increase in pulmonary vascular resistance respectively. 3. L-NOARG (0.1 mM) reduced the maximum relaxation (Rmax) to ionomycin in large and medium-sized pulmonary arteries from control sheep by approximately 70%. By contrast, L-NOARG (0.1 mM) did not inhibit the Rmax to ionomycin in matched vessels from short-term and chronic pulmonary hypertensive sheep. 4. Resistance of ionomycin-induced relaxations to inhibition by L-NOARG, was confined to the arterial vasculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium-sized chronic pulmonary hypertensive veins were, like those in control veins, abolished by L-NOARG. Both large and medium-sized pulmonary veins from short-term pulmonary hypertensive sheep, however, were resistant to block by L-NOARG. 5. Neither sensitivity (pEC50) nor Rmax to ionomycin in large, short-term pulmonary hypertensive arteries was affected when the extracellular concentration of K+ was increased isotonically to 30 mM. Nifedipine (0.3 microM) was present throughout to prevent high K(+)-induced smooth muscle contraction. In the presence of this high extracellular K+, however, L-NOARG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L-NOARG only weakly inhibited ionomycin relaxations. 6. In conclusion, the onset of pulmonary hypertension in sheep following air embolization, is associated with the development of resistance of endothelium-dependent relaxations to block by L-NOARG. The mechanism of L-NOARG resistance appears to be due to the up-regulation of a K+ channel-mediated backup vasodilator mechanism which can compensate for the loss of nitric oxide (NO)-mediated relaxation. Although this mechanism remains functionally 'silent' in the presence of NO it is able to maintain adequate endothelium-dependent vasodilatation during pulmonary hypertension if NO synthesis is compromised.

Animals↗
PubMed1996

Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase.

1. We have previously found that carbon monoxide (CO) potently relaxes the lamb ductus arteriosus and have ascribed this response to inhibition of a cytochrome P450-based mono-oxygenase reaction which sustains contractile tone. Our proposal, however, has been questioned on the evidence of findings in other blood vessels implicating the guanylyl cyclase-based relaxing mechanism as the target for CO. To investigate this issue further, we have carried out experiments in the isolated ductus from near-term foetal lambs and have examined the effect of CO concomitantly on muscle tone and cyclic GMP content, both in the absence and presence of guanylyl inhibitors, or during exposure to monochromatic light at 450 nm. 2. CO (65 microM) reversed completely, or nearly completely, the tone developed by the vessel in the presence of oxygen (30%) and indomethacin (2.8 microM). Cyclic GMP content tended to increase with the relaxation, but the change did not reach significance. Sodium nitroprusside (SNP), a NO donor, mimicked CO in relaxing the ductus. Contrary to CO, however, SNP caused a marked accumulation of cyclic GMP with levels being positively correlated with the relaxation. 3. Methylene blue (10 microM) reduced marginally the CO relaxation, whilst LY-83583 (10 microM) had an obvious, albeit variable, inhibitory effect. Basal cyclic GMP content was lower in tissues treated with either compound and rose upon exposure to CO. However, the levels attained were still within the range of values for tissues prior to any treatment. Furthermore, the elevation in cyclic GMP was not related to the magnitude of the CO relaxation. 4. Illumination of the ductus with monochromatic light at 450 nm reversed the CO relaxation and any concomitant increase in cyclic GMP. In the absence of CO, light by itself had no effect. 5. Ductal preparation with only muscle behaved as the intact preparations in reacting to CO, both in the absence and presence of guanylyl cyclase inhibitors, or during illumination. 6. We conclude that the primary action of CO in the ductus arteriosus is not exerted on the guanylyl cyclase heme and that cyclic GMP may only have an accessory role in the relaxation to this agent. This finding reasserts the importance of a cytochrom P450-based mono-oxygenase reaction for generation of tone and as a target for CO in the ductus.

Aminoquinolines↗