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PubMed2002

Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane.

Volatile anaesthetics relax airway smooth muscle in vitro. The amount of relaxation might depend on the type and concentration of volatile anaesthetics, the calibre and precontraction level of the bronchi, and also on the species considered. These effects were investigated on isolated human bronchi. Isometric relaxations produced by halothane, isoflurane and desflurane bubbled on human bronchial rings precontracted with carbachol were recorded and compared with time controls. Volatile anaesthetics induced a concentration-dependent relaxation at 0.66, 1.33 and 2 minimum alveolar concentration (MAC). The relaxation was greater in mildly (carbachol 3x10(-7) M) than in highly (carbachol 2x10(-6) M) precontracted bronchi. Halothane was more potent in relaxing distal as compared to proximal bronchi; this differential effect was less pronounced with isoflurane and not observed with desflurane. While the three volatile anaesthetics induced similar relaxation on proximal bronchi, halothane was significantly more potent than desflurane on distal bronchi, with isoflurane being intermediate. The relaxation induced by 1.33 MAC of halothane, isoflurane and desflurane on moderately precontracted distal bronchi (carbachol 1x10(-6) M) was attenuated by pretreatment with glibenclamide 1x10(-5) M. In conclusion, halothane, isoflurane and desflurane exert direct but differential relaxant effects on human isolated bronchial smooth muscle. This may provide supplemental bronchodilation during anaesthesia. Although adenosine triphosphate-sensitive K+ channels are involved in these relaxant effects, they are unlikely to explain the observed differences between the three volatile anaesthetics.

Anesthetics, Inhalation↗
PubMed2006

Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma.

BACKGROUND: Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production--due to competition with neuronal NO-synthase (nNOS) for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR), leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity. In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5-16 Hz)-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 microM atropine and 3 microM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor Nomega-nitro-L-arginine (L-NNA, 100 microM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor Nomega-hydroxy-nor-L-arginine (nor-NOHA, 10 microM). Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM). RESULTS: At 6 h after ovalbumin-challenge (after the EAR), EFS-induced relaxation (ranging from 3.2 +/- 1.1% at 0.5 Hz to 58.5 +/- 2.2% at 16 Hz) was significantly decreased compared to unchallenged controls (7.1 +/- 0.8% to 75.8 +/- 0.7%; P < 0.05 all). In contrast to unchallenged controls, the NOS inhibitor L-NNA did not affect EFS-induced relaxation after allergen challenge, indicating that NO deficiency underlies the impaired relaxation. Remarkably, the specific arginase inhibitor nor-NOHA normalized the impaired relaxation to unchallenged control (P < 0.05 all), which effect was inhibited by L-NNA (P < 0.01 all). Moreover, the effect of nor-NOHA was mimicked by exogenous L-arginine. CONCLUSION: The results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS.

Animals↗
PubMed1978

[Research on the contracting and relaxant actions of cardiac steroids on the taenia coli of guinea pig (author's transl)].

Actions of cardiac steroid (CS) such as bufadienolides and cardenolides, on guinea pig taenia coli were studied using the double sucrose-gap method. When an appropriate dose of CS was applied, the taenia coli first contracted, then relaxed. After removal of CS, the relaxation was enhanced and continued for 20-40 min. In decreasing order of the relaxant action were bufalin, ouabain, cinobufagin and resibufogenin. Further application of CS after occurrence of the relaxation induced a secondary gradual contraction. The contraction occurred with the membrane depolarization and increase in spike discharge, and the relaxation corresponded fairly well with decrease in spike discharge and the membrane repolarization. Membrane resistance was decreased during the contraction as well as the relaxation. The decrease in membrane resistance continued during the relaxation after removal of CS, Na, K and Ga conductances were increased by CS application, respectively. The increase of Na conductance was relatively high during the contraction, and the increase of K conductance was remarkable during the relaxation and after removal of CS. From the foregoing results it is considered that the contracting action is due to inhibition of the Na pump and that the relaxant action is due to the change in electrical properties of membrane produced by a marked increase in intracellular Na and the increase of K permeability. The relaxation after removal of CS is considered to be due to the activated electrogenic Na pump as indicated from the changes in electrical properties of membrane.

Action Potentials↗
PubMed1999

Biphasic relaxation caused by electrical field stimulation of the mesenteric arteries of rats.

Electrical field stimulation (EFS) caused biphasic relaxation, first transient and then sustained, of rat mesenteric arteries precontracted by prostaglandin (PG) F2alpha. The transient relaxation was reduced about 45%, and the sustained relaxation was not observed after endothelium denudation of the arteries. N(omega)-Nitro-L-arginine (L-NOARG) inhibited the biphasic relaxation induced by EFS. At 1 - 100 microM, L-NOARG inhibited the transient relaxation more than the sustained relaxation. Methylene blue inhibited the biphasic relaxation and at 100 microM, L-NOARG abolished the transient relaxation. These results suggest that the transient relaxation mainly involves nitric oxide (NO), whereas the sustained relaxation involves both NO and some other factor(s).

Animals↗
PubMed1993

Relatively immediate relaxant effects of cholera toxin on isolated rabbit blood vessels.

A study was made on the relatively immediate relaxant effect of cholera toxin (CTX) on the isolated ear artery, thoracic aorta and saphenous vein of the rabbit. Both preparations of CTX, containing sodium azide (NaN3) and azide-free, showed no effect on the non-precontracted artery, but CTX containing NaN3 relaxed the moderately precontracted blood vessels with methoxamine promptly, i.e., with a time course of min order. However, the immediate relaxation produced by CTX containing NaN3 was attributed mainly to NaN3. Azide-free CTX, on the other hand, at 1-10 micrograms/ml gradually produced concentration-dependent relaxation of the precontracted vessels. The relaxant effects of CTX on the vessels were slow and long-lasting, i.e., with a time course of 10 min order. The relaxation induced by CTX was not influenced by the removal of endothelium nor by pretreatment with 10 microM indomethacin, 3 microM atropine or 3 microM propranolol. Activation of protein kinase C by a phorbol ester inhibited the relaxant effect of CTX. These results indicate that CTX relaxes the blood vessels by directly acting on the smooth muscles, without mediation by known endogenous relaxing factor, such as endothelium-derived relaxing factor (EDRF = NO) or prostaglandin I2 (prostacyclin) and by muscarinic receptor or beta-adrenoceptor.

Animals↗
PubMed1994

Relaxant effects of calcitonin gene-related peptide on isolated small renal arteries in stroke-prone spontaneously hypertensive rats.

The relaxant effects of calcitonin gene-related peptide (CGRP) on the 3rd branches of renal arteries obtained from stroke-prone spontaneously hypertensive rats (SHRSP), and Wistar-Kyoto rats (WKY) were investigated in vitro. CGRP elicited concentration-dependent relaxation, and the relaxant response was not affected by the mechanical removal of endothelium in either SHRSP or WKY. The CGRP-induced relaxant response was markedly greater in SHRSP than in WKY, whereas there was no significant difference in acetylcholine-induced relaxation, which was endothelium-dependent, between the two groups. Additionally, significantly enhanced reactivity to CGRP was also shown in spontaneously hypertensive rats compared to WKY; however, this reactivity was less than that observed in SHRSP. There were also no significant differences between WKY and SHRSP in the relaxation induced by forskolin, dibutyryl cyclic AMP, and 3-isobutyl-1-methylxanthine (IBMX). CGRP-induced relaxation was significantly potentiated in similar manner by the pretreatment with IBMX in both WKY and SHRSP. Incubation with glibenclamide (10(-6) M) had no effect on CGRP-induced relaxation in either group, the WKY or the SHRSP. These results suggest that CGRP produces endothelium-independent relaxation in the small renal arteries in the rat, and that the increased CGRP-induced relaxant response found in SHRSP may not be associated with the altered vasodilation mediated by cyclic AMP, or with functional changes in ATP-sensitive potassium channels.

Acetylcholine↗
PubMed2003

MaxiK channel mediates beta2-adrenoceptor-activated relaxation to isoprenaline through cAMP-dependent and -independent mechanisms in guinea-pig tracheal smooth muscle.

We examined the contribution of large-conductance, Ca(2+)-sensitive K+ (MaxiK) channel to beta2-adrenoceptor-activated relaxation to isoprenaline in guinea-pig tracheal smooth muscle focusing on the role for cAMP in the coupling between beta2-adrenoceptor and MaxiK channel. Isoprenaline-elicited relaxation was confirmed to be mediated through beta2-type of adrenoceptor since the response was antagonized in a competitive fashion by a beta2-selective adrenoceptor antagonist butoxamine with a pA2 value of 6.56. Isoprenaline-induced relaxation was significantly potentiated by a selective inhibitor of cyclic AMP-specific phosphodiesterase, Ro-20-1724 (0.1-1 microM). cAMP-dependent mediation of MaxiK channel in the relaxant response to isoprenaline was evidenced since the potentiated response to isoprenaline by the presence of Ro-20-1724 (1 microM) was inhibited by the channel selective blocker, iberiotoxin (IbTx, 100 nM). This concept was supported by the finding that the relaxation to a membrane permeable cAMP analogue, 8-bromo-cAMP (1 mM), was susceptible to the inhibition by IbTx. On the other hand, isoprenaline-induced relaxation was not practically diminished by an adenylyl cyclase inhibitor SQ 22,536 (100 microM). However, isoprenaline-induced relaxation in the presence of SQ 22,536 was suppressed by IbTx. Characteristics of isoprenaline-induced relaxant response, i.e., impervious to SQ 22,536 but susceptible to IbTx, were practically mimicked by cholera toxin (CTX, 5 microg/ml), an activator of adenylyl cyclase coupled-heterotrimeric guanine nucleotide-binding regulatory protein Gs. These findings indicate that in guinea-pig tracheal smooth muscle: 1) MaxiK channel substantially mediates beta2-adrenoceptor-activated relaxation; 2) both cAMP-dependent and -independent mechanisms underlie the functional coupling between beta2-adrenoceptor and MaxiK channel to induce muscle relaxation; and 3) direct regulation of MaxiK channel by Gs operates in cAMP-independent coupling between beta2-adrenoceptor and this ion channel.

Adrenergic beta-Agonists↗
PubMed2000

Exercise training enhances relaxation of the isolated guinea-pig saphenous artery in response to acetylcholine.

The effects of exercise training were investigated on the vascular responses in the isolated guinea-pig saphenous artery. Exercising animals swam 5 days week-1 for 6 weeks (60 min day-1 for weeks 1 and 2; 75 min day-1 for weeks 3 and 4; 90 min day-1 for weeks 5 and 6), while control animals were placed into shallow water for the same duration. Trained animals had significantly higher ventricular:body weight ratios, increased citrate synthase activity in the latissimus dorsi, and enhanced Na+ pump concentrations in the latissimus dorsi and gastrocnemius muscles (P < 0.05). In vitro isometric techniques were used to measure constriction and relaxation responses of saphenous artery rings from trained and control animals. There were no significant differences in the constriction responses to KCl (50 mm) and phenylephrine (0.3-100 microM) in arterial rings from control versus trained animals. Relaxation responses to acetylcholine (10 microM; ACh-relaxation), following preconstriction with phenylephrine (10 microM), were significantly enhanced in rings from trained animals (P < 0.05). Acetylcholine relaxed the vessels to 47 +/- 6% (control) and 18 +/- 3% (trained) of the preconstriction responses to phenylephrine. The nitric oxide synthase inhibitor N G-nitro-L-arginine (L-NA; 50 microM) significantly attenuated the ACh-relaxation in control and trained animals (P < 0.05). The effect of L-NA on the ACh-relaxation was significantly larger in trained (change in ACh-relaxation with L-NA = 29 +/- 9%) than control (14 +/- 3%) animals (P < 0.05). In conclusion, exercise training enhanced the ACh-relaxation of the isolated guinea-pig saphenous artery. Inhibition of nitric oxide synthase attenuated the ACh-relaxation of rings from control and trained animals, but this effect was significantly larger in the vessels from trained animals. These results are consistent with the idea that nitric oxide could contribute to the enhanced ACh-relaxation of the saphenous artery with exercise training.

Acetylcholine↗
PubMed1992

Antagonists of nitric oxide synthesis inhibit nerve-mediated relaxations of longitudinal muscle in guinea pig ileum.

Enteric inhibitory nerves release nonadrenergic, noncholinergic (NANC) transmitters onto the muscle layers of guinea pig ileum. Nitric oxide (NO), released from endothelial cells, relaxes vascular smooth muscle and NO may also be a chemical messenger released from neurons. The present study investigated the possibility that NO is a NANC transmitter in guinea pig ileum longitudinal muscle myenteric plexus. Segments of longitudinal muscle myenteric plexus were maintained in scopolamine-containing (1 microM) Krebs' solution. Histamine (1 microM) was used to induce tone, and NANC relaxations were produced by trains of transmural electrical stimuli. NANC responses consisted of a fast relaxation (approximately 1 s duration) followed either by a slow relaxation or a slow contraction (approximately 4 s duration). The NO-synthase inhibitors, NG-monomethyl-L-arginine, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, inhibited peak (fast) neurogenic relaxations by a maximum of 62 +/- 6%, 91 +/- 3% and 50 +/- 3%, respectively. NO-synthase inhibitors either completely blocked the slow relaxation revealing a late contraction or increased the amplitude of late contractions. The actions of NG-monomethyl-L-arginine were partially reversed by L-arginine (1 mM) while the actions of NG-nitro-L-arginine methyl ester and NG-nitro-L-arginine were not consistently reversed by L-arginine. L-Arginine itself did not alter neurogenic responses. NG-monomethyl-D-arginine (10-300 microM) did not affect NANC relaxations or contractions. Hemoglobin (10 microM) inhibited peak NANC relaxations by 45 +/- 4% and increased the amplitude of late contractions without affecting papaverine-induced relaxations. Sodium nitroprusside and 8-bromo-cyclic guanosine monophosphate mimicked NANC relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1990

Potentiation of nonadrenergic neural relaxation in guinea pig airways by a cyclic cAMP phosphodiesterase inhibitor.

We have studied the effect of phosphodiesterase inhibitors on relaxation of guinea pig tracheal smooth muscle in an attempt to elucidate the role of cyclic nucleotides in relaxation to stimulation of inhibitory nonadrenergic noncholinergic (i-NANC) nerves. SK&F 94120 (1-10 microM) potentiated relaxation induced by isoproterenol, vasoactive intestinal peptide (VIP) and electrical field stimulation (EFS) in the presence of atropine and propranolol but had no effect on relaxation induced by sodium nitroprusside. Zaprinast (3-30 microM) potentiated relaxation induced by sodium nitroprusside but not by isoproterenol or VIP. A small potentiation of relaxation to EFS was induced by 30 microM zaprinast but not by lower concentrations. Tetrodotoxin attenuated relaxations induced by EFS suggesting that they are at least partly neurogenic in origin. SK&F 94120 and zaprinast had no effect of tetrodotoxin-resistant relaxation to EFS. The guanylate cyclase inhibitor had no effect on EFS-induced relaxation. These findings suggest that cyclic AMP may mediate relaxation of guinea pig tracheal smooth muscle in response to stimulation of i-NANC nerves, and are in agreement with the view that VIP may be the neurotransmitter released by i-NANC nerves in this tissue.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Cyclic GMP: a potential mediator of neurally- and drug-induced relaxation of opossum lower esophageal sphincter.

Electrical field stimulation (EFS) of isolated strips of opossum lower esophageal sphincter (LES) produced a relaxation that was accompanied by an elevation of intracellular cyclic GMP content. In order to compare the time dependence of the EFS-induced relaxation with that of the elevation of cyclic GMP, the ability of EFS to produce relaxation and increase cyclic GMP was measured. The results of these experiments showed that cyclic GMP content increased before the onset of relaxation. Cumulative addition of atriopeptin II, an activator of particulate guanylate cyclase, produced a concentration-dependent relaxation of this tissue and increased cyclic GMP content. In other experiments, zaprinast, an inhibitor of a cyclic GMP selective-phosphodiesterase, produced a concentration-related relaxation of opossum LES and increased cyclic GMP content. However, pretreatment with zaprinast (3 microM) did not potentiate the EFS-induced relaxation or the increase in cyclic GMP content. At this concentration, however, zaprinast increased the basal content of cyclic GMP. Finally, 8-Br-cyclic GMP, a membrane-permeable analog of cyclic GMP, produced a concentration-dependent relaxation of isolated strips of opossum LES. In conclusion, these data extend the initial findings that an elevation in cyclic GMP content is associated with relaxation and suggest that cyclic GMP is a potential intracellular messenger of neurally- and drug-induced relaxation of opossum LES.

Animals↗
PubMed1989

Central and peripheral opioid modulation of gastric relaxation induced by feeding in dogs.

The influence of i.v. vs. i.c.v. administration of [( D-Ala2, MetPhe4, Gly-ol5]enkephalin (DAMGO) and morphine), kappa U 50488 and ethylketocyclazocine and delta ([D-Pen2, D-Pen5]enkephalin (DPDPE)] opioid agonists on gastric relaxation induced by a standard meal was evaluated in conscious dogs with strain-gauge transducers implanted on the gastric fundus and antrum. Under control conditions, the amplitude of the gastric relaxation in response to feeding was 2.46 +/- 0.23 g. Given i.v. 10 min before feeding, both U 50488 (10 micrograms/kg) and ethylketocyclazocine (10 micrograms/kg) significantly (P less than .01) reduced the amplitude of the gastric relaxation by 57 and 68%, respectively, whereas DAMGO and morphine (10 micrograms/kg i.v.) increased markedly the response to feeding by 67 and 51%, respectively. In contrast, DPDPE had no effect on the gastric relaxation induced by feeding. Previous administration of naloxone (0.3 mg/kg i.v.) or MR 2266 (0.3 mg/kg i.v.) blocked the effect of U 50488 on gastric relaxation with no effect per se on the amplitude of response; naloxone also blocked the increase in gastric relaxation induced by DAMGO. When administered i.c.v. (0.1 microgram/kg) DAMGO induced a significant (P less than .05) increase in the amplitude of gastric relaxation whereas U 50488 and DPDPE (0.1 and 1 microgram/kg i.c.v.) had no effect. The effect of i.c.v. DAMGO on gastric relaxation was unaffected by a previous i.v. administration of SR 58002C (1 mg/kg). Truncal vagotomy blocked the increase in gastric relaxation induced by DAMGO (10 micrograms/kg i.v.), but did not change the effect of U 50488 (10 micrograms/kg i.v.) on gastric relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension.

Blood vessel responses to relaxant drugs have been reported to change with aging and with the development of hypertension. In view of the requirement of endothelial cells for the activity of many relaxant drugs, we examined the role of the endothelium in the relaxation response of vascular tissue. Aortic and mesenteric ring segments from normotensive and hypertensive rats, ages 5 to 6, 15 to 18 and 30 to 31 weeks, were examined for relaxation to sodium nitroprusside, sodium nitrite, atrial natriuretic factor and 8-bromo-cyclic GMP. Relaxation responses to the nitrovasodilators were reduced progressively with aging in ring segments of Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) with intact endothelium; however, intact SHR ring preparations displayed less relaxation to nitrovasodilators at 15 to 18 and 30 to 31 weeks than those of WKYs. Rubbed (endothelium denuded) ring preparations displayed greatest relaxation to nitrovasodilators with no difference being observed between SHR and WKY preparations at any age tested. Relaxation to atrial natriuretic factor and 8-bromo-cyclic GMP was not different between rubbed and unrubbed ring segments or between SHRs and WKYs, indicating no detectable impairment of the overall relaxation response in the vascular smooth muscle of SHRs. These results suggest that the total functional capacity of vascular smooth muscle to relax to nitrovasodilators is not changed with aging or hypertension. However, the endothelial cells exert modulatory influences upon the vascular smooth muscle to reduce overall responsiveness to nitrovasodilators, an effect that is enhanced with aging and the development of genetic hypertension.

Aging↗
PubMed1984

Relaxation of Mytilus catch muscle by 8-bromo-cyclic GMP and related compounds.

Relaxation of catch tension by 8-bromo-cyclic GMP in the ABRM of Mytilus was blocked in the presence of mersalyl and was markedly reduced after treatment of the muscle with alpha-methyldopa. In the muscle depolarized by 540 mM KCl + 5 mM EGTA solution, 8-bromo-cyclic GMP could not relax Ca-contracture. Hexylamine and phenylethylamine, which are assumed to relax the catch acting on relaxing nerve terminals, could not relax the contracture either. Serotonin and dopamine, which are known to relax the catch acting directly on the muscle fibre membrane, could relax it. In the muscle depolarized by 250 mM KCl + 5 mM EGTA solution, all of the cyclic nucleotides tested (cyclic AMP, cyclic GMP and their analogues), serotonin and dopamine relaxed Ca-contracture, but hexylamine and phenylethylamine did not relax the contracture. The possibilities of the involvement of cyclic GMP in the presynaptic and postsynaptic relaxing mechanisms in the ABRM are discussed.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Possible role for cyclic GMP in endothelium-dependent relaxation of rabbit aorta by acetylcholine. Comparison with nitroglycerin.

A possible role for cyclic GMP as a mediator of the endothelium-dependent relaxation of rabbit aorta by acetylcholine has been investigated using rabbit aortic rings with and without intact endothelium. In the presence of intact endothelial cells, acetylcholine caused marked increases in tissue levels of cyclic GMP accompanied by relaxation of the muscles. In aortic rings from which the endothelium had been removed, acetylcholine caused neither cyclic GMP elevation nor relaxation of the muscles. Acetylcholine-induced relaxation and cyclic GMP elevation in preparations with intact endothelium were both blocked by atropine. Reasonably good temporal and dose-response correlations between cyclic GMP elevation and relaxation were obtained with acetylcholine. Thus, although a causal relationship has not been definitely established, these results are consistent with the proposed role for cyclic GMP as a mediator of the endothelium-dependent relaxation of rabbit aorta by acetylcholine. In contrast to the results with acetylcholine, elevation of cyclic GMP and relaxation of aortic rings by nitroglycerin were not dependent on the presence of endothelial cells. Lower doses of nitroglycerin relaxed the muscles without elevating cyclic GMP levels. At higher concentrations of nitroglycerin, greater relaxation was obtained for a given degree of cyclic GMP elevation than was the case with acetylcholine. These results suggest that at least part of nitroglycerin's relaxant effect in this tissue is independent of cyclic GMP elevation.

Acetylcholine↗
PubMed1995

Characterization of ciliary muscle relaxation induced by various agents in cats.

PURPOSE: To understand the cellular mechanism underlying the relaxation of ciliary muscle, relaxation induced by prostaglandins (PGs) and some other agents was characterized in the cat. METHODS: Tone of isolated ciliary muscle was measured by means of a force-displacement transducer. Adenylate cyclase activity was determined with membrane fraction of ciliary muscle by measuring the formation of cyclic adenosine monophosphate (cAMP). RESULTS: The addition of various PGs and isoproterenol relaxed the ciliary muscle that had been precontracted with 3 x 10(-6) M carbachol. The relaxation was dose dependent, with an EC50 of 2 x 10(-7) M for PGE2. The rank order of potency by which PGs induced relaxation (PGE2 = E1 > D2 > F2 alpha > I2) was identical with that reported for EP type prostaglandin receptor-mediated responses except for PGD2, which was more potent than expected. Agents that increased cellular cAMP, such as forskolin and IBMX, also relaxed the precontracted muscle. Nitric oxide donors, such as sodium nitroprusside and S-nitroso-N-acetyl-DL-penicillamine (SNAP), also caused dose-dependent relaxation. PGs and isoproterenol, but not nitroprusside, stimulated adenylate cyclase. The rank order of potency by which PGs stimulate adenylate cyclase was similar to that observed for muscle relaxation, suggesting that cAMP is the cellular second messenger for the PG-induced muscle relaxation and thus that PG receptors of EP2 and DP type are involved. CONCLUSIONS: Relaxation of cat ciliary muscle is mediated by two independent mechanisms: a cAMP-dependent one, which includes beta-adrenergic, EP2, and DP receptor-mediated responses, and a cAMP-independent one, which includes the nitric oxide-induced mechanism.

Adenylyl Cyclases↗
PubMed1997

Kinetic studies of desensitization and resensitization of the relaxation response to beta-2 adrenoceptor agonists in isolated guinea pig trachea.

Activation of beta-2 adrenoceptors (BAR) in smooth muscle preparations is associated with a rapid, reversible and incomplete receptor desensitization, resulting in a steady-state relaxation response to BAR agonists. Based on results from cell culture studies, we hypothesize that, in the isolated guinea pig trachea, this steady state is a result of a concurrent resensitization of desensitizing BAR. In tracheal segments maintained at mechanical tone (4-6 g), isoproterenol (ISO) and the partial BAR agonist salbutamol (SALB) elicited a monotonic, rapid (1-3 min) and reproducible relaxation response that could be maintained for up to 45 min and was completely reversed by propranolol. Similarly, tissues preconstricted with 0.1 microM carbachol (CARB) responded with a sustained relaxation response to ISO. In contrast, in tissues preconstricted with 0.3 to 10 microM CARB or with 75 mM KCl, the relaxation elicited by ISO was followed by a slow (20-30 min) and partial restoration of muscle tone ("fade"). The relaxation and fade were observed when CARB-constricted tissues were relaxed with SALB (0.2 or 10 microM) or 10 microM salmeterol. No response to SALB was observed when tissues were preconstricted with KCl. The fade met criteria for its classification as a homologous desensitization of the relaxation response at the BAR level. In desensitized washed tissues, a complete recovery of the original relaxation response could be detected within 60 min of drug removal. A propranolol- and ICI 118-551-sensitive steady state was achieved 30 to 35 min after the addition of BAR agonists to the isolated tissues. A three-compartment phenomenological kinetic model accurately described the observed data, defining one steady-state and three rate constants, describing relaxation (k1), desensitization (k2) and resensitization (k3). The values of k2 and k3 for the response to SALB and to salmeterol were significantly larger than those observed for ISO. In the presence of KCl, the values of k2 and k3 for the response to ISO were indistinguishable from those measured in the presence of CARB. Given the parameters defined by our model, we propose that desensitization and resensitization of BAR in the isolated guinea pig trachea are distinct concurrent processes whose net result actively maintains a sustained partial relaxation response to ISO, SALB or salmeterol. The component of resensitization in the presence of agonist may account for the clinical efficacy of inhaled BAR agonists.

Adrenergic beta-2 Receptor Agonists↗
PubMed1998

Mechanism of gallbladder relaxation in the cat: role of norepinephrine.

We investigated the mechanisms of neurally mediated relaxation of cat gallbladder muscle. Muscle strips from the gallbladder corpus placed in the muscle bath with oxygenated Krebs' solution developed spontaneous active tension. Tension was measured with isometric force transducers, and muscle relaxation was expressed as percent decrease of active basal tension. Electrical field stimulation (EFS) evoked a tetrodotoxin-sensitive and hexamethonium-insensitive frequency-dependent relaxation with a maximal relaxation at 20 Hz. Gallbladder muscle strips also relaxed in response to increasing concentrations of vasoactive intestinal peptide (VIP), isoproterenol and, after pretreatment with phentolamine, norepinephrine. Nitric oxide synthase inhibitors N omega-nitro-L-arginine and N omega-nitro-L-arginine methyl ester at a concentration of 100 microM, which blocked EFS-induced relaxation in the lower esophageal sphincter, had no significant effect on EFS-induced gallbladder muscle relaxation. The VIP antagonists VIP10-28 and [4Cl-D-Phe6,Leu17]VIP at a concentration of 10 microM that blocked exogenous VIP-induced gallbladder relaxation also had no effect on the relaxation caused by EFS. In contrast, either propranolol or guanethidine at concentrations of > or = 1 microM significantly reduced EFS-evoked gallbladder relaxation (P < .01, analysis of variance). It is concluded that norepinephrine utilizing beta adrenergic receptors mediates EFS-stimulating postganglionic intramural neurons in the cat gallbladder.

Animals↗