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At least 397 records · Page 22Linked to original sources
PubMed2002

Functional contribution of voltage-dependent and Ca2+ activated K+ (BK(Ca)) channels to the relaxation of guinea-pig aorta in response to natriuretic peptides.

We examined the relaxant effects of natriuretic peptide family on the isolated guinea-pig aorta to determine the receptor subtype which primarily mediates this vascular relaxation, with particular attention to the apparent contribution of voltage-dependent and Ca2+-activated KS (BK(Ca)) channels to the response. Three endogenous natriuretic peptide ligands (natriuretic peptide, ANP; brain natriuretic peptide, BNP; C-type natriuretic peptide, CNP) produced a concentration-dependent relaxation in de-endothelialized guinea-pig aorta pre-contracted by noradrenaline (NA), with a potency order of ANP > or = BNP >> CNP. Although the relaxations elicited by these three natriuretic peptide ligands were significantly diminished by iberiotoxin (IbTx, 10(-7) M), a selective BK(Ca) channel blocker, the inhibitory effect of IbTx was most pronounced for the CNP-induced relaxation; when estimated at 10(-7) M of each peptide, the apparent extent of BK(Ca) channel contribution to the total relaxant response was approximately 60% for CNP > approximately 20% for either ANP or BNP. Supporting the substantial role of BK(Ca) channels in the vascular responses, high-KCl (80 mM) potently suppressed the relaxations induced by these natriuretic peptide ligands. The relaxant response to 8-Bromo-cyclic GMP, a membrane permeable cyclic GMP analogue, was also diminished by IbTx (10(-7) M) and high-KCl (80 mM), which indicates the key role of cyclic GMP in the BK(Ca) channel-mediated, natriuretic peptide-elicited vascular relaxation. These results indicate that the A-type receptor (NPR-A, which is more selective for ANP and BNP) rather than the B-type receptor (NPR-B, which is more selective for CNP) predominates in the guinea-pig aorta as the natriuretic peptide receptor which mediates this vascular smooth muscle relaxation. Although activation of BK(Ca) channels substantially contributes to both NPR-A- and NPR-B-activated relaxations, particularly in the NPR-B-activated relaxation, this K channel may function as a primary relaxant mediator in this conduit artery.

Animals↗
PubMed1992

Activation of a relaxation cascade in isolated coronary arteries by brief electrical pulses.

Superfused cattle coronary artery rings contracted with endothelin or with a thromboxane A2 mimetic respond to transmural stimulation with relaxation. These relaxations are not reduced by denudation of the endothelium, or by combined pretreatment with quanethidine, atropine and propranolol, nor do they involve free radicals. Stimulation at 0.5 Hz with an increasing number of pulses, from 1 to 50, each of 500 microseconds in duration, produced progressively greater and more prolonged relaxations. Human coronary arteries, denuded and pretreated with guanethidine or tetrodotoxin, also showed prominent relaxations of both spontaneous and induced contractions with minimal transmural stimulation at 0.5 Hz. The delivery of 10 pulses briefly depressed near-maximal contractions to combinations of two or even three spasmogens in the cattle preparations. Reduction of extracellular potassium to near zero did not reduce stimulation-induced relaxations, but decreases in extracellular calcium did. The participation of ATP-sensitive potassium channels in stimulation-induced relaxations was unlikely because glibencamide did not reduce them, although it antagonized the relaxation produced by the potassium channel opener pinacidil. Tetraethylammonium blocked the relaxations to stimulation, indicating the involvement of calcium-dependent potassium channels, but block of small to moderate conductance SK channels with apamin was ineffective in antagonizing relaxations, making it likely that activation of large conductance SK channels or maxi-K channels was involved. Blockade of stimulation-induced relaxation in low sodium Krebs', but not by vanadate (1 mM), indicated the likely involvement of the Na+/Ca++ exchanger rather than a Ca(++)-ATPase as the calcium extrusion component of the relaxation process. Restoration of prestimulation tone required calcium influx through nifedipine-sensitive channels. It is concluded that a highly effective relaxation cascade is initiated by the delivery of one to five 0.5-msec pulses at 0.5 Hz, whose effects long outlast the stimulation parameters. The significance of this finding for coronary pathophysiology and as a means of selectively activating a relaxation cascade in an intact coronary artery segment is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Mechanism of nicotine-induced relaxation in the porcine basilar artery.

The present experiment was designed to examine possible influence of adrenergic nerves on nicotine-induced neurogenic vasodilation in porcine basilar arteries denuded of endothelium. Nicotine and transmural nerve stimulation (TNS) induced relaxation of basilar arteries. Tetrodotoxin (TTX) abolished the relaxation elicited by TNS, but only partially blocked that induced by nicotine. Relaxation induced by both nicotine and TNS was abolished by N-nitro-L-arginine. The N-nitro-L-arginine inhibition of both TNS- and nicotine-induced relaxation was reversed by L-arginine but not by D-arginine. Hexamethonium abolished the relaxation induced by nicotine, but did not affect that elicited by TNS. Relaxation induced by nicotine was diminished by guanethidine, which did not affect the relaxation induced by TNS, suggesting that guanethidine blockade of nicotine-induced relaxation is not due to its local anesthetic effect. Results from histochemical studies indicated that catecholamine fluorescence and NADPH-diaphorase fibers were not appreciably affected by guanethidine. Following incubation with 6-hydroxydopamine for 1 hr, the catecholamine fluorescence fibers in the basilar arteries completely disappeared, although the NADPH-diaphorase fibers were not affected. In these adrenergically denervated arteries, nicotine-induced relaxation was abolished, while the TNS-elicited relaxation was not affected. Furthermore, norepinephrine-induced relaxation in basilar arteries was blocked by N-nitro-L-arginine, but was not affected by N-nitro-D-arginine or hexamethonium. These results suggest that in porcine cerebral arteries nicotine-induced nitric oxide-mediated relaxation is dependent on an intact adrenergic innervation. Nicotine appears to act on nicotinic receptors on the presynaptic adrenergic nerve terminals to release norepinephrine or a related substance, which then stimulates release of nitric oxide from the neighboring nitric oxidergic nerves. The TNS-elicited nitric oxide-mediated relaxation, however, is resulted from direct depolarization of nitric oxidergic nerves.

Animals↗
PubMedDate not supplied

A physiological and subjective evaluation of meditation, hypnosis, and relaxation.

Ss were monitored for respiratory rate, pulse rate, blood pressure, skin resistance, EEG activity, and muscle activity. They were monitored during the alert state, meditation (TM or simple word type), hypnosis (relaxation and task types), and relaxation. Ss gave a verbal comparative evaluation of each state. The results showed significantly better relaxation responses for the relaxation states (relaxation, relaxation-hypnosis, meditation) than for the alert state. There were no significant differences between the relaxation states except for the measure "muscle activity" in which meditation was significantly better than the other relaxation states. Overall, there were significant differences between task-hypnosis and relaxation-hypnosis. No significant differences were found between TM and simple word meditation. For the subjective measures, relaxation-hypnosis and meditation were significantly better than relaxation, but no significant differences were found between meditation and relaxation-hypnosis.

Adult↗
PubMedDate not supplied

Neuronally released (-)-noradrenaline relaxes smooth muscle of calf trachea mainly through beta 1-adrenoceptors: comparison with (-)-adrenaline and relation to adenylate cyclase stimulation.

The nature of the receptors that mediate the relaxation of smooth muscle by field stimulation, (-)-noradrenaline and (-)-adrenaline was investigated in calf tracheal smooth muscle. The relation between relaxation, stimulation of the adenylate cyclase and density of beta-adrenoceptor subtypes was studied with the help of antagonists of beta 1- and beta 2-adrenoceptors. The question of the existence of catecholamine-containing nerves was also investigated. (1) Nerves with varicosities exhibiting catecholaminergic fluorescence were observed between bundles of smooth muscle cells. (2) Consistent with the existence of adrenergic nerves (-)-noradrenaline was also found. The content of (-)-noradrenaline (1 microgram.g-1 w.w.) was the same in smooth muscle strips from the sublaryngeal region and from the region close to the bifurcation of the calf trachea. (-)-Adrenaline was not detected. (3) Smooth muscle relaxation by low (-)-noradrenaline concentration (0.6-2 nmol/l) was mediated through beta 1-adrenoceptors. Low concentrations of (-)-adrenaline (0.06-1 nmol/l) relaxed through beta 2-adrenoceptors. High concentrations of (-)-noradrenaline and (-)-adrenaline also caused relaxation through beta 2- and beta 1-adrenoceptors respectively. (4) Field stimulation caused relaxation which was half maximal at 0.2-0.8 Hz. Blockade of beta 1-adrenoceptors strongly attenuated the relaxant response to field stimulation and shifted the frequency-relaxation curves to 4 times higher frequencies. These results are consistent with a beta 1-adrenoceptor-mediated relaxation caused by (-)-noradrenaline released from sympathetic nerve endings at low stimulation frequencies. (5) Blockade of beta 2-adrenoceptors failed to reduce smooth muscle relaxation caused by field stimulation at low stimulation frequencies (0.1-1 Hz). However, after beta 1-adrenoceptor blockade, additional blockade of beta 2-adrenoceptors reduced the relaxant effects observed at high frequencies (2-400 Hz). The results suggest that high concentrations of endogenous (-)-noradrenaline cause relaxation through beta 2-adrenoceptors. (6) Binding experiments with 3H-(-)-bupranolol and 3H-ICI 118,551 revealed between 10,000 and 20,000 beta-adrenoceptors per smooth muscle cell of which 3/4 were beta 2 and 1/4 beta 1. The equilibrium dissociation constant of (-)-adrenaline for both beta 1- and beta 2-adrenoceptors and of (-)-noradrenaline for beta 1-adrenoceptors was 1 mumol/l. The affinity of (-)-noradrenaline for beta 2-adrenoceptors was 10 to 20 times lower than for beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

The role of nitric oxide (NO) in 5-HT-induced relaxations of the guinea-pig stomach.

In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide (NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hydroxytryptamine (5-HT) also induced relaxations in the guinea-pig stomach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establish whether NO is involved in the 5-HT-induced relaxations in the guinea-pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and alpha- and beta-adrenoceptor blocking agents did not influence the relaxation and since tetrodotoxin (TTX) blocked the relaxations, this effect is mediated via NANC-neurons. Administration of a NO-synthase-inhibitor NG-nitro-L-arginine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxations. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanylate cyclase, reduced the relaxations by 50%. Addition of an opioid receptor agonist (loperamide), a 5-HT1 antagonist (methiothepin or metergoline) or a 5-HT4 receptor agonist (cisapride) or -antagonist (tropisetron in micromolar concentrations) inhibited the 5-HT-induced relaxations. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1986

Effects of carbon dioxide and tetanus duration on relaxation of frog skeletal muscle.

Sartorius and semitendinosus muscles of the frog Rana temporaria (0 degrees C) were stimulated under isometric (fixed-end) conditions and force during stimulation and relaxation was recorded. Relaxation time was assessed by measuring the time from the last stimulus until force declined to 90% or 50% of its value at that time. The relaxation time increased linearly with concentration of CO2 in the Ringer's solution (pH 7.2), whereas, at constant CO2, relaxation was hardly affected by changes in extracellular HCO3- and pH. This is consistent with the view that CO2 enters the cells, but H+ and HCO3- do not, and that entry of CO2 causes intracellular acidification and slows relaxation. For tetani lasting between 0.5 and 5s, relaxation is slower the longer the tetanus; further increase in tetanus duration to 10 s has little additional effect. The presence of 3.3 mmol 1(-1) CO2 in the Ringer's solution has a small effect on relaxation after a brief tetanus, but greatly slows relaxation as tetanus duration increases. Experiments with paired tetani (conditioning and test) showed that relaxation from a test tetanus was slower if a conditioning tetanus was given. However, the size of this effect was independent of muscle length during the conditioning tetanus. After a conditioning tetanus, an interval of many minutes is required for the muscle to recover its ability to relax quickly from a test tetanus. The results indicate that changes in metabolite levels caused by contraction itself are not responsible for the slowing of relaxation. Possible mechanisms of the effects of CO2 on relaxation are discussed.

Animals↗
PubMed1997

Characterization by antagonists of P2-receptors mediating endothelium-dependent relaxation in the rat aorta.

The receptors through which 2-methylthio ATP (MeSATP), adenosine 5'-O-(2-thiodiphosphate) (ADP beta S), UTP and ATP elicit endothelium-dependent relaxation of noradrenaline-precontracted rings of the rat aorta were characterized by means of a series of antagonists. The acetylcholine-induced relaxation and the degradation of MeSATP, UTP and ATP were also studied. The potency of the nucleotides at producing relaxation decreased in the order MeSATP (EC50 0.24 microM) > ADP beta S (0.43 microM) > UTP (1.09 microM) > ATP (3.53 microM). MeSATP, ADP beta S and UTP did not cause relaxation when the endothelium had been destroyed; high concentrations of ATP still caused some relaxation. The relaxation by MeSATP, ADP beta S and UTP became very small after treatment of the rings with NG-nitro-L-arginine methyl ester; the relaxation by ATP was less affected. Pre-exposure to MeSATP (100 microM) abolished or almost abolished the relaxation normally elicited by MeSATP and ADP beta S, did not change that elicited by UTP and slightly enhanced the relaxation elicited by ATP. Of nine compounds examined as antagonists, six attenuated selectively the effect of some or all of the nucleotides (as compared to acetylcholine): suramin, reactive blue 2, pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS), pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), reactive red 2 and 5,5'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-7-amino -6-hydroxy-naphthalene-1,4-disulphonate (NH05). Decreases of maximal relaxations and slopes different from unity in Schild plots often indicated non-competitive kinetics of the antagonism. For each of the six 'selective' antagonist, the apparent Kd values against MeSATP and against ADP beta S were similar: none of the six differentiated between MeSATP and ADP beta S. Also, for each of four 'selective' antagonists, the apparent Kd values against UTP and against ATP were similar: none of the four differentiated between these two nucleotides (two antagonists did not act against UTP and ATP in the 'selective' concentration range). On the other hand, for five of the six 'selective' antagonists (the exception being NH05), the apparent Kd values against MeSATP and ADP beta S were considerably lower than those against UTP and ATP. At the highest concentrations tested against agonist-evoked relaxations, the antagonists did not alter the removal from the incubation medium, by pieces of rat aorta, of MeSATP, UTP and ATP. It is concluded that nucleotides cause endothelium-dependent relaxation of the rat aorta through two sites: a P2Y-receptor and a P2U-receptor. The receptors may be pharmacologically similar to a bovine endothelial P2Y (P2Y1) and a cloned rat P2U (P2Y2) receptor, respectively. ATP acts mainly through the P2U-receptor. Suramin, reactive blue 2, iso-PPADS, PPADS and reactive red 2 are more potent at the P2Y- than the P2U-receptor. NH05 does not discriminate between the two receptors but is the most potent P2U antagonist so far described.

Acetylcholine↗
PubMed2003

Evidence for the primary role for 4-aminopyridine-sensitive K(v) channels in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles.

Gastrointestinal smooth muscles exhibit relaxation in response to the stimulation of beta-adrenoceptors with catecholamines. Subtypes of beta-adrenoceptors which mediate catecholamine-elicited relaxations in gastrointestinal smooth muscles are predominantly atypical beta-adrenoceptors including beta(3)-adrenoceptors. Gastrointestinal smooth muscle relaxations mediated via beta(3)-adrenoceptors can occur independently of intracellular cyclic adenosine monophosphate (AMP) elevation. One of the mechanisms responsible for cyclic AMP-independent smooth muscle relaxation following activation of G(s) protein-coupled receptors could be activation of voltage-gated K(+) channels. In the present study, possible contribution of two types of K(+) (large-conductance, Ca(2+)-sensitive and voltage-gated K(+), BK(Ca); voltage-gated, K(v)) channels to beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations was compared in gastric fundus and duodenum smooth muscles isolated from the guinea-pig. In these gastrointestinal smooth muscles, three catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline) and two beta(3)-adrenoceptor agonists ((R(*), R(*))-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium (BRL37344) and (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy] -1,3-dihydro-2H-benzimidazol-2-one] hydrochloride ((+/-)-CGP12177A)) elicited a concentration-dependent relaxation in the presence of beta(1)- and beta(2)-adrenoceptor antagonists. The relaxations were unaffected by an adenylyl cyclase inhibitor, SQ-22536 (100 microM), which indicates their characteristic of cyclic AMP-independency. On the other hand, the SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxant components were potently attenuated when the tone was raised using high-KCl (80 mM) or in the presence of a K(v) channel blocker, 4-aminopyridine (4-AP, 1-3 mM). Iberiotoxin (100 nM), a selective blocker of BK(Ca) channels which significantly contribute to cyclic AMP-independent vascular smooth muscle relaxations induced through activation of G(s) protein-coupled receptors, did not apparently show any inhibitory effects on SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxations in these gastrointestinal smooth muscles. The present results indicate that 4-AP-sensitive K(v) channels play a primary role in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles. In these smooth muscles, BK(Ca) channels seem to apparently contribute insignificantly to cyclic AMP-independent relaxations following stimulation of beta(3)-type of adrenoceptors.

4-Aminopyridine↗
PubMed1985

Relaxant effect of phospholipase A2 from Vipera russelli snake venom on rat aorta.

The effect of the acidic phospholipase A2 (PLA2) from Vipera russelli venom on the rat aortic ring was studied and compared with that of acetylcholine (ACh). PLA2 induced relaxation of the aortic ring precontracted with noradrenaline (NA) in a dose-dependent manner. Removal of the endothelium did not reduce the relaxant effect of PLA2. Replacement of Ca2+ by Sr2+ in the medium to inhibit the PLA2 enzyme activity reduced the relaxant effect. Atropine, a muscarinic receptor antagonist, did not affect the relaxant response. The cyclooxygenase inhibitor indomethacin, when equilibrated for 50 min, potentiated the relaxation. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) partially reduced the relaxation. This relaxation was also partially reduced by the guanylate cyclase inhibitor methylene blue. In contrast, the relaxation elicited by ACh was abolished by de-endothelialization, atropine, NDGA or methylene blue. 6-keto-PGF1 alpha (degradation product of prostacyclin) and PGE2 produced by aortic rings were measured by radioimmunoassay. PLA2 (3 X 10(-6) g/ml) increased the output of 6-keto-PGF1 alpha about 10-fold. The production of PGE2 was also increased but to a lesser extent. ACh also increased the output of 6-keto-PGF1 alpha and PGE2. However, prostacyclin released by PLA2 and ACh appears not to contribute to the relaxant effect, since prostacyclin does not relax the rat aorta. It is concluded that the relaxation elicited by PLA2 in the rat aorta is endothelium-independent and partially mediated by lipoxygenase product(s) and cyclic GMP whereas the relaxation induced by ACh was endothelium-dependent, mediated by lipoxygenase product(s) and cyclic GMP, and blocked by atropine.

Acetylcholine↗
PubMed1989

Roles of calcium and the endothelium in the relaxations produced by 5'-N-ethylcarboxamidoadenosine (NECA).

The aim of the present investigation was to evaluate the endothelium dependency in the relaxations by the adenosine analog, 5'-N-ethylcarboxamidoadenosine (NECA), and the requirement for extracellular calcium in endothelium-dependent and independent relaxations. In prostaglandin F2 alpha (PGF2 alpha)-contracted bovine coronary arteries with intact endothelium, bradykinin produced relaxations in calcium medium but not in calcium-free medium. Removal of the endothelium abolished the relaxing response to bradykinin. In calcium medium, NECA produced similar relaxations in coronary arteries with intact and mechanically disrupted endothelium. The relaxation-response curves for NECA were shifted to the right in parallel in calcium free medium. Sodium nitroprusside produced concentration-dependent relaxations which were endothelium-independent. Removal of calcium from the bathing medium caused partial but significant attenuation of these relaxations. The results indicated that in bovine coronary artery, relaxations induced by NECA were endothelium-independent. Also bradykinin-induced relaxations are totally dependent on calcium whereas the endothelium-independent relaxing agents such as NECA and sodium nitroprusside require calcium only partially for their relaxations.

Adenosine↗
PubMed2005

Beta-adrenoceptor-mediated vascular relaxation in spontaneously hypertensive rats.

Although the impairment of beta-adrenoceptor (beta-AR)-induced vascular relaxation to isoprenaline has been extensively described, discrepancy persisted in the literature. In this work, we investigated beta-AR-induced relaxation in spontaneously hypertensive and normotensive rats aorta. We attempted to determine beta-AR subtypes involved in order to understand the conflicting data regarding the beta-AR-induced vasodilation to isoprenaline. Aortic rings isolated from 12-week-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were placed in organ baths and constricted with phenylephrine (alpha1-AR agonist). Then, cumulative concentration-relaxation curves (CCRC) to AR agonists were constructed. In intact aortic rings from both strains, isoprenaline (a nonselective beta-AR agonist) (0.001-10 microM) induced similar concentration-dependent relaxations. CCRC was shifted to the right and upward in the presence of nadolol (a nonspecific beta1 and beta2-AR antagonist) (10 microM). After endothelium removal, the response to isoprenaline was partly inhibited in WKY rats, but was strongly inhibited in SHRs. In WKY rats, isoprenaline-induced endothelium-independent relaxation was not modified in the presence of nadolol but was inhibited in the presence of CGP 20712A (low-affinity-state beta1-AR antagonist). In endothelium-denuded rings, SR 58611A (a preferential beta3-AR agonist) (0.1-30 microM) produced a very small relaxation in both strains. In WKY rats, CGP 12177 (CGP) (0.1-30 microM) and cyanopindolol (0.01-3 microM) (partial beta3-AR and low-affinity-state beta1-AR agonists with beta1-AR and beta2-AR antagonistic properties) produced endothelium-independent relaxations. CGP-induced effect was significantly inhibited by CGP 20712A (10 microM) or bupranolol (10 microM) (low-affinity-state beta1-AR antagonists). In SHRs, similarly to the impaired endothelium-independent relaxation to isoprenaline, endothelium-independent relaxations to CGP and cyanopindolol were greatly blunted. These relaxations were not modified in the presence of CGP 20712A. In endothelium-denuded rings pretreated with pertussis toxin, CGP-induced relaxation was not modified in WKY rats, but was partly restored in SHRs. In conclusion, these results showed, that in 12-week-old SHRs, the endothelium-independent component of the relaxation to isoprenaline was impaired, and this impairment could involve the low-affinity-state beta1-AR. G(i) protein overexpression and/or overstimulation may be possible factors that contribute to this alteration in hypertension.

Adrenergic beta-Agonists↗
PubMed2006

Effect of anandamide on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum.

The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide on the nonadrenergic noncholinergic (NANC) relaxant responses to electrical field stimulation in isolated rat corpus cavernosum. The corporal strips were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 microM) and atropine (1 microM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated relaxation. The expression of CB1, CB2 and vanilloid receptor proteins within the rat corpus cavernosum was evaluated using western blot analysis. The results showed that the relaxant responses to electrical stimulation were significantly enhanced in the presence of anandamide at 1 and 3 microM. The potentiating effect of anandamide (1 microM) on relaxation responses was significantly attenuated by either the selective cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; 1 microM) or the vanilloid receptor antagonist capsazepine (3 microM), but not by the selective cannabinoid CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl (4-methoxyphenyl)methanone (AM630; 1 microM). Neither of these antagonists had influence on relaxation responses. Indomethacin (20 microM) had no effect on NANC-mediated relaxation in the presence or absence of anandamide (1 microM). Preincubation with Nw-Nitro-L-Arginine Methyl Ester (L-NAME; 1 microM) significantly inhibited the relaxation responses in the presence or absence of 1 microM anandamide. Although at 30 nM, L-NAME did not cause a significant inhibition of relaxant responses individually, it significantly inhibited the potentiating effect of anandamide (1 microM) on relaxation responses. Anandamide (1 microM) had no influence on concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1 mM), a nitric oxide (NO) donor. The western blotting of corporal tissues demonstrated the existence of both vanilloid and CB1 receptors in corporal strips. In conclusion, our results showed that anandamide has a potentiating effect on NANC-mediated relaxation of rat corpus cavernosum through both CB1 and vanilloid receptors and the NO-mediated component of the NANC relaxant responses to electrical stimulation is involved in this enhancement.

Animals↗
PubMed2003

5-HT7 receptor-mediated relaxation of the oviduct in nonpregnant proestrus pigs.

The effects of 5-hydroxytryptamine (5-HT) on the muscle tonus of the ampulla and isthmus of the oviduct isolated from nonpregnant proestrus pigs were investigated, and the 5-HT receptor subtype and mechanisms of the responses were analyzed. 5-HT (1 nM-10 microM) caused a relaxation of longitudinal and circular muscles of the isthmus in a concentration-dependent manner. Tetrodotoxin did not change the relaxation, indicating a direct action of 5-HT on smooth muscle cells. The EC(50) value in the longitudinal muscle was significantly lower than that in the circular muscle but the maximum relaxations were similar. 5-HT also caused a relaxation of both muscle layers in the ampulla but the maximum relaxation of both muscles was smaller than that of the isthmus. 5-Carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) mimicked the relaxation of the isthmic longitudinal muscle by 5-HT, and the ranking order was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT), alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT), [endo-N-8-methyl-8-azabicyclo-(3,2,1) oct-3-yl]-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide (BIMU-1), ergotamine and dihydroergotamine were less effective. The relaxation by 5-HT was not decreased by ketanserin, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester (tropisetron) or [1[2-(methylsulphonyl) amino ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) but was antagonized by the following compounds in a competitive manner (with pK(b) values in parentheses): 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydro-benzo[cd]indol-2(1H)-one (DR4004, 9.31), methiothepin (8.91), methysergide (7.95), metergoline (7.98), mianserin (7.69), mesulergine (8.4), spiperone (6.86) and clozapine (7.4). The correlation of these pK(b) values with pK(i) values of cloned 5-HT(7) receptor or pA(2) values of porcine uterus was high and significant. 4-(3-Butoxy-4-methoxybenzyl)-imidazolidin-2-one (Ro20-1724) significantly enhanced the relaxation by 5-HT but zaprinast, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and L-nitroarginine methylester (L-NAME) did not change the responses to 5-HT. 5-HT increased cyclic AMP in the isthmic oviduct. Ampulla and isthmus contained a single class of [3H]5-CT binding sites with a similar K(d) value (0.4 nM), but the density of the receptors in the isthmus was 2.4 times higher than that in the ampulla. A significant correlation was found between the pK(i) values in the oviduct and those of the cloned 5-HT(7) receptors. Isoprenaline, sodium nitroprusside, vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide were less effective in causing the relaxation of the oviduct. In conclusion, the 5-HT receptor, functionally correlated to the 5-HT(7) type, mediates the relaxation of the porcine oviduct by 5-HT through an increase in intracellular cyclic AMP. The degrees of 5-HT-induced relaxation in the isthmus and ampulla of the oviduct were different due to the heterogeneous distribution of 5-HT(7) receptors. The strongest relaxation through 5-HT(7) receptor activation suggests that 5-HT plays an important physiological role in the regulation of porcine oviduct contractility.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase.

Endothelial cells play an important role in the regulation of vascular activity through the release of endothelium derived relaxing factor (EDRF) now believed to be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane has been shown to inhibit the action of NO on blood vessels. This study was designed to further investigate the mechanisms by which halothane attenuates NO-induced vascular relaxations. This was done by examining the effects of halothane on nitroglycerin and NO-induced relaxations in the presence and absence of the inhibitors of soluble guanylyl cyclase, methylene blue and 6-anilino-5,8-quinolinedione (LY 83583). Thoracic aortas from anesthetized male Sprague-Dawley rats were excised and cut into rings and the endothelium was removed. The aortic rings were suspended in organ baths containing Krebs solution and equilibrated at their optimal passive tension. When a stable plateau of contraction was produced by EC60 concentrations of norepinephrine, increasing concentrations of nitroglycerin or NO were added to the baths to relax the rings. This contraction-relaxation procedure was repeated three or four times. In some baths halothane was administered by a calibrated vaporizer 10 min before beginning the second procedure. Either methylene blue or LY 83583 was added to the baths 20 min before the third procedure. The combination of halothane, methylene blue or LY 83583 was added before the fourth procedure. Halothane, methylene blue or LY 83583 significantly inhibited nitroglycerin-induced relaxation individually. Halothane and LY 83583 also significantly inhibited NO-induced relaxations (5 x 10(-9)-3 x 10(-8) M and 5 x 10(-9)-3 x 10(-5) M, respectively) individually. The combination of halothane and methylene blue or halothane and LY 83583 significantly inhibited nitroglycerin-induced relaxation, also, the combination of halothane and LY 83583 significantly inhibited NO-induced relaxations. Halothane, methylene blue and LY 83583 treatment led to rightward shift in the concentration-effect curves. Halothane, in combination with methylene blue or LY 83583, produced inhibition equivalent to the sum of their individual effects. The present study demonstrates that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO-induced relaxations of endothelium-denuded rat aortic rings. This suggests that halothane, methylene blue and LY 83583 may act through competitive antagonism at a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation pathway.

Aminoquinolines↗
PubMed1999

K(+) channel blockers and cytochrome P450 inhibitors on acetylcholine-induced, endothelium-dependent relaxation in rabbit mesenteric artery.

Acetylcholine caused an endothelium-dependent relaxation in isolated rabbit mesenteric small artery in the presence of nitro L-arginine and indomethacin. The acetylcholine-induced relaxation was attenuated by high K(+) solution, suggesting that the response is mediated by a membrane potential-sensitive mechanism, presumably an endothelium-derived hyperpolarizing factor. The acetylcholine-induced relaxation was also inhibited with tetraethylammonium, 4-aminopyridine and charybdotoxin, but not with Ba(2+), apamin, iberiotoxin nor glibenclamide. The relaxation was abolished by a combination of apamin and charybdotoxin, but iberiotoxin could not replace charybdotoxin in this combination. The responses to charybdotoxin and 4-aminopyridine were synergistic but neither apamin nor iberiotoxin increased the effect of 4-aminopyridine. Clotrimazole and proadifen inhibited the acetylcholine-induced relaxation, but these drugs also inhibited the cromakalim-induced relaxation, while protoporphyrin IX inhibited the acetylcholine- but not cromakalim-induced relaxation. 17-Octadecynoic acid and 1-aminobenzotriazole did not affect the response to acetylcholine. Four regioisomers of epoxyeicosatrienoic acids did not relax endothelium-denuded artery. A gap junction inhibitor 18alpha-glycyrrhetinic acid attenuated the relaxation to acetylcholine. It is suggested that in rabbit mesenteric artery, the acetylcholine-induced, nitric oxide- and prostacyclin-independent relaxation is mainly mediated by 4-aminopyridine- and charybdotoxin-sensitive K(+) channels and that the relaxation is not mediated through cytochrome P450 enzyme metabolites. The contribution of heterocellular gap junctional communication to the relaxation is discussed.

8,11,14-Eicosatrienoic Acid↗
PubMed1998

Comparison of relaxations evoked by photoactivation of NO-containing compounds and nitrergic nerve stimulation in 5-hydroxytryptamine- and potassium-contracted rat gastric fundus.

1. The aim of the present study was to further investigate our earlier proposal of liberation of nitric oxide (NO) by photoactivation of molecules containing NO or NO2, which in turn relaxes gastric smooth muscle, and to determine whether presynaptic- and/or postsynaptic NO-mediated relaxation is affected differently by the degree of membrane depolarization in rat gastric fundus smooth muscle. 2. During contraction of rat gastric fundus with 5-hydroxytryptamine (5-HT, 10 microM), low (K+, 25 mM) and high potassium (K+, 65.4 mM), relaxation responses to nitrergic nerve stimulation, photo-activation of caged NO compounds (streptozotocin [STZ], N omega-nitro-L-arginine-methylacetate [L-NAME], N omega-nitro-D-arginine-methylacetate [D-NAME]), and sodium nitroprusside (SNP) were compared. 3. Nitrergic nerve (presynaptic) stimulation and photoactivation (postsynaptic) of all caged NO compounds produced rapid, transient and reversible relaxation of 5-HT and low-K(+)-contracted tissues. However, when contractions were induced by high K+, the relaxation induced by nerve stimulation was abolished, whereas relaxations induced by photoactivated NO compounds were significantly (P < 0.01) reduced. 4. The relaxation induced by sodium nitroprusside (SNP), but not papaverine, was also diminished in high-K(+)-contracted tissues. The magnitude of photoactivated NO-induced relaxation was related to the amount of NO release, light intensity and concentration of compounds. 5. The evidence that photoactivated NO-induced relaxation is mediated by cGMP comes from the observation that zaprinast, but not forskolin, potentiated the relaxation. 6. It is concluded that rat gastric smooth muscle relaxes to photoactivation of NO or NO2-carrying molecules via NO, and it appears that degree of membrane depolarization may be a critical factor in dissociating the response to presynaptic- and postsynaptic NO-mediated relaxation in this muscle.

Animals↗
PubMed1999

Methodologic aspects of acetylcholine-evoked relaxation of rabbit aorta.

The acetylcholine-evoked relaxation of rabbit isolated thoracic aorta precontracted by phenylephrine was studied. Phenylephrine caused a steady contraction that was maintained for 6 h. In the presence of calcium disodium ethylenediaminetetraacetate (EDTA) and ascorbic acid the contraction decreased with time. N(G)-Nitro-L-arginine abolished the inhibitory effect of EDTA and ascorbic acid. Acetylcholine evoked a rapid concentration-dependent relaxation that recovered spontaneously and slowly, but fully, with time. Relaxation evoked by equieffective concentrations of carbachol and acetylcholine had the same time course. Cumulative addition of acetylcholine (10(-7)-3 x 10(-5) M) caused a marked relaxation that was reverted slightly at high concentrations. The relaxation was the same with rings derived from the upper, middle, and lower part of the thoracic aorta. Two consecutive concentration-response curves for acetylcholine obtained at a 2-h interval demonstrated a slight development of tachyphylaxis. The relaxation was inversely related to precontractile tension evoked by phenylephrine when expressed as a percentage, but independent when expressed as g tension. Storage of aorta in cold salt solution for 24 h did not alter the relaxation. EDTA and ascorbic acid did not alter the relaxation. It is concluded that (1) EDTA and ascorbic acid can not be used with impunity to stabilize catecholamines used as preconstriction agents; (2) the reversal of the acetylcholine-evoked relaxation is not due to hydrolysis of acetylcholine; (3) the relaxation is uniform in all segments of thoracic aorta; (4) cold storage of aorta does not alter the relaxation; and (5) acetylcholine releases the same amount of relaxing factor, irrespective of the precontractile tension.

Acetylcholine↗