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PubMed2005

The relaxant activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]-pyridazine 1,5,6-trioxide in the mouse corpus cavernosum.

We have studied the effect of an activator of soluble guanylate cyclase 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (FPTO) on the tone and nitrergic relaxation responses of mouse cavernous strips and compared FPTO to a known nitric oxide donor sodium nitroprusside. FPTO thiol-dependently generated nitric oxide measured by polarography and activated purified human soluble guanylate cyclase. FPTO and sodium nitroprusside relaxed the cavernous tissue in a concentration-dependent manner. A nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine did not alter the relaxations to FPTO or sodium nitroprusside, whereas soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) suppressed relaxation to FPTO and sodium nitroprusside. Exogenously added thiols L-cysteine or dithiothreitol inhibited the relaxant responses to FPTO but not to sodium nitroprusside, whereas glutathione did not influence the responses to both agents. Thiol alkylation agent N-ethylmaleimide significantly enhanced FPTO-induced relaxation, and thiol-modifying agent diamide inhibited relaxation to FPTO. The potentiating effect of N-ethylmaleimide was neutralized by coadministration of N-ethylmaleimide with glutathione, L-cysteine, dithiothreitol, or ODQ. N-Ethylmaleimide but not diamide significantly inhibited relaxation induced by sodium nitroprusside. FPTO potently suppressed contraction to electrical field stimulation, which was prevented by glutathione or L-cysteine. In addition, FPTO did not affect relaxation produced by electrical field stimulation in phenylephrine-precontracted tissue. Our results show that FPTO can relax mouse corpus cavernosum and that the relaxant activity of this agent is thiol- and soluble guanylate cyclase-dependent. This effect could be potentiated by N-ethylmaleimide. FPTO does not potentiate nitrergic relaxation induced by electrical field stimulation.

Animals↗
PubMed2005

Pharmacologic characterization of intrinsic mechanisms controlling tone and relaxation of porcine lower esophageal sphincter.

The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 microM), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 microM), ATP (10 microM-30 mM), and tricarbonyldichlororuthenum dimer (1 microM-1 mM) was unaffected by tetrodotoxin (1 microM) or l-N(G)-nitroarginine methyl ester (l-NAME; 100 microM). Calcitonin gene-related peptide (CGRP; 1 nM-1 microM) did not affect LES tone. ATP relaxation was blocked by 1 microM apamin and the P2Y(1) antagonist MRS 2179 (N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate; 10 microM). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml alpha-chymotrypsin. L-NAME (-62.52 +/- 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-alpha]quinoxalin-1-one (ODQ; 10 microM, -67.67 +/- 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 microM) was inhibited by L-NAME (-60.37 +/- 10.8%) and ODQ (-41.90 +/- 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by alpha-chymotrypsin and the P2X(1,2,3) receptor antagonist NF 279 (8,8 cent-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 microM), and unaffected by tin protoporphyrin IX (100 microM). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y1 receptors and a minor contribution of purinergic P2X1,2,3 receptors and PACAP. Nitrergic and purinergic co-transmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.

Adenosine Diphosphate↗
PubMed1997

The influence of intermittent fatigue exercise on early and late phases of relaxation from maximal voluntary contraction.

Twenty-two young male subjects were tested to estimate the behavior of the early and late phases of relaxation from a 3-s maximal voluntary contraction (MVC) under the influence of fatigue. Less demanding and more demanding protocols of intermittent hand grip exercise were used to fatigue muscle. Before and after fatigue, the early and late relaxation time, maximal relaxation rate, and half-relaxation time were measured. The results showed that during voluntary movement (a) the early phase of relaxation was independent of the mode of intermittent exercise and did not change significantly after fatigue; (b) the late relaxation time and absolute maximal relaxation rate were slower after both protocols, with the changes more pronounced following the more demanding protocol; and (c) the half-relaxation time and relative maximal relaxation rate were changed only in the more demanding protocol. It is concluded that unlike the relaxation following electrical stimulation of isolated muscle, the early phase of relaxation from voluntary contraction appears to be the most resistant to the type of intermittent fatiguing exercise used in the present study, whereas the late relaxation time was the most sensitive to this type of fatigue.

Adult↗
PubMed1991

Inhibition of the acetylcholine-induced relaxation of canine isolated basilar artery by potassium-conductance blockers.

Canine basilar artery rings precontracted with 5-hydroxytryptamine (0.1-0.5 microM) relaxed in the presence of acetylcholine (25-100 microM), sodium nitroprusside (0.1 microM), or stimulation of the electrogenic sodium pump by restoration of extracellular K+ (4.5 mM) after K(+)-deprivation. Acetylcholine-induced relaxation is believed to be caused by the release of endothelium-derived relaxing factor (EDRF) and is prevented by mechanical removal of the endothelium, while relaxations induced by sodium nitroprusside or restarting of the sodium pump are endothelium-independent. Acetylcholine-induced relaxation was selectively blocked by pretreatment of the tissue with the nonselective K+ conductance inhibitors, 4-aminopyridine (4-AP, 3 mM), Ba2+ (1 mM), and tetraethylammonium (20 mM), 4-AP also blocked ACh-mediated relaxation in muscles contracted with elevated external K+. Relaxation of 5-hydroxytryptamine-induced contraction by sodium nitroprusside, or by addition of K+ to K(+)-deprived muscle, was not affected by 4-AP. Relaxation of basilar artery with acidified sodium nitrite solution (containing nitric oxide) was reduced by 4-AP. These results suggest that 4-AP and possibly Ba2+ inhibit acetylcholine-induced endothelium-dependent relaxation by inhibition of the action of EDRF on the smooth muscle rather than through inhibition of release of EDRF. The increase in K+ conductance involved in acetylcholine-induced relaxation is not due to ATP-inhibited K+ channels, as it is not blocked by glyburide (10(-6) M). Endothelium-derived relaxant factor(s) may relax smooth muscle by mode(s) of action different from that of sodium nitroprusside or by hyperpolarization due to the electrogenic sodium pumping.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed2006

Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers.

Our aim was to define normal esophagogastric junction (EGJ) morphology and relaxation characteristics using high-resolution manometry (HRM). To this end, 75 asymptomatic controls underwent HRM with a solid-state manometric assembly incorporating 36 circumferential sensors spaced at 1-cm intervals positioned to record from the hypopharynx to the stomach. Ten 5-ml water swallows were obtained. EGJ relaxation was quantified by 1) nadir pressure, 2) the lowest 3-s mean residual pressure after swallow (E-sleeve), and 3) the transsphincteric gradient 2-6 s after swallowing measured from 2 cm above to 2 cm below the EGJ. A new parameter, integrated relaxation resistance (IRR), was also calculated. The IRR calculation accounted for both the duration of EGJ relaxation and instantaneous E-sleeve-type relaxation pressures during the entire interval of relaxation. The means and ranges (5-95th percentile) for nadir lower esophageal sphincter relaxation pressure (mean: 3.9 mmHg, range: 0-10.1 mmHg) and E-sleeve relaxation pressure (mean: 8.1 mmHg, range: 4.1-15.1 mmHg) were consistent with previously reported values. The mean relaxation interval was 7.95 +/- 0.2 s (mean +/- SE), whereas the median relaxation pressure during that interval was 10.7 +/- 0.5 mmHg (mean +/- SE). Mean IRR was 1.3 mmHg/s (95th percentile: 3.0 mmHg/s). Mean EGJ length was 3.7 cm. In conclusion, HRM provides a seamless dynamic representation of pressure within and across the EGJ. In addition to providing conventional EGJ relaxation parameters, this technology also creates opportunities to quantify more precise measures of EGJ relaxation and morphology.

Adult↗
PubMed1998

Rat gastroduodenal motility in vivo: interaction of GABA and VIP in control of spontaneous relaxations.

Spontaneous relaxations occurring within motor activity in the rat gastroduodenum in vivo can be distinguished by their dependence on either nitric oxide (NO) or ATP. We examined the interaction of gamma-aminobutyric acid (GABA) and vasoactive intestinal peptide (VIP) within pathways controlling this activity in the antrum (S) and duodenum (D) of anesthetized Sprague-Dawley rats, using miniaturized extraluminal foil strain gauges oriented perpendicular to (S1, D1) or in the axis of (S2) the circular smooth muscle. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) attenuated (P < 0.05) antral relaxations and, in the duodenum, nonpropagating "intergroup" relaxations. The GABAA receptor antagonist bicuculline (350 micrograms/kg sc) had similar effects. The GABAA agonist 3-amino-1-propanesulfonic acid stimulated L-NAME-sensitive relaxations at S1 and D1. Propagating "grouped" responses were unchanged. VIP (6 micrograms/kg iv) always induced a relaxation of the duodenum, which was attenuated by bicuculline and L-NAME. VIP caused simultaneous responses at S1 and S2; however, the antrum displayed either contraction or relaxation in response to VIP. All antral relaxations in response to VIP were attenuated (P < 0. 05) by L-NAME; however, only VIP-induced relaxations at S1 were sensitive to bicuculline. VIP-induced contractions were also unaffected. GABAA receptors mediate the pathway(s) controlling NO-related spontaneous relaxations of the antrum and duodenal circular muscle. All VIP-induced relaxations are mediated by NO. Spontaneous relaxations of the rat gastroduodenum include responses that involve a GABAAergic NO-related pathway, which is targeted by VIP. In addition, VIP can target NO relaxations of the antrum via other pathways.

Animals↗
PubMed1994

Isometric relaxation of isolated diaphragm muscle: influence of load, length, time, and stimulation.

Determinants of the isometric relaxation rate were investigated in isolated rat diaphragm (n = 30). We tested the hypothesis that these determinants could include loading conditions, namely preload and afterload; abrupt changes in load during the contraction phase; stimulation conditions; and time. Two relaxation sequences were studied. When isometric relaxation occurred at initial muscle length (isotonic-isometric sequence), an increase in total load (P) accelerated the negative peak rate of tension decline (-dP/dtmax). Variations in initial length, stimulation, and onset of relaxation did not modify the -dP/dtmax vs. afterload relationship. When isometric relaxation was analyzed after -dP/dtmax, for a given afterload level the instantaneous rate of tension decline (-dP/dt) was a unique function of instantaneous tension, regardless of previous loading conditions, stimulation mode, or time. When the isometric relaxation occurred at end-shortening muscle length (isometric-isotonic sequence), the -dP/dtmax vs. P relationship was flat. The rate of tension decay, as attested by either -dP/dtmax or instantaneous -dP/dt vs. instantaneous tension phase plane, differed markedly depending on stimulation conditions. Thus the regulation of isometric relaxation rate differed according to the relaxation sequence. In muscle isometrically relaxing at initial muscle length, peak isometric relaxation rate was mainly determined by afterload. Conversely, in muscle isometrically relaxing at end-shortening length, isometric relaxation rate was highly dependent on the level of activation and was independent of preload and afterload.

Animals↗
PubMed2002

Relaxation of guinea pig trachealis during electrical field stimulation increases with age.

Our laboratory has previously shown that maturation of airway smooth muscle (ASM) contractility may play a role in the airway hyperresponsiveness displayed by juveniles of many species, including humans (Chitano P, Wang J, Cox CM, Stephens NL, and Murphy TM. J Appl Physiol 88: 1338-1345, 2000). ASM relaxation, which could also contribute to airway hyperresponsiveness, has neither been described nor quantified during maturation. Therefore, we studied ASM relaxation during and after electrical field stimulation (EFS) in tracheal strips from 1-wk-old, 3-wk-old, and 3-mo-old guinea pigs. Strips were stimulated (60 Hz, 18 V) at their optimal length for 15, 20, and 25 s, with and without the cyclooxygenase inhibitor indomethacin. To evaluate the role of the epithelium, deepithelialized strips from adult animals were also studied. New indexes were developed to quantify relaxation during EFS. We measured the time course of tension relaxation and its maximum rate (RTR) during the EFS, as well as the residual tension at the end of the EFS (TCT(end)). After EFS, we measured the maximum RTR and the time needed to reduce to half the TCT(end). Relaxation during the EFS significantly increased with age. Indomethacin reduced this age difference by increasing relaxation in strips from younger animals. By contrast, removal of the epithelium in adult strips decreased relaxation. Relaxation after EFS decreased with age and was not affected by indomethacin. In adult strips, it was further reduced by epithelium removal. Our results show that during EFS 1) airway smooth muscle relaxation increases with age, 2) cyclooxygenase metabolites oppose relaxation in younger animals, and 3) epithelium removal inhibits relaxation. We suggest that a reduced ASM relaxing ability during stimulation may be involved in juvenile airway hyperresponsiveness.

Aging↗
PubMedDate not supplied

Cold storage induces an endothelium-independent relaxation to hypoxia/reoxygenation in porcine coronary arteries.

Tissues are often cold stored for physiological studies and for clinical transplantation. We report that cold storage induces a relaxation to reoxygenation after hypoxia (H/R) in de-endothelialized porcine coronary arteries. In fresh denuded arteries stimulated with U46619, H/R did not elicit relaxation. However, after overnight cold storage (4 degrees C), H/R elicited a transient relaxation with peak relaxation of 56 +/- 8% (n = 8), which was reproducible after 2 days of cold storage. The H/R relaxation was inhibited by methylene blue (10 microM) and LY83583 (10 microM), O2-hemoglobin (1 microM), or N(G)-methyl-L-arginine (0.2 mM), but neither N(G)-nitro-L-arginine (0.2 mM) nor cyclo-oxygenase inhibition was effective. Importantly, the H/R relaxation was attenuated by KCl (40 mM) or tetrabutylammonium chloride (5 mM), a non-selective inhibitor of K+ channels. Interestingly, authentic nitric oxide (NO)- or S-nitroso-N-acetylpenicillamine (SNAP)-induced relaxations were enhanced by cold storage in U46619 (0.1 microM) contractures. When tissues were contracted with KCl (40 mM), the enhancement in NO- or SNAP-induced relaxation by cold storage was markedly smaller than with U46619. Neither catalase (1,200 U/ml) nor 3-amino-triazole (50 mM), an inhibitor of catalase, affected the H/R relaxation. The duration of H/R relaxation also increased with the period of incubation at 37 degrees C in the organ bath. This was blocked by inhibition of NO synthesis or guanylate cyclase. Moreover, inhibition of protein synthesis with actinomycin D (0.1 microM) and cycloheximide (10 microM), or dexamethasone (1 microM), an inhibitor of NO synthase induction, blocked this increase in the duration of the H/R relaxation. The results suggest that in smooth muscle induction of NO pathway relaxation, which is in part mediated by K+ channels and inducible NO synthase, may be of importance to the understanding of ischemia/reperfusion responses in cold-stored arteries.

Animals↗
PubMed1989

Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta.

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Neural control of muscle relaxation in echinoderms.

Smooth muscle relaxation in vertebrates is regulated by a variety of neuronal signalling molecules, including neuropeptides and nitric oxide (NO). The physiology of muscle relaxation in echinoderms is of particular interest because these animals are evolutionarily more closely related to the vertebrates than to the majority of invertebrate phyla. However, whilst in vertebrates there is a clear structural and functional distinction between visceral smooth muscle and skeletal striated muscle, this does not apply to echinoderms, in which the majority of muscles, whether associated with the body wall skeleton and its appendages or with visceral organs, are made up of non-striated fibres. The mechanisms by which the nervous system controls muscle relaxation in echinoderms were, until recently, unknown. Using the cardiac stomach of the starfish Asterias rubens as a model, it has been established that the NO-cGMP signalling pathway mediates relaxation. NO also causes relaxation of sea urchin tube feet, and NO may therefore function as a 'universal' muscle relaxant in echinoderms. The first neuropeptides to be identified in echinoderms were two related peptides isolated from Asterias rubens known as SALMFamide-1 (S1) and SALMFamide-2 (S2). Both S1 and S2 cause relaxation of the starfish cardiac stomach, but with S2 being approximately ten times more potent than S1. SALMFamide neuropeptides have also been isolated from sea cucumbers, in which they cause relaxation of both gut and body wall muscle. Therefore, like NO, SALMFamides may also function as 'universal' muscle relaxants in echinoderms. The mechanisms by which SALMFamides cause relaxation of echinoderm muscle are not known, but several candidate signal transduction pathways are discussed here. The SALMFamides do not, however, appear to act by promoting release of NO, and muscle relaxation in echinoderms is therefore probably regulated by at least two neuronal signalling systems acting in parallel. Recently, other neuropeptides that influence muscle tone have been isolated from the sea cucumber Stichopus japonicus using body wall muscle as a bioassay, but at present SALMFamide peptides are the only ones that have been found to have a direct relaxing action on echinoderm muscle. One of the Stichopus japonicus peptides (holothurin 1), however, causes a reduction in the magnitude of electrically evoked muscle contraction in Stichopus japonicus and also causes 'softening' of the body wall dermis, a 'mutable connective tissue'. It seems most likely that this effect of holothurin 1 on body wall dermis is mediated by constituent muscle cells, and the concept of 'mutable connective tissue' in echinoderms may therefore need to be re-evaluated to incorporate the involvement of muscle, as proposed recently for the spine ligament in sea urchins.

Amino Acid Sequence↗
PubMed1992

[Mechanisms of histamine-induced relaxation in isolated dog mesenteric arteries and veins].

Mechanisms of histamine-induced relaxation in dog mesenteric artery and vein strips were compared. Histamine elicited a concentration-related relaxation in the arterial strips contracted with prostaglandin (PG) F2 alpha; the relaxations induced at 5 x 10(-7) M or higher were composed of phasic and tonic patterns. The phasic component of relaxation was inhibited by chlorpheniramine, but not by cimetidine. Combined treatment with the H1 and H2 antagonists abolished the amine-induced relaxation. The tonic component was inhibited by cimetidine. The phasic relaxation was attenuated by removal of the endothelium. Treatment with indomethacin inhibited the phasic component in the strips with endothelium, but did not influence the relaxation after endothelium denudation. Combined treatment with indomethacin and cimetidine, but not chlorpheniramine, abolished the response. On the other hand, histamine produced a concentration-related, tonic relaxation in the mesenteric vein strips. The relaxation was not influenced by indomethacin, endothelium-denudation, and chlorpheniramine, but was abolished by cimetidine. It may be concluded that the phasic relaxation of dog mesenteric arterial strips is mediated mainly by H1 receptors in the endothelium, resulting in the synthesis and release of PGI2. The tonic relaxation appears to be elicited by activation of H2 receptors in smooth muscle. Mesenteric vein relaxations induced by histamine are likely to be mediated solely by H2 receptors in smooth muscle.

Animals↗
PubMed1999

A role for N-arachidonylethanolamine (anandamide) as the mediator of sensory nerve-dependent Ca2+-induced relaxation.

We tested the hypothesis that an endogenous cannabinoid (CB) receptor agonist, such as N-arachidonylethanolamine (anandamide), is the transmitter that mediates perivascular sensory nerve-dependent Ca2+-induced relaxation. Rat mesenteric branch arteries were studied using wire myography; relaxation was determined after inducing contraction with norepinephrine. Cumulative addition of Ca2+ caused dose-dependent relaxation (ED50 = 2.2 +/- 0.09 mM). The relaxation was inhibited by 10 mM TEA and 100 nM iberiotoxin, a blocker of large conductance Ca2+-activated K+ channels, but not by 5 microM glibenclamide, 1 mM 4-aminopyridine, or 30 nM apamin. Ca2+-induced relaxation was also blocked by the selective CB receptor antagonist SR141716A and was enhanced by pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (pefabloc; 30 microM), an inhibitor of anandamide metabolism. Anandamide also caused dose-dependent relaxation (ED50 =.72 +/- 0.3 microM). The relaxation was not inhibited by endothelial denudation, 10 microM indomethacin, or 1 microM miconazole, but was blocked by 3 microM SR141716A, 10 mM TEA, precontraction with 100 mM K+, and 100 nM iberiotoxin, and was enhanced by treatment with 30 microM pefabloc. Mesenteric branch arteries were 200-fold more sensitive to the relaxing action of anandamide than arachidonic acid (ED50 = 160 +/- 7 microM). These data show that: 1) Ca2+ and anandamide cause hyperpolarization-mediated relaxation of mesenteric branch arteries, which is dependent on an iberiotoxin-sensitive Ca2+-activated K+ channel, 2) relaxation induced by both Ca2+ and anandamide is inhibited by CB receptor blockade, and 3) relaxation induced by anandamide is not dependent on its breakdown to arachidonic acid and subsequent metabolism. These findings support the hypothesis that anandamide, or a similar cannabinoid receptor agonist, mediates nerve-dependent Ca2+-induced relaxation in the rat.

Animals↗
PubMed2000

Nonadrenergic, noncholinergic relaxation of bovine iris sphincter: role of endogenous nitric oxide.

PURPOSE: To investigate the role of endogenously generated nitric oxide (NO) in the relaxation of bovine iris sphincter. METHODS: Isolated bovine sphincters were mounted on an isometric tension apparatus. Contraction-relaxation response was elicited by electrical field stimulation (ES; 12 Hz, 50-msec duration, 70-80 V). Relaxation was arbitrarily defined as maximal decrease of tension below prestimulation baseline after cessation of ES. We also determined the tissue levels of cyclic guanosine monophosphate (cGMP) by radioimmunoassay. RESULTS: ES produced a biphasic response: contraction followed by relaxation. After cessation of ES, the muscle relaxed to below the initial baseline tension. Tetrodotoxin (TTX) abolished most of the contraction and all the relaxation response. Atropine blocked most of the contraction component, leaving the relaxation component unchanged. Prazosin and bupranolol (alpha1-adrenergic and beta-adrenergic antagonists, respectively) also did not affect the relaxation component of the response. Neither substance P nor its antagonist (N-acetyl-L-tryptophane 3,5-bis (trifluoromethyl)-benzyl ester; ATTB) inhibited or mimicked the response. The nitric oxide synthase (NOS) inhibitors Nomega-nitro-L-arginine methyl ester (L-NAME), Nomega-nitro-L-arginine (L-NNA), and aminoguanidine dose-dependently inhibited the relaxation response by 50% to 70%. The free radical scavenger 2-(4-carboxyphenyl) 4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO) and the guanylyl cyclase inhibitor methylene blue also abrogated 70% and 45% of the relaxation response, respectively. ES caused an increase in muscle cGMP from 2.3+/-0.3 to 3.9+/-0.5 picomoles per muscle. L-NNA or L-NAME significantly decreased the tissue cGMP content (to 1.2+/-0.1 picomoles per muscle) and prevented the increase caused by ES. CONCLUSIONS: The relaxation component of the iris sphincter response to ES is a distinct nonadrenergic, noncholinergic, ES-induced event. Most of the relaxation is mediated by the endogenously generated NO-guanylyl cyclase-cGMP cascade.

Adrenergic Agents↗
PubMedDate not supplied

[A study on Korean concepts of relaxation].

Relaxation technique is an independent nursing intervention used in various stressful situations. The concept of relaxation must be explored for the meaning given by the people in their traditional thought and philosophy. Korean relaxation technique, wanting to become culturally acceptable and effective, is learning to recognize and develop Korean concepts, experiences, and musics of relaxation. This study was aimed at discovering Korean concepts, experiences and musics of relaxation and contributing the development of the relaxation technique for Korean people. The subjects were 59 nursing students, 39 hospitalized patients, 61 housewives, 21 rural residents and 16 researchers. Data were collected from September 4th to October 24th, 1991 by interviews or questionnaires. The data analysis was done by qualitative research method, and validity assured by conformation of the concept and category by 2 nursing scientists who had written a Master's thesis on the relaxation technique. The results of the study were summarized as follows; 1. The meaning of the relaxation concept; From 298 statements, 107 concepts were extracted and then 5 categories "Physical domain", "Psychological domain", "Complex domain", "Situation", and "environment" were organized. 'Don't have discomforts, 'don't have muscle tension', 'don't have energy (him in Korean)', 'don't have activities' subcategories were included in "Physical domain". 'Don't have anxiety', 'feel good', 'emotional stability', 'don't have wordly thoughts', 'feel one's brain muddled', 'loss of desire' subcategories were included in "physical domain" 'Comfort body and mind', 'don't have tension of body and mind', 'be sagged' 'liveliness of thoughts' subcategories were included in "Complex domain". 'Rest', 'sleep', 'others' subcategories were included in "Situation domain". And 'quite environment' & 'comfortable environment' subcategories were included in "Environmental domain". 2. The experiences of the relaxation; From 151 statements, 59 experiences were extracted. And then 9 categories--at rest after physical activities, after problem solving, fancy, bathing in the bed, situation, rest, particular time, others--were organized. 3. The musics of the relaxation; From 229 statements, 108 musics were extracted, and the 9 categories--Western classical music, semi classical music, Korean song, Korean popular classical music, song, western popular song, hymn, characteristics of music, others--were organized. In conclusion, There are some differences between Korean concepts, experiences and musics of relaxation and western concepts, experiences and musics of relaxation.

Female↗
PubMed1986

Participation of vascular H1-receptors in histaminergic relaxation of rabbit middle cerebral artery in vitro.

4-Methylhistamine relaxed potassium-constricted perfused rabbit middle cerebral arteries at low concentrations (3 X 10(-11) - 3 X 10(-8) M) and constricted them at high concentrations (3 X 10(-7) - 10(-4) M). The relaxation was antagonized by either cimetidine (3 X 10(-7) or 10(-6) M) or mepyramine (3 X 10(-8) M) given 20 min before testing a series of increasing concentrations of 4-methylhistamine, whereas the constriction was slightly potentiated by cimetidine and reversed by mepyramine. The reduction of relaxation was enhanced by a combination of both blockers. These results suggest the involvement of both H1- and H2-receptors in the 4-methylhistamine-induced relaxation. When dimaprit was compared with 4-methylhistamine, it acted only as a relaxing agent, not as a constricting agent. The dimaprit-induced relaxation was antagonized by either cimetidine (3 X 10(-7) M) or mepyramine (3 X 10(-8) M). The inhibition of relaxation was enhanced with a combination of both blockers. This supports the hypothesis that the dimaprit-induced relaxation in the rabbit cerebral artery is also mediated through both H1- and H2-receptors. The H1-agonists 2-methylhistamine and 2-pyridyl ethylamine induced two kinds of responses: an initial relaxation at low concentrations which was reversed by mepyramine (3 X 10(-8) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M); this relaxation was followed at higher concentrations by a vasoconstriction which was antagonized by mepyramine (3 X 10(-8), 3 X 10(-7) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M). Relaxation by these agents therefore seems to involve the participation of H1-receptors. The pharmacological effects of the histaminergic agonists and antagonists used could be explained by assuming that a distinction exists in the rabbit middle cerebral artery between the receptors concerned in H1-mediated relaxation and H1-mediated constriction.

Animals↗
PubMedDate not supplied

Calcium- and endothelial-mediated vascular smooth muscle relaxation in rabbit aorta.

The role of calcium in the relaxations evoked by methacholine and A23187 in intact rabbit aortic rings was investigated. Methacholine (10(-8) to 10(-6) M) and the calcium ionophore A23187 (10(-8) to 10(-6) M) produced dose-dependent relaxations of rings which had been contracted with the alpha-adrenergic agonist phenylephrine. The ability of a ring to relax in this manner was correlated with the presence of endothelium as judged by transmission and scanning electron microscopy. Purposely disrupting the endothelium led to a loss of the relaxation response. In these rings methacholine caused dose-dependent contractions at concentrations greater than 10(-7) M. Deletion of Ca++ from the incubation medium inhibited maximum methacholine-induced relaxations by 67% and A23187-induced relaxations by 92%. The Ca++-channel blockers verapamil (10 microM) and nifedipine (0.5 microM) inhibited maximum methacholine-induced relaxations by 39% and 45%, respectively. The blockers had no effect on the methacholine ED50 (2.5 x 10(-7) M) for relaxation. Verapamil and nifedipine also inhibited maximum A23187-induced relaxations by 43% and 47% with no effect on the ED50 (6 x 19(-8) M) for relaxation. A structurally dissimilar vasodilator, sodium nitroprusside (10(-7) M), had no effect on the A23187-induced relaxation. These data are consistent with a role of Ca++ in regulating either the production or release of endothelial-derived relaxing factor(s).

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PubMedDate not supplied

Captopril produces endothelium-dependent relaxation of dog isolated renal arteries. Potential role of bradykinin.

The effects of the angiotensin-converting enzyme inhibitors, captopril, lisinopril and enalapril-maleate (the latter being a prodrug that has to be converted into enalaprilat), and bradykinin were investigated in the presence or absence of indomethacin and bradykinin receptor antagonists in dog renal arterial rings precontracted with either prostaglandin F2 alpha or phenylephrine. At a high precontraction level (10 microM of prostaglandin F2 alpha), captopril did not relax the arteries. However, when the tension was low (0.5 microM), both captopril and lisinopril produced endothelium-dependent relaxations. The maximum relaxations for captopril and lisinopril were 57 +/- 6% and 64 +/- 15%, respectively. Enalapril-maleate failed to relax the renal arteries even when the vascular tone was low. In endothelium-intact arteries precontracted with phenylephrine (0.2 microM), captopril and lisinopril produced a maximum relaxation of 60 +/- 9% and 29 +/- 5%, respectively, in arteries with intact endothelium, whilst responses to enalapril-maleate were inconsistent. Renal artery rings with rubbed endothelium failed to relax in response to bradykinin or captopril. We observed significant variations in both captopril- and lisinopril-induced endothelium-dependent relaxations in one tenth of the preparations. The relaxations to bradykinin and captopril were not affected by indomethacin (3 microM), whereas they were markedly attenuated by NG-nitro-L-arginine (0.1 mM). The bradykinin-antagonist, N alpha-adamantane-acetyl-D-Arg-(Hyp3, Thi5,8, D-Phe7)BK, or the specific bradykinin2 receptor antagonist, HOE140, completely abolished the relaxation responses to captopril and reduced the potency of bradykinin, but failed to affect the acetylcholine-induced responses. The results suggest that the relaxant effect of captopril is mediated by endogenous bradykinin or by activation of bradykinin receptors. The proposed mechanisms by which captopril relaxes the renal arteries are: (1) inhibition of tissue kininase II, which leads to accumulation of endogenous bradykinin; (2) shift in angiotensin I metabolism towards (a) relaxant angiotensin derivative(s); and (3) interaction with bradykinin receptors.

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