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PubMed2006

Roles of CaM kinase II and phospholamban in SNP-induced relaxation of murine gastric fundus smooth muscles.

The mechanisms by which nitric oxide (NO) relaxes smooth muscles are unclear. The NO donor sodium nitroprusside (SNP) has been reported to increase the Ca2+ release frequency (Ca2+ sparks) through ryanodine receptors (RyRs) and activate spontaneous transient outward currents (STOCs), resulting in smooth muscle relaxation. Our findings that caffeine relaxes and hyperpolarizes murine gastric fundus smooth muscles and increases phospholamban (PLB) phosphorylation by Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) suggest that PLB phosphorylation by CaM kinase II participates in smooth muscle relaxation by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and the frequencies of SR Ca2+ release events and STOCs. Thus, in the present study, we investigated the roles of CaM kinase II and PLB in SNP-induced relaxation of murine gastric fundus smooth muscles. SNP hyperpolarized and relaxed gastric fundus circular smooth muscles and activated CaM kinase II. SNP-induced CaM kinase II activation was prevented by KN-93. Ryanodine, tetracaine, 2-aminoethoxydiphenylborate, and cyclopiazonic acid inhibited SNP-induced fundus smooth muscle relaxation and CaM kinase II activation. The Ca2+-activated K+ channel blockers iberiotoxin and apamin inhibited SNP-induced hyperpolarization and relaxation. The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one inhibited SNP-induced relaxation and CaM kinase II activation. The membrane-permeable cGMP analog 8-bromo-cGMP relaxed gastric fundus smooth muscles and activated CaM kinase II. SNP increased phosphorylation of PLB at Ser16 and Thr17. Thr17 phosphorylation of PLB was inhibited by cyclopiazonic acid and KN-93. Ser16 and Thr17 phosphorylation of PLB was sensitive to 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one. These results demonstrate a novel pathway linking the NO-soluble guanylyl cyclase-cGMP pathway, SR Ca2+ release, PLB, and CaM kinase II to relaxation in gastric fundus smooth muscles.

Animals↗
PubMed1991

Relaxation, [Ca2+]i, and the latch-bridge hypothesis in swine arterial smooth muscle.

During vascular smooth muscle relaxation, myosin light-chain phosphorylation values decrease to resting values more rapidly than do stress values. Because phosphorylation is proportionally low, the latch-bridge hypothesis predicts that stress during relaxation should be predominantly carried by latch bridges. I evaluated the mechanical properties of latch bridges by changing tissue length and measuring myoplasmic Ca2+ concentration ([Ca2+]) with aequorin during relaxation of swine carotid medial tissues. Stress production was predicted with the latch-bridge model of Hai and Murphy, in which the measured aequorin [Ca2+] signal is the only determinant of stress. The aequorin-based latch-bridge model predicted relaxation induced by removal of the histamine stimulation. However, when tissues were relaxed by removal of extracellular Ca2+ or Ca(2+)-channel blockers in the continued presence of histamine, the aequorin-based model modestly underestimated the resulting relaxation. This underestimation was most likely caused by a small increase in the [Ca2+] sensitivity of phosphorylation since a model with an altered [Ca2+] sensitivity of phosphorylation more accurately predicted the resulting relaxation. The time course of relaxation in swine carotid artery was not substantially altered when the tissue was either briefly stretched or shortened and then returned to the original length. Because stretch should detach cross bridges, I modified the aequorin-based latch-bridge model to account for stretch-induced cross-bridge detachment. Because [Ca2+] values were slightly above resting values both before and after the stretch, the model predicted that phosphorylated cross bridges could reattach, be dephosphorylated, and form new latch bridges. The model predicted relaxation except during the first few seconds after stretch. These results suggest that latch-bridge reattachment is not necessary to explain the majority of the response to stretch during relaxation. The rate-limiting step for relaxation appears to be removal of [Ca2+] and not latch-bridge detachment.

Actins↗
PubMed1991

Acetylcholine-induced release of endothelium-derived relaxing factor from lymphatic endothelial cells.

Ring segments of dog thoracic ducts precontracted with a high concentration of norepinephrine (NE) relaxed in a concentration-dependent manner in response to acetylcholine (ACh) or sodium nitroprusside (SNP). Pretreatment with atropine inhibited the ACh-induced relaxation in a competitive manner. The Schild plot showed a slope of 1.1 +/- 0.2 and a pA2 value of 10.4 +/- 0.4 (n = 6 ring segments). Removal of endothelium caused a complete inhibition of the ACh-induced relaxations in precontracted dog thoracic ducts. ACh, which failed to relax precontraction of the ring segment when mounted separately, induced relaxation in the same preparation when it was mounted as a "sandwich" with the longitudinal strip. The ACh-induced relaxations in the lymphatic preparations with endothelium were suppressed or abolished by pretreatment with oxyhemoglobin (10(-6) and 10(-5) M), methylene blue (10(-6) and 10(-5) M), and NG-monomethyl-L-arginine (3 x 10(-5) M), but the relaxations were unaffected by aspirin (10(-5) M). Pretreatment with methylene blue (10(-5) M) also caused a significant reduction of the SNP-induced relaxations in the precontracted thoracic ducts. It may be concluded that ACh-induced relaxation in dog thoracic ducts precontracted with NE is mediated by high-affinity muscarinic receptors in the lymphatic endothelial cells. Also, stimulation of the endothelial muscarinic receptors liberates a transferable endothelium-derived relaxing factor, which results in the relaxation of the lymphatic smooth muscles via the accumulation of cellular guanosine 3',5'-cyclic monophosphate.

Acetylcholine↗
PubMed1993

Involvement of the "tethered ligand" receptor in thrombin-induced endothelium-mediated relaxations.

The mechanisms by which the serine protease, alpha-thrombin, mediates relaxations were examined in isolated dog and pig coronary arteries and dog saphenous veins. In rings of coronary arteries and saphenous veins contracted submaximally with prostaglandin F2 alpha or U46619, alpha-thrombin (0.1-10 nM) caused relaxations that were abolished by treatment with N omega-nitro-L-arginine (L-NNA) or removal of the endothelium, indicating that the relaxations were mediated by endothelium-derived nitric oxide. These relaxations were blocked by the thrombin active site inhibitor, MD-805, indicating the requirement of thrombin's catalytic site to induce the relaxations. The thrombin exosite inhibitor, BMS-180742, decreased the sensitivity to alpha-thrombin without altering maximal relaxations. Indomethacin, a cyclooxygenase inhibitor, had no inhibitory effect on the relaxations caused by alpha-thrombin, indicating that the relaxations were not mediated by cyclooxygenase products. Similar to alpha-thrombin, the thrombin receptor activating peptide (human sequence: SFLLRNP, 1-100 microM) caused relaxations in pig coronary artery and dog saphenous vein but not in dog coronary artery. These relaxations were blocked by L-NNA but not by indomethacin. The results indicate that alpha-thrombin induces endothelium-dependent relaxations by a novel signaling mechanism that involves proteolytic cleavage of the thrombin receptor to expose a new amino terminus that functions as a "tethered peptide ligand" to activate thrombin receptors on the endothelial cells and release nitric oxide.

Amino Acid Sequence↗
PubMed1993

Use of a new index to study relaxation in a vascular model of anaphylactic shock.

We have reported increased smooth muscle shortening ability in ragweed pollen-sensitized saphenous vein (SSV). This may account for the vascular hyperreactivity of anaphylactic shock. We have now investigated relaxation in SSV. Because isotonic relaxation is load and initial contractile element length dependent, we developed an adjusted half-relaxation time index, which was independent of these variables. Muscle activation state was monitored by measuring maximum unloaded velocity. The relaxation index showed no difference between SSV and control saphenous vein after 2.5, 10, and 15 s of electrical stimulation; however, after 1 s of stimulation it was prolonged significantly in SSV. We concluded that the cross bridges activating early in contraction demonstrated prolonged relaxation. Activation state during muscle relaxation spontaneously increased toward the end of relaxation, coincident with a slowing in isotonic re-elongation rate. This was seen only in muscles relaxing from 15 s of stimulation. Our results indicate that 1) the relaxation properties of early cycling (1 s) cross bridges are altered after sensitization; and 2) toward the end of isotonic relaxation, cross-bridge cycling rate increases spontaneously, a phenomenon not previously reported. We speculate that the rapid re-elongation in late relaxation may reactivate muscle.

Allergens↗
PubMedDate not supplied

Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats.

OBJECTIVE: The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors. METHODS: Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10(-9)-3 x 10(-5) M)- or sodium-nitroprusside (10(-9)-3 x 10(-4) M)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro-L-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin. RESULTS: Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (E(max)) to acetylcholine was decreased in the insulin resistance group (56 +/- 7%) versus control (93 +/- 3%). LNNA pretreatment further impaired E(max) in the IR group from 56 +/- 7 to 17 +/- 2% (p < 0.01). In control, E(max) was only slightly impaired by LNNA (93 +/- 3 to 63 +/- 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 +/- 3 to 47 +/- 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 +/- 5% with CTX/apamin vs. 56 +/- 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups. CONCLUSIONS: Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.

Acetylcholine↗
PubMedDate not supplied

Role of nitric oxide and potassium channels in the cholinergic relaxation of rabbit ear and femoral arteries: effects of cooling.

The main objective of this work was to study the role of potassium channels in the cholinergic relaxation of cutaneous arteries during cooling. Acetylcholine (10(-8)-10(-4) M) produced isometric concentration-dependent relaxation of precontracted segments of rabbit ear (cutaneous) and femoral (noncutaneous) arteries; this relaxation was higher at 24 degrees C (cooling) than at 37 degrees C in ear, but not in femoral, arteries. In both types of arteries, at 37 and 24 degrees C, the relaxation to acetylcholine was partially reduced by the inhibitor of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), and the relaxation that remained after L-NAME was higher at 24 degrees C than at 37 degrees C in ear, but not in femoral, arteries. At 37 and 24 degrees C, the persistent relaxation to acetylcholine after L-NAME was further reduced by smooth muscle depolarization with medium containing a high concentration of potassium (6 x 10(-2) M), and with the nonspecific inhibitors of potassium channels tetraethylammonium (10(-2) M) or 4-aminopyridine (5 x 10(-3) M) in both ear and femoral arteries. In ear arteries, the inhibitor of high conductance calcium-activated potassium channels charybdotoxin (10(-7) M), alone or combined with L-NAME, reduced the relaxation to acetylcholine at 24 degrees C, but not at 37 degrees C. In femoral arteries, charybdotoxin alone did not modify, but combined with L-NAME reduced, the relaxation to acetylcholine at either temperature. At 37 and 24 degrees C, the inhibitor of low conductance calcium-activated potassium channels apamin (10(-7) M), the inhibitor of ATP-dependent potassium channels glibenclamide (10(-5) M) and the cyclooxygenase inhibitor meclofenamate (10(-5) M), alone or combined with L-NAME, did not modify the relaxation of both ear and femoral arteries to acetylcholine. These results suggest: (1) the cholinergic relaxation of cutaneous (ear) and noncutaneous (femoral) arteries could be mediated by endothelial nitric oxide and by activation of potassium channels, and (2) cooling increases the relaxation of cutaneous arteries to cholinergic stimulation, which may be mediated, in part, by an increased response of potassium channels.

Acetylcholine↗
PubMed1992

Inhibition by L-NG-nitro-L-arginine of nonadrenergic-noncholinergic-mediated relaxations of human isolated central and peripheral airway.

Human isolated central (5 to 12 mm) and peripheral (< 2 mm) bronchi were contracted with 3 microM histamine. Relaxations were then evoked by electrical field stimulation (EFS) (1 to 32 Hz, 1 ms, 12 V for 15 s in the presence of indomethacin, atropine, and propranolol). The magnitude, time-course, and frequency-response relationship of these nonadrenergic, noncholinergic (NANC) relaxations were similar in the central and the peripheral airways. NG-Nitro-L-arginine (L-NOARG) (10 microM) inhibited the tetrodotoxin-sensitive NANC relaxations in both central and peripheral bronchi, whereas the stereoisomer D-NOARG was without effect. This inhibition was reversed by L-arginine (1 mM) but not be D-arginine (1 mM). The nitric oxide donor compound, 3-morpholinosydnonimine (SIN-1), was equipotent at relaxing the central and peripheral airways. Vasoactive intestinal peptide (VIP), although it relaxed central airways, was virtually ineffective in relaxing the peripheral airways. In addition, the peptidase, alpha-chymotrypsin, at a concentration that blocked relaxations to VIP, was without effect on NANC relaxations in the central bronchi. The results support the following hypotheses: (1) both central and peripheral airways receive nonadrenergic relaxant innervation; (2) the relaxant response to electrical stimulation of this system is dependent on a pathway involving L-arginine; and (3) the relaxant response does not appear to involve VIP, but it may involve the production of nitric oxide.

Arginine↗
PubMed2002

Mechanisms involved in the relaxant action of the ethanolic extract of propolis in the guinea-pig trachea in-vitro.

This study examines the mechanisms by which the standardised ethanolic extract of propolis induces relaxation of the guinea-pig trachea in-vitro. In guinea-pig trachea with or without epithelium and contracted by histamine, the propolis extract caused reproducible and graded relaxation, with a mean EC50 value of 3.8 or 10.5 microg mL(-1) and Emax of 100%, respectively. The propolis extract-induced relaxation was markedly reduced (26+/-9 and 96+/-3%) when guinea-pig tracheas were exposed to Krebs solution containing elevated K+ in the medium (40 or 80 mM). Pre-incubation of guinea-pig tracheas with tetraethylamonium (100 mM) or with 4-aminopyridine (10mM) reduced the propolis extract-induced relaxation by 31+/-10% and 28+/-2%. Likewise, apamin (0.1 microM), charybdotoxin (0.1 microM) or iberiotoxin (0.1 microM) caused marked inhibition of propolis extract-mediated relaxation in guinea-pig trachea (percentage of inhibition: 65+/-3%, 60+/-5% and 65+/-9%, respectively). Also, glibenclamide (1 microM) inhibited the relaxant response caused by the propolis extract by 57+/-4%. Omega-conotoxin GIVA (0.1 microM) or capsaicin (1 microM) produced small but significant inhibition (30+/-5% or 47+/-7%, respectively) of the propolis extract-induced relaxation. The vasoactive intestinal peptide (VIP) antagonist D-p-Cl-Phe6,Leu17[VIP] porcine (0.1 microM) inhibited relaxation by 55+/-5%, while propranolol (1 microM) induced a parallel rightward displacement (about 20 fold) of the propolis extract concentration-response curve. Finally, the propolis extract-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-N(G)-nitroarginine (L-NOArg, 100 microM) (48+/-6%), and by the soluble guanylatecyclase inhibitormethylene blue (10 microM) (37+/-6%), whilethe moreselectivesoluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3-alquinoxalin-1-one (ODQ, 1 microM) produced only a parallel (about 3 fold) rightward displacement of the propolis extract concentration-response curve. Collectively, these results support the notion that the propolis extract-mediated relaxation in the guinea-pig trachea involves the release of nitric oxide, probably from sensory neurons, besides the activation of soluble guanylate cyclase and activation of Ca2+- and ATP-sensitive K+ channels. Furthermore, the stimulation of beta2-adrenergic and VIP receptors also seems to account for its relaxant action.

Adrenergic beta-Antagonists↗
PubMed1997

Nonadrenergic, noncholinergic relaxation in longitudinal muscle of rat jejunum.

The mediators of nonadrenergic, noncholinergic (NANC) relaxation in the longitudinal muscle of rat jejunum were studied in vitro. Electrical field stimulation (EFS) of segments of rat jejunum induced a rapid transient relaxation followed by a subsequent contraction in the presence of atropine and guanethidine. NG-Nitro-L-arginine (L-NOARG, 10 microM) inhibited the EFS-induced NANC relaxation by about 25%, and L-arginine (1 mM) completely reversed this inhibition. Exogenously added nitric oxide (0.1-10 microM) induced relaxation of the segment. Treatment of the segment with alpha-chymotrypsin resulted in about 50% inhibition of the EFS-induced relaxation. Several peptide candidates for the mediator of NANC relaxation were examined by using selective antagonists of their receptors or by a receptor-desensitization method. Results indicated that vasoactive intestinal peptide, pituitary adenylate cyclase activating peptide, peptide histidine isoleucine, atrial natriuretic peptide and neurotensin are not associated with NANC relaxation of the segments. On the other hand, apamin at 1 microM inhibited the EFS-induced relaxation by 74%. Inhibitory effects of L-NOARG and, apamin or alpha-chymotrypsin treatment on the EFS-induced relaxation were additive and almost complete. Exogenous nitric oxide-induced relaxation was not affected by apamin. Inhibitory junction potentials (i.j.p.'s) were recorded from longitudinal muscle cells of rat jejunum. Apamin at 200 nM abolished i.j.p.'s induced by two pulses of EFS. These results suggest that NANC relaxation in longitudinal muscle of rat jejunum involves two independent components: one is a nitric oxide-mediated minor component, and the other is an unknown substance-mediated apamin-sensitive major component that is inhibited by alpha-chymotrypsin treatment.

Adrenergic Fibers↗
PubMed1997

New aspects of gastric adaptive relaxation, reflex after food intake for more food: involvement of capsaicin-sensitive sensory nerves and nitric oxide.

To accommodate the intake of food or liquid, gastric reservoir functions are important as the physiological reflex. There exist two major responses as a reservoir function of the stomach; adaptive and receptive relaxations. Adaptive relaxation is a reflex in which the fundus of the stomach dilates in response to small increases in intragastric pressure when food enters the stomach. Receptive relaxation is a reflex in which the gastric fundus dilates when food passes down the pharynx and the esophagus. The mechanisms of these two types of functional responses are to some extent different, although a nitric oxide (NO) dependent non adrenergic, non cholinergic neural pathway is involved in the both relaxation reflexes. Adaptive relaxation is an intragastric pressure induced reflex. Stretch of the gastric wall activates the mechanoreceptors in gastric mucosa (Mu), which generate impulses carried by the capsaicin-sensitive afferent sensory neuron. The sensory neuron can synapse on the inhibitory efferent neuron directly or activate it via interneurons of the myenteric plexus. This leads to the release of NO from the nitroxergic efferent neuron, which causes relaxation of circular muscle and hence of the fundus. Alternatively, an axon reflex causes the NO release from the sensory neuron, resulting in hexamethonium resistant gastric relaxation. Receptive relaxation is mediated by vagal motor fibers. In contrast with the pressure-induced adaptive relaxation, ganglionic nicotinic transmission is essential in the vagally induced relaxation. VIP and CGRP are important neurotransmitters of the inhibitory sensory neuron, which, however, may not mediate both adaptive and receptive relaxations. Disorders of these reservoir functions result in symptoms of early satiety and anorexia, which are the major symptoms of patients with functional dyspepsia.

Adaptation, Physiological↗
PubMed1999

Studies on the mechanisms involved in the ATP-induced relaxation in human and rabbit corpus cavernosum.

The effect of ATP in human and rabbit corpus cavernosum (CC) smooth muscle was investigated. Strips of human CC were vertically mounted in an organ bath and the tonic tension was recorded. ATP (0.1-3 mM) induced a concentration-dependent relaxant effect, with a pD2 value of 3.01+/-0.3. The purine-induced relaxation was not affected by L-NAME (100 microM). In rabbit CC, ATP also induced a concentration-dependent relaxation, which was not influenced by L-NAME or by indomethacin (3 microM), with a pD2 value of 3.1 +/-0.4. The ATP-induced relaxant effect in rabbit CC was increased by both the inhibitor of adenosine reuptake, dipyridamole (3 microM) and by the inhibitor of adenosine deaminase, EHNA (0.3 microM). Moreover CGS 15943 (3 microM), an A2a adenosine antagonist, reduced the ATP-induced relaxation. UTP was not able to produce relaxation. The two ATP analogues 2-methylthioATP and alpha,beta-methylene ATP were able to induce relaxation in rabbit CC, with the following order of potency: 2-methylthioATP > ATP > alpha,beta-methylene ATP thus suggesting a role for P2y receptors. However, reactive blue (500 microM), an unspecific P2y antagonist, did not modify the ATP relaxant response. The inhibition of phospholipase C by U73122 (3 microM) and of the endoplasmic reticulum Ca2+ATPase by thapsigargin (1 microM) did not modify the ATP-induced relaxation. The P2x specific antagonist PPADS (30 microM) and suramine (500 microM) were not able to modify the ATP relaxation either in the absence or presence of CGS 15943 (3 microM). These results confirm that ATP acts as a potent and NO-independent relaxant agent of human and rabbit CC. Our findings also show that the ATP effect is partially attributable to the metabolic breakdown of ATP to adenosine, which acts through A2a receptor stimulation, but is also due to a direct stimulation of P2 receptors that are different from the classical P2y and P2X receptor subtypes for ATP.

Adenine↗
PubMed1999

Pharmacologic characteristics of non-prostanoid, non-nitric oxide mediated and endothelium-dependent relaxation of guinea-pig aorta in response to substance P.

The pharmacologic characteristics of the non-prostanoid (prostacyclin, PGI2), non-nitric oxide (NO) mediated endothelium-dependent relaxation in response to substance P were examined in the guinea-pig aorta. Substance P, in a concentration-dependent manner, relaxed the ring preparations of guinea-pig thoracic aorta preconstricted with norepinephrine (NE) in an endothelium-dependent manner. Substance P-induced endothelium-dependent relaxation was not affected by indomethacin (3 x 10(-6) M) as in the case of acetylcholine (ACh)-induced endothelium-dependent relaxation. Although N(G)-nitro-L-arginine (L-NNA, 3 x 10(-5) M), an inhibitor of nitric oxide (NO) synthase, significantly inhibited substance P-induced endothelium-dependent relaxation in the presence of indomethacin, about 50% of the vasorelaxant response to substance P remained in the combined presence of L-NNA and indomethacin. By comparison, indomethacin-resistant component of endothelium-dependent relaxation to ACh was mostly suppressed by the treatment with L-NNA plus indomethacin. Substance P-induced non-PGI2, non-NO mediated vascular relaxation was attenuated markedly in high (40 mM) KCl solution or by tetraethylammonium (TEA, 5 x 10(-3) M). Furthermore, substance P-induced non- PGI2, non-NO mediated vascular relaxation was not appreciably affected by glibenclamide (10(-6) M), apamin (10(-7) M), iberiotoxin (1(-7) M), but was greatly attenuated by the combined treatment with charybdotoxin (10(-7) M) plus apamin (10(-7) M), which suggesting that endothelium-derived hyperpolarizing factor(s) (EDHF(s)) mediates the response. Interestingly, after applied repetitively, the substance P-induced vasorelaxant component remaining in the combined presence of indomethacin and L-NNA was decreased more profoundly than the response to substance P in the presence of indomethacin alone. Possible contribution of non-PGI2, non-NO vasorelaxant(s) (EDHF(s)) from the endothelium to the total relaxation response to substance P was greater in thoracic aorta isolated from adult guinea-pigs than that from neonatal ones. These findings suggest that 1) endothelium-dependent vascular relaxation of guinea-pig thoracic aorta in response to substance P is attributable to the release of both NO and EDHF(s); 2) possible release of EDHF(s) from the endothelium of guinea-pig thoracic aorta decreases after repetitive stimulation with substance P; and 3) contribution of EDHF(s) to substance P-induced functional relaxation of the thoracic aorta is greater in adult guinea-pigs than neonatal ones.

Aging↗
PubMed2001

The relaxation induced by S-nitroso-glutathione and S-nitroso-N-acetylcysteine in rat aorta is not related to nitric oxide production.

S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine (NACysNO) are nitrosothiols that release nitric oxide (NO) and mimic the effects of endogenous NO. This study investigated the relaxation induced by GSNO and NACysNO in rat aorta and the relation between relaxation and NO formation. Both compounds at concentrations from 10(-9) M to 10(-4) M relaxed the rat aorta in a concentration-dependent manner. However, NO production depended on the concentration of nitrosothiols present and was detected only above 100 microM GSNO or NACysNO. To determine whether K+ channels are involved in the relaxation induced by nitrosothiols, the contractions were induced with KCl at concentrations of 30, 60, or 90 mM. The concentration-effect curves for the relaxation induced by nitrosothiols were shifted to the right for all the K+ concentrations compared with aortas precontracted with phenylephrine. These results indicate the participation of K+ channels in the relaxation induced by GSNO and NACysNO. A selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, significantly inhibited the relaxation induced by the nitrosothiols. The relaxation induced by GSNO and NACysNO was inhibited by the K+ channel blockers glibenclamide, selective K(ATP) channels, and apamin, selective for low-conductance Ca2+-activated K+ channels in rat aorta, but was not inhibited by charybdotoxin, a potent and selective Ca2+-activated K+ channel blocker, or by 4-aminopyridine, a voltage-gated K+ channel blocker. These results indicate that relaxation induced by GSNO and NACysNO is partially due to activation of K(ATP) channels and partially due to activation of low-conductance Ca2+-activated K+ channels. However, the ability of the nitrosothiol compounds to overcome the inhibitory effect of high extracellular K+ concentrations suggests another mechanism of relaxation contributing to the nitrosothiol response. The most intriguing finding is that relaxation is not related to the NO produced in rat aorta.

Acetylcysteine↗
PubMed1992

Serotonin-induced relaxation in canine coronary artery smooth muscle.

Serotonin (5-HT) is a potent contractile agonist in canine coronary artery devoid of endothelium; however, in higher concentrations 5-HT produces concentration-dependent relaxation by activating an as yet uncharacterized receptor. This study explored the possibility that 5-HT-induced relaxation was mediated by interaction with a member of the 5-HT1, 5-HT2, 5-HT3, or 5-HT4 receptor family. 5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine produced concentration-dependent relaxation in vitro in tissues precontracted with prostaglandin F2 alpha (10 microM). The agonist rank order potency for relaxation was 5-carboxamidotryptamine > 5-HT > 5-MeOT. 8-hydroxydipropylaminotetralin (8-OH-DPAT), dipropyl-5-CT, 5-methyltryptamine, sumatriptan, alpha-methyl-5-HT and 2-methyl-5-HT did not produce significant relaxation. The 5-HT1/beta adrenergic receptor antagonist propranolol (1 microM) did not antagonize 5-HT-induced relaxation. 5-HT-induced relaxation was not blocked by tetrodotoxin (0.3 microM), suggesting that neuronal depolarization to release mediators from nerves was not responsible for the relaxation. Neither ketanserin (1 microM) nor ritanserin (1 microM) antagonized 5-HT-induced relaxation, suggesting that 5-HT2 and 5-HT1C receptors do not mediate relaxation. ICS 205-930 (10 microM), a 5-HT3/5-HT4 receptor antagonist, shifted the 5-HT concentration-response curve modestly to the right (pKB = 5.1 +/- 0.1). Cisapride, a 5-HT4 receptor agonist, was not effective either as an agonist (up to 10 microM), or as an antagonist (1 microM) of 5-HT-induced relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Inhibition of adenylate cyclase attenuates adenosine receptor-mediated relaxation in coronary artery.

This study was designed to evaluate whether the adenylate cyclase inhibitor 2',5'-dideoxyadenosine (DDA) would attenuate the relaxation produced by adenosine analogs in order to provide functional evidence in support of the working hypothesis that adenosine receptor-mediated relaxation of coronary artery involves adenylate cyclase. Rings from porcine left anterior descending coronary artery were mounted in organ chambers for measurement of isometric force. Rings contracted with KCl (30 mM) relaxed in a concentration-dependent manner to 2-chloroadenosine (CAD), 5'-N-ethylcarboxamidoadenosine (NECA), isoproterenol, sodium nitroprusside (SNP) and forskolin. Treatment of coronary rings with DDA (50 microM) significantly attenuated the relaxation produced by CAD, NECA, forskolin and isoproterenol, but had no effect on the relaxation response to SNP. The nucleoside transport inhibitor dilazep (10 microM) completely reversed the inhibitory effect of DDA on the relaxation produced by forskolin and CAD, whereas dilazep only partially reversed the DDA inhibition of NECA-induced relaxation. In a membrane preparation from porcine coronary artery CAD, but not NECA, increased cyclic AMP production in a GTP-dependent manner. DDA significantly decreased basal cyclic AMP production and also decreased CAD-, forskolin-, GTP- and NaF-stimulated cyclic AMP production. These results provide functional and biochemical evidence in support of the working hypothesis that adenosine receptor-mediated coronary relaxation involves adenylate cyclase. Furthermore, the results from this study suggest that the signaling mechanisms responsible for adenosine receptor-mediated coronary relaxation are more complicated than a single receptor coupled with adenylate cyclase because 1) dilazep completely reversed the inhibitory effect of DDA on the CAD relaxation but not the NECA relaxation, and 2) NECA did not increase cyclic AMP production.

2-Chloroadenosine↗
PubMed1991

15-lipoxygenase metabolites of arachidonic acid evoke contractions and relaxations in isolated canine arteries: role of thromboxane receptors, endothelial cells and cyclooxygenase.

The 15-hydroperoxy metabolite of arachidonic acid (15-hydroperoxyeicosatetraenoic acid; 15-HPETE) and its hydroxyderivative 15-hydroxyeicosatetraenoic acid (15-HETE) are known to evoke contractions in a variety of isolated blood vessels. In this study, segments of isolated canine coronary, splenic, femoral and renal arteries were exposed to 15-HETE and 15-HPETE; both metabolites induced small basal relaxations followed by contractions at higher concentrations. The contractions were augmented by indomethacin and could be blocked by the thromboxane A2 receptor antagonists BM13177 and BM13505. In vessels in which the tone was raised with prostaglandin F2 alpha, both 15-lipoxygenase metabolites evoked marked relaxations, which were in part dependent on the presence of the endothelium. When the segments were contracted with norepinephrine or increased KCl concentration, 15-HETE and 15-HPETE induced relaxations followed by additional contractions. The relaxations to the fatty acid derivatives were not inhibited by BM13505. In tissues without endothelium, the relaxations to 15-HETE and 15-HPETE were completely blocked by indomethacin; in tissues with endothelium, indomethacin only partly inhibited the relaxations to 15-HETE, whereas the drug did not interfere with the relaxing effects of 15-HPETE. Our experiments indicate that in isolated canine arteries 15-lipoxygenase metabolites of arachidonic acid can 1) induce contractions, most likely by direct activation of thromboxane A2 receptors on smooth muscle cells, and 2) evoke relaxations that are in part endothelium dependent; the endothelium-independent part of the relaxations was inhibited by indomethacin. Thus, the relaxations to these metabolites seem to occur via the release of an endothelium-derived relaxing factor and via production of a cyclooxygenase metabolite.

Animals↗
PubMed1985

Vasoactive intestinal peptide. Relaxant neurotransmitter in tenia coli of the guinea pig.

Two main candidates have been proposed for the role of relaxant neurotransmitter in the intestine: (a) the purine nucleotide, 5'-adenosine triphosphate (ATP) and (b) the neuropeptide, vasoactive intestinal peptide (VIP). The candidacy of VIP is favored by its precise location in nerve fibers that innervate circular smooth muscle and tenia coli. We have used a photoaffinity analog of ATP, 3'-O-(4-Benzoyl)benzoyl ATP, that binds irreversibly to ATP receptors and inactivates them in the presence of light, and a specific VIP antiserum to examine the claims of VIP and ATP as relaxant neurotransmitters in tenia coli of the guinea pig. Both VIP and ATP caused dose-dependent, tetrodotoxin-insensitive relaxation of tenia coli. The effect of ATP was equipotent to that of its stable isostere alpha, beta-methylene ATP and resistant to degradation by adenosine deaminase, indicating interaction of ATP with purinergic-P2 receptors. Photoactivated 3'-O-(4-Benzoyl) benzoyl adenosine triphosphate selectively inhibited relaxation induced by ATP but had no effect on relaxation induced by VIP or by field (i.e., neural) stimulation. Vasoactive intestinal peptide antiserum (final dilution 1:60), on the other hand, inhibited relaxation caused by VIP and by field stimulation but had no effect on relaxation caused by ATP. Neither normal rabbit serum nor preneutralized VIP antiserum had any effect on relaxation induced by ATP, VIP, or field stimulation. Inhibition of neurally induced relaxation by VIP antiserum ranged from 52% +/- 7% (p less than 0.01) at the lowest frequency of stimulation to 15% +/- 4% (p less than 0.01) at the highest frequency, consistent with competitive interaction between antiserum and neurally released VIP. Near-maximal field stimulation at 1 Hz caused an eightfold (800% +/- 49%, p less than 0.01) increase in VIP release into the bathing medium. The results favor VIP (and probably peptide histidine isoleucine, a relaxant homologue known to be cosynthesized with VIP) as the main neural mediator of relaxation in tenia coli.

Adenosine Triphosphate↗