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At least 631 records · Page 35Linked to original sources
PubMed1998

Endothelium-dependent relaxation induced by hawthorn extract in rat mesenteric artery.

The extract prepared from hawthorn (Crataegus fruit) was examined for its relaxant effect in rat isolated mesenteric arteries. Hawthorn extract induced concentration-dependent relaxation of the U46619-precontracted artery with an IC50 of 0.22 +/- 0.02 mg/ml. Removal of the functional endothelium reduced by approximately 85% the maximum relaxant response to hawthorn extract. Pretreatment of the arterial tissues with N(G)-nitro-L-arginine methyl ester (3-10 microM) or methylene blue (3-10 microM) inhibited the relaxation induced by hawthorn extract, while indomethacin (10 microM) had no effect. L-arginine (3 mM) did not affect the relaxation induced by hawthorn extract but partially reversed the effect of 10 microM N(G)-nitro-L-arginine methyl ester. Iberiotoxin (100 nM) slightly but significantly inhibited the relaxant effect of hawthorn extract whilst glibenclamide (3 microM) was ineffective. Glibenclamide at 3 microM reversed the relaxation induced by pinacidil. N(G)-nitro-L-arginine methyl ester and methylene blue markedly inhibited acetylcholine-induced relaxation in endothelium-intact arteries. Hawthorn extract also reduced the contraction induced by phenylephrine (1 microM) or high Ki (60 mM) with respective IC50 values of 0.13 +/- 0.01 mg/ml and 0.11 +/- 0.01 mg/ml. In high K+-contracted arteries, hawthorn extract induced only 55% of relaxation while it caused a complete inhibition of the U46619- or phenylephrine-induced contraction. These results suggest that hawthorn contains active components which cause vasorelaxation in rat isolated mesenteric arteries. Nitric oxide but not other endothelium-derived vasoactive factors was probably involved in the relaxation induced by hawthorn extract.

Animals↗
PubMed2001

Modulation of nitrergic relaxant responses by peptides in the mouse gastric fundus.

The effects of pituitary adenylate cyclase-activating peptide (PACAP-38) and vasoactive intestinal polypeptide (VIP) were investigated in the gastric fundus strips of the mouse. In carbachol (CCh) precontracted strips, in the presence of guanethidine, electrical field stimulation (EFS) elicited a fast inhibitory response that may be followed, at the highest stimulation frequencies employed, by a sustained relaxation. The fast response was abolished by the nitric oxide (NO) synthesis inhibitor L-N(G)-nitro arginine (L-NNA) or by the guanylate cyclase inhibitor (ODQ), the sustained one by alpha-chymotrypsin. alpha-Chymotrypsin also increased the amplitude of the EFS-induced fast relaxation. PACAP-38 and VIP caused tetrodotoxin-insensitive sustained relaxant responses that were both abolished by alpha-chymotrypsin. Apamin did not influence relaxant responses to EFS nor relaxation to both peptides. PACAP 6-38 abolished EFS-induced sustained relaxations, increased the amplitude of the fast ones and antagonized the smooth muscle relaxation to both PACAP-38 and VIP. VIP 10-28 and [D-p-Cl-Phe6,Leu17]-VIP did not influence the amplitude of both the fast or the sustained response to EFS nor influenced the relaxation to VIP and PACAP-38. The results indicate that in strips from mouse gastric fundus peptides, other than being responsible for EFS-induced sustained relaxation, also exerts a modulatory action on the release of the neurotransmitter responsible for the fast relaxant response, that appears to be NO.

Animals↗
PubMed2002

The effects of vasodilators on the relaxation of guinea-pig aorta during acute recoil.

BACKGROUND: We have investigated the effects of various vasodilators on smooth muscle relaxation during acute recoil with guinea-pig aorta to find effective therapies to prevent acute recoil at percutaneous transluminal coronary angioplasty (PTCA). METHODS: Muscle strips from guinea-pig aorta without endothelium were placed in a bath filled with modified Krebs solution. The strip was isotonically stretched with a tension of 9 mN for 1 min, and then isometric tension was measured until the tension reached a steady state. Various vasodilators were applied during isometric tension measurement. RESULTS: When no drug was applied (control), isometric tension reached a steady state within 20 min. The steady state was approximately 10% lower (more relaxed) than the stretched level. When isosorbide dinitrate (ISDN, 1 mM) was applied during isometric measurement, 18.7+/-5.3% greater relaxation occurred than in control relaxation (P<0.05, n=5). When nicorandil (1 mM) was applied, the following relaxation was 18.6+/-5.7% greater than control (P<0.05, n=8). The simultaneous application of glibenclamide (1 mM) completely inhibited such additional relaxation by nicorandil. Application of nifedipine (10 microM) caused a 12.9+/-2.5% greater relaxation than control (P=0.066, n=4). The first metabolite of sarpogrelate (BP984, 10 microM) caused much greater relaxation than control (23.7+/-7.9%, P<0.05, n=6). Amlodipine (10 microM), phentolamine (10 microM), and sarpogrelate (10 microM) had no influence on the relaxation of the strip. CONCLUSIONS: ISDN, nicorandil and BP984 significantly increase relaxation of the muscle strips after stretching compared to the control. These vasodilators may reduce acute recoil of the smooth muscle after PTCA.

Adrenergic alpha-Antagonists↗
PubMed1999

The potentiating effect of genistein on the relaxation induced by isoproterenol in rat aortic rings.

In rat aortic rings, the mechanism of potentiating effect of genistein, a tyrosine kinase inhibitor, on the relaxation induced by isoproterenol was examined. Pretreatment of the aortic rings by genistein, but not by daidzein, an inactive analogue of genistein, potentiated the relaxation induced by isoproterenol. Genistein also potentiated the relaxation induced by forskolin, an activator of guanylyl cyclase, and dibutyryl cyclic AMP. In addition, theophylline, an inhibitor of phosphodiesterase, potentiated the relaxation induced by isoproterenol and forskolin. Theophylline partly inhibited the potentiation of isoproterenol-induced relaxation by genistein while it completely inhibited the potentiation of forskolin-induced relaxation by genistein. Iberiotoxin, an inhibitor of Ca-activated K (KCa) channels, partly inhibited the isoproterenol-induced relaxation and the potentiating effect of genistein on the relaxation induced by isoproterenol. Quinacrine (an inhibitor of phospholipase A2), alpha-naphthoflavone (an inhibitor of cytochrome P-450 enzymes), and 8-methoxypsoralen (an inhibitor of cytochrome P-450 enzymes), partly inhibited the potentiating effect of genistein on the isoproterenol-induced relaxation, but metyrapone (an inhibitor of cytochrome P-450 enzymes), indomethacin (an inhibitor of cyclooxygenase), and AA861 (an inhibitor of 5-lipoxygenase) did not. These results suggest that the potentiation of isoproterenol-induced relaxation by genistein may be related to the activities of phosphodiesterase, KCa channels, and cytochrome P-450 enzymes.

Adrenergic beta-Agonists↗
PubMed1999

Pharmacological characterization of metamizol-induced relaxation in phenylephrine-precontracted rabbit thoracic aorta smooth muscle.

Metamizol produced a dose- and time-dependent relaxation in rabbit thoracic aorta smooth muscle that was precontracted by phenylephrine. Such a relaxation was not observed with indomethacin, which is also a nonsteroidal anti-inflammatory drug. The relaxing effect of metamizol was independent of the presence of vascular endothelium. Tetraethylammonium (a calcium-activated potassium channel inhibitor), glybenclamide (an ATP-dependent potassium channel inhibitor), indomethacin (a cyclooxygenase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) did not have any effect on metamizol-induced relaxation response. Metamizol did not produce any relaxation effect on aortic smooth muscle when KCl (30, 60, and 117 mM KCl) was used instead of phenylephrine to precontract the preparation. Ouabain (a Na-K ATPase pump inhibitor) showed a dose-dependent inhibition on metamizol's relaxation response. However, in potassium-free medium, which is an alternative way to block the Na-K ATPase pump, no inhibition in metamizol-induced relaxation response was observed. When metamizol was incubated for 2 h in organ-bath conditions before evaluating its relaxing effect, it produced a relatively faster relaxation, indicating that the relaxing effect of metamizol is produced by one of its (active) spontaneous degradation products (possibly 4-methylaminoantipyrine).

Animals↗
PubMed1998

Nitric oxide-related cyclic GMP-independent relaxing effect of N-acetylcysteine in lipopolysaccharide-treated rat aorta.

1. We have recently demonstrated the formation of protein-bound dinitrosyl-iron complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and shown that N-acetylcysteine (NAC) can promote vasorelaxation in these arteries, possibly via the release of nitric oxide (NO) as low molecular weight DNIC from these storage sites. The aim of the present study was to investigate further the mechanism of the relaxation induced by NAC in LPS-treated vessels. 2. In rings incubated with LPS (10 microg ml(-1) for 18 h) and precontracted with noradrenaline (NA, 3 microM) plus N(omega)-nitro-L-arginine methylester (L-NAME, 3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM, a selective inhibitor of soluble guanylyl cyclase) but not affected by Rp-8-bromoguanosine 3'5'-cyclic monophosphorothioate (Rp-8BrcGMPS, 60 microM a selective inhibitor of cyclic GMP-dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+ channels blocker) or elevated concentration of external KCl (25 or 50 mM) significantly attenuated the NAC-induced relaxation. Selective K+ channels blockers (10 microM glibenclamide, 0.1 microM charybdotoxin, 0.5 microM apamin or 3 mM 4-aminopyridine) did not affect the NAC-induced relaxation. The relaxing effect of NAC (10 mM) was not associated with an elevation of guanosine 3':5' cyclic monophosphate (cyclic GMP) in LPS-treated rings. 3. In aortic rings precontracted with NA (0.1 microM), low molecular weight DNIC (with thiosulphate as ligand, 1 nM to 10 microM) evoked a concentration-dependent relaxation which was antagonized by ODQ (1 microM) and Rp-8BrcGMPS (150 microM) but not significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as preconstricting agent. The relaxation produced by DNIC (0.1 microM) was associated with an 11 fold increase in aortic cyclic GMP content, which was completely abolished by ODQ (1 microM). 4. Taken together with our previous data, the main finding of the present study is that the vascular relaxation induced by NAC in LPS-treated aorta, although probably related to NO through an interaction via preformed NO stores, was not mediated by activation of the cyclic GMP pathway. It may involve the activation of TBA-sensitive K+ channels. The differences in the mechanism of relaxation induced by NAC and by exogenous DNIC suggest that the generation of low molecular weight DNIC from protein-bound species does not play a major role in the NAC-induced relaxation observed in LPS-treated rat aorta. In addition, it is suggested that ODQ may display other properties than the inhibition of soluble guanylyl cyclase.

Acetylcysteine↗
PubMed1999

Hyperosmolarity reduces the relaxing potency of nitric oxide donors in guinea-pig trachea.

1. Non-responders to inhaled nitric oxide treatment have been observed in various patient groups. The bronchodilatory effect of inhaled nitric oxide was attenuated when the airway lumen was rendered hyperosmolar in an in vivo study on rabbits. We used a guinea-pig tracheal perfusion model to investigate the effects of increased osmolarity (450 mOsm, NaCl added) on the relaxing potency of the nitric oxide donors sodium nitroprusside (SNP) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). 2. Under iso-osmolar conditions SNP relaxed the carbachol (CCh, 1 microM) contracted trachea by 83+/-3%. After pretreatment with intraluminal hyperosmolarity SNP relaxed the CCh-contracted trachea by only 31+/-7% (P<0.05). When the trachea was contracted to the same extent under untreated and hyperosmolar conditions, the untreated trachea was completely relaxed by SNP but, after hyperosmolar pretreatment, SNP could no longer relax the trachea. 3. SNAP relaxed the CCh contracted trachea by 27+/-5%. After pretreatment with intraluminal hyperosmolarity, SNAP relaxed the trachea by 11+/-4%, which was less than in the iso-osmolar control (P<0.05). 4. Extraluminal hyperosmolarity did not affect carbachol elicited contraction, and SNP administered externally during extraluminal hyperosmolarity was able to relax the trachea (P<0.05). 5. The cell permeable guanosine 3'5'-cyclic monophosphate analogue 8-Br-cGMP relaxed the CCh contracted trachea in both iso-osmolar (P<0.05) and hyperosmolar conditions (P<0.05). 6. The relaxant effect of nitric oxide donors on tracheal smooth muscle is markedly reduced when the airway epithelium is exposed to hyperosmolar solution.

Animals↗
PubMed2000

The mechanism of bradykinin-induced endothelium-dependent contraction and relaxation in the porcine interlobar renal artery.

The mechanism of endothelium-dependent regulation of vascular tone of bradykinin was investigated by simultaneously monitoring the changes in the cytosolic Ca(2+) concentration and the force of smooth muscle in fura-2-loaded strips of the porcine renal artery with endothelium. During phenylephrine-induced sustained contraction, bradykinin (>3x10(-9) M) caused endothelium-dependent triphasic changes in the force of the strips, composed of an initial relaxation, a subsequent transient contraction and a late sustained relaxation. At low concentrations (10(-10) - 10(-9) M), bradykinin caused an endothelium-dependent biphasic relaxation with no contraction. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited, while a TXA(2) synthase inhibitor (10(-5) M OKY-046) only partially inhibited, the transient contraction induced by bradykinin. Under conditions where the bradykinin-induced contraction was inhibited by ONO-3708 during the phenylephrine-induced contraction, bradykinin induced only a transient relaxation in the presence of N(Omega)-nitro-L-arginine methyl ester (L-NAME). This transient relaxation was inhibited when the precontraction was initiated by phenylephrine plus 40 mM extracellular K(+). The removal of L-NAME from this condition caused a partial reappearance of the initial relaxation and a complete reappearance of the sustained relaxation. In conclusion, bradykinin caused the endothelium-dependent triphasic regulation of vascular tone in the porcine renal artery. The concentrations of bradykinin required to induce a contraction was higher than that required to induce relaxation. Both TXA(2) and PGH(2) were involved in the bradykinin-induced contraction. The initial relaxation was mediated by nitric oxide and hyperpolarizing factors while the sustained relaxation depended on nitric oxide.

Animals↗
PubMed2000

Nitrergic relaxation of the mouse gastric fundus is mediated by cyclic GMP-dependent and ryanodine-sensitive mechanisms.

1. Ryanodine-sensitive, Ca(2+) release ('Ca(2+) sparks') from the sarcoplasmic reticulum (SR) can activate plasmalemmal Ca(2+)-activated K(+) channels (K(Ca)) to cause membrane hyperpolarization and smooth muscle relaxation. Since cyclic guanosine monophosphate (cyclic GMP) can modulate Ca(2+) spark activity, the aim of the present study was to determine if Ca(2+) spark-like events are involved in NO-dependent, NANC relaxations to electrical field stimulation (EFS) of mouse, longitudinal smooth muscle of the gastric fundus in isolated strips contracted to approximately 40% of their maximum contraction. 2. NANC relaxations to EFS were almost abolished by both the NO synthase inhibitor, N(G)-nitro-L-arginine (L-NOARG; 100 microM) and the guanylate cyclase inhibitor, 1-H-oxodiazol-[1,2,4]-[4,3-alpha] quinoxaline-1-one (ODQ; 10 microM). Also, ODQ abolished relaxations to the NO donor, sodium nitroprusside (SNP; 1 nM - 30 microM). NANC relaxations and SNP-evoked relaxations were both partly ryanodine (10 microM)- and nifedipine (0.3 microM)-sensitive, but in each case, the inhibitory effects of ryanodine and nifedipine were additive. 3. Apamin (1 microM), charybdotoxin (0.1 microM), iberiotoxin (0.1 microM), tetraethylammonium (TEA; 1 mM), glibenclamide (10 microM) and 4-aminopyridine (1 mM) had no effect on either NANC- or SNP-evoked relaxations, the latter of which were also unaffected by high extracellular K(+) (68 mM). 4. Caffeine (0.1 - 1 mM) caused concentration-dependent relaxations of gastric fundus which were inhibited by ryanodine but unaffected by L-NOARG. 5. Relaxation to ATP (30 microM) was abolished by nifedipine, partly inhibited by apamin and ryanodine, but was unaffected by L-NOARG. 6. In conclusion, the results of the present study show that nitrergic relaxations in the mouse longitudinal gastric fundus occur via a cyclic GMP-activated ryanodine-sensitive mechanism, which does not appear to involve activation of K(+) channels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Role of PGE(2) in protease-activated receptor-1, -2 and -4 mediated relaxation in the mouse isolated trachea.

1. The potential mediator role of the prostanoid PGE(2) in airway smooth muscle relaxations induced by peptidic and proteolytic activators of PAR-1, PAR-2, PAR-3 and PAR-4 was investigated in carbachol-precontracted mouse isolated tracheal segments. 2. The tethered ligand domain sequences of murine PAR-1 (SFFLRN-NH(2)), PAR-2 (SLIGRL-NH(2)) and PAR-4 (GYPGKF-NH(2)), but not PAR-3 (SFNGGP-NH(2)), induced smooth muscle relaxation that was abolished by the non-selective cyclo-oxygenase (COX) inhibitor, indomethacin. The relative order for mean peak relaxation was SLIGRL-NH(2)>GYPGKF-NH(2) approximately amp; SFFLRN-NH(2)>SFNGGP-NH(2). 3. SFFLRN-NH(2), SLIGRL-NH(2) and GYPGKF-NH(2), but not SFNGGP-NH(2), induced significant PGE(2) release that was abolished by indomethacin. Like that for relaxation, the relative order for mean PGE(2) release was SLIGRL-NH(2)>GYPGKF-NH(2)>SFFLRN-NH(2)>SFNGGP-NH(2). 4. In dose-response studies, SLIGRL-NH(2) induced concentration-dependent increases in PGE(2) release (EC(50)=20.4 microM) and smooth muscle relaxation (EC(50)=15.8 microM). 5. The selective COX-2 inhibitor, nimesulide, but not the COX-1 inhibitor valeryl salicylate, significantly attenuated SLIGRL-NH(2)-induced smooth muscle relaxation and PGE(2) release. 6. Exogenously applied PGE(2) induced potent smooth muscle relaxation (EC(50)=60.3 nM) that was inhibited by the mixed DP/EP(1)/EP(2) prostanoid receptor antagonist, AH6809. SLIGRL-NH(2)-induced relaxation was also significantly inhibited by AH6809. 7. In summary, the results of this study strongly suggest that PAR-mediated relaxation in murine tracheal smooth muscle is dependent on the generation of the spasmolytic prostanoid, PGE(2). PAR-stimulated PGE(2) release appears to be generated preferentially by COX-2 rather than COX-1, and induces relaxation via activation of the EP(2) receptor.

Animals↗
PubMed2003

Effect of tumour necrosis factor-alpha and interleukin 1beta on endothelium-dependent relaxation in rat mesenteric resistance arteries in vitro.

1. Pre-eclampsia is associated with elevated proinflammatory cytokine levels and endothelial dysfunction. This study examined the effect of two cytokines, tumour necrosis factor-alpha (TNF) and interleukin-1beta (IL-1) on endothelium-dependent relaxation in response to acetylcholine (ACH), bradykinin (BK) and histamine (HIS) in rat mesenteric small arteries in vitro. 2. Rat mesenteric arteries were mounted in an isometric myograph. Tone was induced with phenylephrine (PE) or a depolarizing solution containing 80 mM KCl (K(80)). Relaxation was measured in response to ACH, BK, HIS and sodium nitroprusside (SNP), an endothelium-independent relaxant. Inhibition of NO synthase by a combination of N(omega)-monomethyl-L-arginine (L-NMMA) and N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly inhibited relaxation in response to ACH and BK. Addition of an inhibitor of cyclooxygenase, indomethacin, had no additional effect when added to L-NMMA and L-NAME. Inhibition of endothelium-derived hyperpolarizing factor (EDHF) by K(80) partially reduced responses to ACH and BK. Inhibition of HIS-induced relaxation was more marked with K(80). L-NMMA and L-NAME largely abolished the remaining relaxation to ACH, BK and HIS in arteries contracted with K(80). 3. Preincubation with TNF for 30 min caused an inhibition of relaxation in response to ACH and BK in arteries contracted with PE. Responses to HIS and SNP were not affected by TNF under these conditions. TNF also inhibited ACH-induced relaxation in arteries contracted with K(80). IL-1 had no effect on responses to ACH and the combination of TNF and IL-1 was not more effective than TNF alone. 4. The inhibitory effect of TNF on ACH-induced relaxation was abolished by coincubation with superoxide dismutase (SOD) and was not seen if NO synthase was inhibited by L-NMMA and L-NAME. 5. TNF inhibits the NO-dependent component of endothelium-dependent relaxation in response to ACH and BK, but does not inhibit the EDHF-dependent component. This effect may be attributable to the ability of TNF to increase levels of superoxide anions (O(2)(-)) and the ability of O(2)(-) to inactivate NO. This mechanism could contribute to the endothelial dysfunction seen in situations where TNF is elevated, such as pre-eclampsia.

Acetylcholine↗
PubMed2004

Impairment of the low-affinity state beta1-adrenoceptor-induced relaxation in spontaneously hypertensive rats.

1 In hypertension, a decrease of the vascular beta-adrenergic relaxation has been described. However, the specific involvement of each beta-adrenoceptor (beta-AR) subtype, in particular the low-affinity state of beta1-AR, has not yet been evaluated. We investigated whether the low-affinity state of beta1-AR-induced relaxation was impaired in Spontaneously Hypertensive Rats (SHR). 2 The relaxant responses to CGP 12177 and cyanopindolol, low-affinity state beta1-AR agonists (with beta1-/beta2-AR antagonistic and partial beta3-AR agonistic properties) were evaluated on thoracic aortic rings isolated from 12-weeks-old Wistar Kyoto rats (WKY) and SHR. 3 In WKY, CGP 12177 and cyanopindolol produced an endothelium and nitric oxide (NO)-independent relaxation. CGP 12177-induced endothelium-independent relaxation was not modified either by beta1-, beta2-AR (nadolol) or beta3-AR (L-748337 or SR 59230A) antagonists but was significantly reduced by high concentrations of CGP 20712A (P<0.05). This relaxation was also reduced by adenylyl cyclase inhibitors, SQ 22536 or MDL 12330A. 4 In SHR, CGP 12177 produced mainly an endothelium and NO-dependent relaxation. This effect was not modified by nadolol, but was strongly reduced by beta3-AR blockade. Endothelium-independent relaxation to CGP 12177 was not altered by adenylyl cyclase inhibition, but was amplified in preparations from pertussis toxin-pretreated SHR. 5 The immunohistochemical analysis revealed an upregulation of beta3-AR in the endothelial layer of SHR aorta, whereas the beta3-AR-induced relaxation was not modified. 6 In conclusion, we demonstrated an impaired low-affinity state of the beta1-AR-induced relaxation and an upregulation of the beta3-AR in hypertension. Some clinical implications of those findings are discussed.

Adrenergic beta-Antagonists↗
PubMed1999

Nitrergic and purinergic mechanisms and their interactions for relaxation of the rat internal anal sphincter.

1. The NANC neuronal mechanisms for relaxations of the rat internal anal sphincter in response to electrical field stimulation (EFS) were studied in isolated preparations in the presence of atropine (1 microM), propranolol (3 microM) and phentolamine (3 microM). 2. EFS-induced relaxations were abolished by tetrodotoxin (1 microM) and reduced to 64% of control by the guanylate cyclase inhibitor ODQ (1 microM), but were not significantly reduced by the nitric oxide synthase inhibitor L-NAME (100 microM) or oxyhaemoglobin (10 microM). However, in the presence of tubocurarine (10 microM) or apamin (0.1 microM), L-NAME or oxyhaemoglobin greatly reduced or abolished EFS-induced relaxations. 3. The EFS-induced relaxations were mimicked by NO (10-100 microM) and by ATP (3-10 mM). The relaxations elicited by these agents were not affected by tetrodotoxin, L-NAME, tubocurarine or apamin. However, ATP-induced relaxations were reduced by the combination of L-NAME with tubocurarine or apamin. 4. Nicotine (10-100 microM) produced concentration-dependent relaxations that were abolished by tubocurarine (10 microM) or hexamethonium (200 microM). After desensitisation to nicotine (100 microM) and in its continued presence, the addition of L-NAME (100 microM) resulted in almost complete abolition of EFS-induced relaxations. 5. It is suggested that tubocurarine, hexamethonium and desensitisation to nicotine have an apamin-like action in the rat internal anal sphincter, the main effect being blockade of a purinergic component of the relaxant transmission process. 6. The findings suggest that both nitrergic and purinergic transmissions are involved in EFS-induced NANC relaxations of the rat internal anal sphincter, and there appears to be a complex interaction between these two pathways of transmission.

Adrenergic Antagonists↗
PubMed1999

Effects of propranolol and L-NAME on beta-adrenoceptor-mediated relaxation in rat carotid artery.

1. The properties of beta-adrenoceptors mediating vascular relaxation in rat isolated carotid artery were investigated. Ring segments of arteries were preconstricted with the thromboxane A2 receptor agonist U-46619 and relaxation to beta-adrenoceptor agonists determined. 2. Isoprenaline produced a concentration-dependent relaxation of U-44619-constricted arteries. The concentration-response curve (CRC) to isoprenaline was shifted to the right by propranolol (1 microM) although the shift was less (105 fold; pA2, 8.02) than would be expected for an effect of isoprenaline at classical beta-adrenoceptors (300-1000 fold; pA2, 8.5-9). L-NAME (100 microM) significantly reduced responses to isoprenaline, lowering the slope of the CRC and reducing the maximum response. 3. The selective beta3-adrenoceptor agonists, BRL 37344 and ZD2079, also produced concentration-dependent relaxation of the arteries. L-NAME (100 microM) shifted the BRL 37344 CRC to the right 15 fold with no reduction in the slope or maximum response. L-NAME (100 microM) had no significant effect on the ZD2079 CRC. 4. In conclusion, relaxation to isoprenaline in rat carotid artery is inhibited by propranolol in a manner suggesting a mixed population of classical (beta1-/beta2-) and atypical (beta3-) adrenoceptors. The presence of beta3-adrenoceptors was confirmed by the relaxant effects of the selective beta3-adrenoceptor agonists BRL 37344 and ZD2079. L-NAME attenuated responses to both isoprenaline and the beta3-adrenoceptor agonist BRL 37344, suggesting a role for endothelial release of nitric oxide in beta-adrenoceptor mediated relaxation. However, the relaxant effect of BRL 37344 was attenuated by L-NAME to a lesser extent than that of isoprenaline. In addition, L-NAME had no effect on relaxation induced by ZD2079. These results suggest that there may be a differential contribution of endothelium to classical beta-and beta3-adrenoceptor-mediated effects, with endothelium contributing less to beta3-adrenoceptor-mediated relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Effect of hydroquinone, hydroxocobalamin and carboxy-PTIO on non-adrenergic non-cholinergic nerve mediated relaxations of the rat duodenum.

Relaxation induced by NANC-nerve stimulation is reduced by nitric oxide synthase (NOS) inhibitors but not by superoxide generators or NO scavengers, casting doubts on the precise nature of the neurotransmitter being released by these nerves. The lack of effect of superoxide anion generators to inhibit nitrergic nerve-mediated relaxations has been attributed to the protective action of high tissue levels of superoxide dismutase (SOD). The effects of hydroquinone, hydroxocobalamin and carboxy-PTIO, three NO inactivators which do not depend on superoxide anion generation, upon nitrergic nerve-mediated relaxations of the rat proximal duodenum were determined in order to elucidate whether they are mediated by free NO. GABA and nicotine caused relaxations of isolated segments of the rat proximal duodenum in a concentration-dependent manner that were abolished by tetrodotoxin (TTX). Similarly, transmural electrical stimulation (TES) caused frequency-dependent relaxations that were also abolished by TTX. The NOS inhibitors L-NAME and L-NOARG reduced in a concentration-dependent manner nerve-mediated relaxations elicited by TES, nicotine and GABA. The effect of NOS inhibitors was prevented by L-arginine but not D-arginine. NO caused concentration-dependent relaxations that were not affected by TTX or L-NOARG but were abolished by hydroquinone, hydroxocobalamin and carboxy-PTIO. In contrast, these compounds failed to affect TES-, nicotine- and GABA-induced relaxations. The lack of effect of hydroquinone, hydroxocobalamin and carboxy-PTIO upon nerve-mediated relaxations was unaltered by pretreatment with the SOD irreversible inhibitor DETCA. The present findings show that nitrergic nerve-mediated relaxations of the rat duodenum are unaffected by NO inactivators that do not generate superoxide anion. It is suggested that either a NO-containing molecule that is unreactive with the inactivators tested is the inhibitory neurotransmitter released by nitrergic nerves or that NOS activity fulfills another role in nitrergic nerves which could be related to the release of an still unidentified transmitter.

Animals↗
PubMed2002

Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferrets.

An understanding of the neural control of lower oesophageal sphincter (LOS) relaxation is clinically relevant because transient LOS relaxations (TLOSRs) are a mechanism of acid reflux into the oesophagus. Preganglionic motor neurones innervating the LOS are localized in the dorsal motor nucleus of the vagus (DMV). Based on a single study in cats, it is now widely accepted that these neurones are functionally organized into two separate populations, such that stimulation of the caudal and rostral DMV evokes LOS relaxation and contraction, respectively. Our goal was to map the functional LOS responses to chemical stimulation in the DMV and nucleus tractus solitarius (NTS) of ferrets, an animal model commonly used for conscious studies on TLOSRs, and to test whether DMV-evoked LOS relaxation is mediated through hexamethonium-sensitive vagal-inhibitory pathways to the LOS. We used miniaturized manometry with Dentsleeve to monitor LOS and oesophageal pressures in decerebrate unanaesthetized ferrets. LOS relaxation was evoked readily in response to gastric insufflation, which shows that the vago-vagal reflex was intact in this preparation. Microinjections of l-glutamate (12.5 nmol L-1 in 25 nL) were made into the DMV from approximately - 1.5 to + 2.0 mm relative to the obex. Microinjections into the caudal (- 1.5 to + 0.0 mm behind obex) and intermediate (+ 0.1 to + 1.0 mm rostral to obex) DMV both significantly decreased LOS pressure, and complete LOS relaxation was noted in 28/32 and 11/18 cases, respectively. LOS relaxation responses to DMV microinjection were highly reproducible and abolished by bilateral vagotomy or hexamethonium (15 mg kg-1 intravenously). A nitric oxide synthase inhibitor (l-NAME 100 mg kg-1 intramuscularly) significantly increased the time taken to reach the maximal response. Increases in LOS pressure (24 +/- 4 mmHg; n = 3) were obtained only when stimulation sites were located equal to greater than 1.5 mm rostral to the obex. LOS relaxation (- 78 +/- 10%; n = 6) was evoked by stimulation of the NTS but not immediately outside of the NTS (11 +/- 27%; n = 5). We conclude that there is a very extensive population of 'inhibitory' motor neurones in the DMV that may account for the predominant vagal-inhibitory tone in ferrets. As NTS stimulation evokes LOS relaxation and the predominant response to DMV stimulation is also LOS relaxation, this vago-vagal reflex may involve an excitatory interneurone between the NTS and DMV vagal inhibitory output.

Animals↗
PubMed2001

Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism.

The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 microM) and yohimbine (30 microM) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of alpha-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of alpha-adrenergic receptor blockade.

Adrenergic alpha-Antagonists↗
PubMed2002

Mechanisms of relaxant action of 3-O-methylquercetin in isolated guinea pig trachea.

We investigated the mechanisms of action of 3-O-methylquercetin (3-MQ), isolated from Rhamnus nakaharai (Hayata) Hayata (Rhamnaceae) which is used as a folk medicine for treating constipation, inflammation, tumors and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. 3-MQ concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)- and KCl (30 mM)-induced precontractions, and inhibited cumulative histamine-, and carbachol-induced contractions in a non-competitive manner. 3-MQ also concentration-dependently and non-competitively inhibited cumulative Ca(2+)-induced contractions in depolarized (K(+), 60 mM) guinea-pig trachealis. The nifedipine (10 microM)-remaining tension of histamine (30 microM)-induced precontraction was further relaxed by 3-MQ, suggesting that no matter whether VDCCs were blocked or not, 3-MQ may have other mechanisms of relaxant action. The relaxant effect of 3-MQ was unaffected by the removal of epithelium or by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), N(omega)-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/ml). However, 3-MQ (7.5 - 15 microM) and IBMX (3 - 6 microM), a positive control, produced parallel and leftward shifts of the concentration-response curve of forskoline (0.01 - 3 microM) or nitroprusside (0.01 - 30 microM). 3-MQ or IBMX at various concentrations (10 - 300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis. The IC50 values of 3-MQ were estimated to be 13.8 and 14.3 microM, respectively. The inhibitory effects of 3-MQ on both enzyme activities were not significantly different from those of IBMX, a non-selective PDE inhibitor. The above results reveal that the mechanisms of relaxant action of 3-MQ may be due to its inhibitory effects on both PDE activities and its subsequent reducing effect on [Ca(2+)]i of the trachealis.3-MQ:3-O-methylquercetinIBMX:3-isobutyl-1-methylxanthineVDCCs:voltage dependent calcium channelscAMP:adenosine 3',5'-cyclic monophosphatecGMP:guanosine 3',5'-cyclic monophosphatePDE:phosphodiesteraseWe investigated the mechanisms of action of 3-O-methylquercetin (3-MQ), isolated from Rhamnus nakaharai (Hayata) Hayata (Rhamnaceae) which is used as a folk medicine for treating constipation, inflammation, tumors and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. 3-MQ concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)- and KCl (30 mM)-induced precontractions, and inhibited cumulative histamine-, and carbachol-induced contractions in a non-competitive manner. 3-MQ also concentration-dependently and non-competitively inhibited cumulative Ca(2+)-induced contractions in depolarized (K(+), 60 mM) guinea-pig trachealis. The nifedipine (10 microM)-remaining tension of histamine (30 microM)-induced precontraction was further relaxed by 3-MQ, suggesting that no matter whether VDCCs were blocked or not, 3-MQ may have other mechanisms of relaxant action. The relaxant effect of 3-MQ was unaffected by the removal of epithelium or by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), N(omega)-nitro-L-arginine (20 microM), or alpha-chymotrypsin (1 U/ml). However, 3-MQ (7.5 - 15 microM) and IBMX (3 - 6 microM), a positive control, produced parallel and leftward shifts of the concentration-response curve of forskoline (0.01 - 3 microM) or nitroprusside (0.01 - 30 microM). 3-MQ or IBMX at various concentrations (10 - 300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-PDE activities of the trachealis. The IC50 values of 3-MQ were estimated to be 13.8 and 14.3 microM, respectively. The inhibitory effects of 3-MQ on both enzyme activities were not significantly different from those of IBMX, a non-selective PDE inhibitor. The above results reveal that the mechanisms of relaxant action of 3-MQ may be due to its inhibitory effects on both PDE activities and its subsequent reducing effect on [Ca(2+)]i of the trachealis.3-MQ:3-O-methylquercetinIBMX:3-isobutyl-1-methylxanthineVDCCs:voltage dependent calcium channelscAMP:adenosine 3',5'-cyclic monophosphatecGMP:guanosine 3',5'-cyclic monophosphatePDE:phosphodiesterase

Animals↗