Investigation the relaxant effects of proton pump inhibitors and their relaxation mechanism on sheep sphincter of Oddi.

BACKGROUND: Using a relaxant agent before an endoscopic retrograde cholangiopancreatography (ERCP) might reduce complications. STUDY AIMS: We aimed to investigate the relaxant effects of proton pump inhibitors (PPIs) on sheep sphincter of Oddi (SO) and the mechanisms that might take part in this relaxant effect. PATIENTS AND METHODS: The sheep SO was mounted in an organ bath filled with Krebs-Ringer bicarbonate solution under 1.5 g tension and the relaxant effects of PPIs were evaluated in the tissues precontracted by carbachol (10-6 mol/l). The relaxant responses to the PPIs were tested in the presence of various blockers to enlighten the underlying mechanism by the PPIs. RESULTS: The PPIs exerted relaxant responses in a concentration-dependent manner in the sheep SO (P < 0.05). Esomeprazole produced the strongest relaxation. The administration of atropine, indomethacin, L-NAME, methylene blue, clotrimazole, glibenclamide, and 4-aminopyridine into the organ baths did not change the relaxations induced by PPIs in vitro (P> 0.05). On the other hand, Ca+2-activated potassium channel blocker tetraethylammonium (TEA) reduced the relaxation responses created by PPIs (P < 0.05). CONCLUSIONS: The present study suggests that PPIs create relaxation on SO partially via Ca+2-activated potassium channels. PPIs, especially esomeprazole, may be beneficial during the ERCP procedure. Further clinical studies are needed to confirm our results.

Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect.

OBJECTIVES: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS: Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS: PPIX, SIN-1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION: These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29).

In vitro motility changes in Roux limb after Roux-en-Y reconstruction.

BACKGROUND: The aim of this study is to compare the motility of Roux limb with that of normal segment. MATERIALS AND METHODS: Rats were divided into 3 equal groups as control, Roux-en-Y (Group A) and Roux-en-Y with vagotomy (Group B). Only midline incision and manipulations were applied in control group. Following distal gastrectomy, Roux-en-Y reconstruction was applied in Group A, while vagotomy Roux-en-Y gastrojejunostomy was applied in Group B. Rats were sacrificed 1 month later by cervical dislocations under anesthesia. The obtained jejunal segments were cut into four equal parts. The bath was 37 °C warm while 95 % O2 and 5 % CO2 gases were supplied in 10 ml bicarbonate Krebs' solution. RESULTS: KCl responses were similar in all three groups. Acetylcholine contraction responses in the vagotomy and non-vagotomy Roux-en-Y groups was higher than in those in control group significantly (p < 0.05). This response in vagotomy Roux-en-Y group was also higher than that in non-vagotomy group (p < 0.05). The induced electrical field stimulation contraction response in the vagotomy + Roux-en-Y group was lower than those in control group and non-vagotomy group (p < 0.05). CONCLUSIONS: These results show that muscarinic receptor density and/or function may increase after vagotomy and non-vagotomy group operation, and vagotomy may contribute to this increase. The decrease in electrical signal response in vagotomy Roux-en-Y group may depend on the decrease in acetylcholine oscillation from the cholinergic nerve ending (Tab. 1, Fig. 5, Ref. 25).

Effect of nitric oxide/cyclic guanosine mono-phosphate pathway on gallbladder relaxant response in bile duct-ligated guinea pigs.

BACKGROUND/AIMS: Common bile duct ligation (CBDL) in the guinea pig is a well-defined model of acalculous cholecystitis. Nitric oxide (NO) mediates smooth muscle relaxation by stimulating the activity of soluble guanylate cyclase. The aim of this study was to determine whether the NO/cyclic guanosine monophosphate pathway plays a role in gallbladder relaxant response after CBDL. METHODS: Relaxant response of gallbladder muscle strips from CBDL and sham-operated guinea pigs was studied in vitro. Animals were treated with saline, aminoguanidine or an aminoguanidine + L-arginine combination in vivo. Concentration-response curves of papaverine, diethylamine/NO, YC-1, sildenafil and amrinone were obtained and relaxations in each group were calculated as the percent of the contractions induced by carbachol (10(-6) M). RESULTS: There was a significant decrease in the gallbladder muscle relaxant responses to these substances in CBDL and aminoguanidine groups compared with sham surgical controls. The decreased relaxant response was reversed by aminoguanidine + L-arginine but not by aminoguanidine alone. CONCLUSION: Decreased relaxant responses might be due to the reduced guanylate cyclase enzyme activity, but further studies are required.

Effect of hypothyroidism on the purinergic responses of corpus cavernosal smooth muscle in rabbits.

AIMS: Several studies have reported evidence of hormonal abnormalities in 25-35% of impotent men. Hypothyroidism has been reported to occur in 6% of impotent men. In the present study, we examined purinergic relaxation responses in hypothyroidism in an experimental rabbit model and compared them with controls to evaluate the possible involvement of the purinergic pathway. MATERIALS AND METHODS: The study comprised 20 male New Zealand white rabbits. The rabbits were divided into two equal groups. We tested the effects of ATP, alpha beta ATP, and adenosine precontracted with phenylephrine on the isolated corpus cavernosum preparations from control and hypothyroid rabbits. We also evaluated the effects of ATP, alpha beta ATP, and adenosine on the cGMP levels in the isolated corpus cavernosum preparations from control and hypothyroid rabbits. RESULTS: T3, T4, and testosterone levels were significantly lower in hypothyroid rabbits. ATP, alpha beta ATP, carbachol, and electrical field stimulation (EFS)-induced frequency-dependent relaxation responses in the isolated rabbit corpus cavernosum strips precontracted with phenylephrine reduced significantly (P<0.05). Adenosine-induced relaxation responses did not change significantly in hypothyroid rabbits. CONCLUSION: Reduction of relaxation response in hypothyroid rabbits corpus cavernosum can depend on a decreased release of nitric oxide (NO) from nitrergic nerves and endothelium.

Interactive effect of sevoflurane with isradipine or indomethacin on spontaneous contractile activity of isolated pregnant rat myometrium.

Volatile anesthetics, calcium antagonists and non-steroidal anti-inflammatory drugs inhibit contractile activity of myometrial smooth muscle. The aim of this study was to investigate the interactive effect of sevoflurane with isradipine or indomethacin on spontaneous contractile activity of myometrial strips isolated from pregnant rats. The myometrial strips were excised from rats (250-300 g) at 19-21 days of gestation and mounted in tissue baths for recording of isometric tension. Sevoflurane (0.5 to 3 MAC) inhibited the amplitude and frequency of spontaneous myometrial contractions in a concentration-dependent manner (P<0.05). Sevoflurane responses were repeated in the presence of isradipine (a dihydropyridine-type calcium channel blocker) and indomethacin (a non-selective cyclooxygenase (COX) inhibitor). Pretreatment with isradipine (10(-6) M) or indomethacin (10(-7) M), concentrations that themselves had no effect on spontaneous contractility, significantly increased the inhibitor responses to sevoflurane on amplitude and frequency of myometrial contractions, beginning at 1 MAC (P<0.05). Blockade of calcium channels in myometrial smooth muscle may increase the inhibitor effect of sevoflurane. Further work is needed to determine the cellular mechanism(s) of this interaction.

Effects of fluoxetine and LY 367265 on tolerance to the analgesic effect of morphine in rats.

Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. The aim of this study was to investigate effects of fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, and LY 367265, an inhibitor of the 5-HT transporter and 5-HT2A receptor antagonist, on tolerance induced to the analgesic effect of morphine in rats. The study was carried out on male Wistar Albino rats (weighing 170-190 g). To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After last dose of morphine, injected on day 4, morphine tolerance was evaluated. The analgesic effects of fluoxetine (10 mg/ kg; i.p.), LY 367265 (3 mg/kg; i.p.) and morphine were considered at 30-min intervals by tail-flick and hot-plate tests. The results showed that fluoxetine and LY 367265 significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effects were obtained 30 min after administration of fluoxetine and 60 min after administration of LY 367265. In conclusion, we observed that co-injection of morphine with fluoxetine and LY 367265 increased the analgesic effects of morphine and delayed development of tolerance to morphine analgesia.

Investigation of the relaxant effects of propofol on ovalbumin-induced asthma in guinea pigs.

BACKGROUND AND OBJECTIVE: Because the incidence of asthma appears to be increasing, the importance of proper perioperative management of individuals with asthma will also continue to increase. Although its mechanism of smooth muscle relaxation is unknown, propofol has been associated with less bronchoconstriction during anaesthetic induction. The aim of this study was to investigate the possible mechanism of these effects and the effects of propofol on the isolated trachea preparations from control and ovalbumin-sensitized guinea pigs. METHODS: Adult male guinea pigs, weighing 280-330 g, were randomly allocated to two experimental groups, each consisting of 10 animals. Ten guinea pigs were sensitized by intramuscular injections of 0.30 mL of a 5% (w/v) ovalbumin/saline solution into each thigh (0.6 mL total) on days 1 and 4, whereas the remaining 10 served as controls receiving a total of 0.6 mL distilled water on days 1 and 4 as placebo. The isolated trachea preparations were mounted in tissue baths with modified Krebs-Henseleit solution and aerated with 95% oxygen and 5% carbon dioxide. We tested the effects of propofol (10(-7)-10(-3) M) on resting tension and after precontraction with carbachol and histamine on isolated trachea preparations from control and ovalbumin-sensitized guinea pigs. We also tested the effect of propofol on isolated trachea preparations precontracted with carbachol and histamine in the absence and presence of different inhibitors or antagonists. We investigated propofol responses in tracheal smooth muscle precontracted with CaCl2. RESULTS: Propofol (10(-7)-10(-3) M) produced a concentration-dependent relaxation of isolated tracheal preparations precontracted by carbachol (10(-6) M) and histamine (10(-6) M) in both groups. Preincubation with N(w)-nitro L-arginine methyl ester (3x10(-5) M), indomethacin (10(-5) M) or propranolol (10(-4) M) did not produce a significant alteration on propofol-induced relaxation responses (P>0.05), while preincubation with tetraethylammonium (3x10(-4) M) significantly decreased the propofol-induced relaxation responses in both groups (P<0.05). Propofol (10(-7)-10(-3) M) induced concentration-dependently relaxations in isolated trachea rings precontracted with CaCl2 in both the control and ovalbumin-sensitized groups. CONCLUSION: Propofol induced concentration-dependent relaxations in precontracted, isolated trachea smooth muscle of guinea pigs in both the control and ovalbumin-sensitized groups. These relaxations were independent of epithelial function and stimulation of beta adrenergic receptors. Opened Ca2+-sensitive K+ channels and inhibited L-type Ca2+ channels can contribute to these relaxations.

Vasorelaxant effect of opioid analgesics on the isolated human radial artery.

BACKGROUND AND OBJECTIVE: Arterial grafts are prone to vasospasm. Opioid analgesics are commonly used in the perioperative course of cardiac surgical procedures. Therefore, we investigated the direct effects of morphine, meperidine, fentanyl and remifentanil on the human radial artery. METHODS: Radial artery segments, obtained from 20 patients, were precontracted with phenylephrine. Using the organ bath technique, the endothelium-independent vasodilatation was tested in vitro by addition of cumulative concentrations of morphine, meperidine, fentanyl and remifentanil in separate organ baths, in the presence or absence of naloxone. Indomethacin and NG-nitro-L-arginine methyl ester was added to all organ bath in order to determine the effects of prostaglandins and nitric oxide, respectively. RESULTS: Morphine (10(-8) - 10(-4) mol L-1), meperidine (10(-10) - 10(-6) mol L-1), fentanyl (10(-10) - 10(-6) mol L-1) and remifentanil (10(-8) - 10(-4) mol L-1) caused a concentration-dependent vasorelaxation in the human being artery rings. The relaxations in the presence of naloxane did not change. The maximal relaxant effects of meperidine and fentanyl were significantly greater than those of morphine and remifentanil (P < 0.05). CONCLUSIONS: These findings indicate that morphine, meperidine, fentanyl and remifentanil produce concentration-dependent and endothelium-independent relaxations in human being radial artery rings. Meperidine and fentanyl are more potent relaxant agents than morphine and remifentanil in the human being radial artery in vitro.

Relaxation induced by omeprazole does not change in diabetic rabbit corpus cavernosum.

OBJECTIVE: To investigate the changes in relaxation responses to omeprazole in corpus cavernosal strips from rabbits with diabetes induced by alloxan. MATERIALS AND METHODS: Diabetes was induced in 10 New Zealand white rabbits. After 8 weeks, the reactivity to electrical-field stimulation, carbachol and omeprazole of corporal strips from the penises of the diabetic animals and from 10 untreated controls was assessed in organ chambers. RESULTS: In the diabetic group, the relaxation responses of corpus cavernosal strips to omeprazole were comparable with those of the control group, whereas the relaxation responses to electrical field stimulation and carbachol were impaired. CONCLUSION: The relaxant effect of omeprazole in corpus cavernosum was not affected by diabetes, in which neurogenic and endothelium-mediated relaxations were impaired.

Relaxation effects of adrenomedullin in isolated rabbit corpus cavernosum smooth muscle.

OBJECTIVES: To clarify the pharmacological effects of adrenomedullin, a potent vasodilator and hypotensive peptide isolated from human phaeochromocytoma cells, on corpus cavernosal smooth muscle in vitro, as the intracavernosal injection of adrenomedullin induces penile erection in the anaesthetized cat. MATERIALS AND METHODS: The effects of adrenomedullin were investigated in isolated muscle strips from New Zealand rabbit corpus cavernosum smooth muscle pre-contracted with phenylephrine alone, in the presence of indomethacin (cyclooxygenase inhibitor), Nomega-nitro l-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), and K+-channel blockers. RESULTS: Adrenomedullin caused relaxation of isolated pre-contracted rabbit corpus cavernosum strips in a concentration-dependent manner. The response of corpus cavernosum was unaffected L-NAME, indomethacin and K+-channel blockers. CONCLUSION: The relaxation exerted by adrenomedullin in rabbit corporal tissue may arise from the effect of the drug on its specific receptors and/or calcitonin gene-related peptide-1 receptors. The relaxant effect of adrenomedullin might lead to novel clinical applications for erectile dysfunction.

The evaluation of the effects of renal failure on erectile dysfunction in a rabbit model of chronic renal failure.

OBJECTIVE: To determine whether chronic renal failure (CRF) reduces nitrergic relaxant responses in a rabbit model. MATERIALS AND METHODS: Ten rabbits underwent surgery to induce uraemia (CRF rabbits) and a further 10 a sham operation (controls). Corpus cavernosal tissue was prepared and used in organ-chamber experiments, with relaxation assessed against a background of pre-contraction with phenylephrine. At the plateau of contraction, relaxation responses to cumulative concentrations of carbachol or sodium nitroprusside (SNP), to test endothelium-dependent and -independent relaxations, respectively, were assessed. Before electrical-field stimulation (EFS), the tissue was treated with an adrenergic nerve blocker and a muscarinic receptor blocker to eliminate the adrenergic and cholinergic components, and to determine the relaxation responses to the stimulation of nonadrenergic, noncholinergic (NANC) nerves. The relaxation responses in corporal strips obtained from CRF rabbits were compared with those from controls. RESULTS: When tissues were contracted with KCl, tensions were similar in all groups. The impairment in concentration-dependent relaxation with carbachol was significant in CRF rabbits, but SNP- and papaverine-induced concentration-dependent relaxation responses were no different among the groups. EFS-induced frequency-dependent relaxations were significantly lower in CRF rabbits than in controls. CONCLUSION: CRF inhibits the NANC-mediated relaxation of rabbit corpus cavernosum smooth muscle. Changes in NANC-mediated and carbachol-induced (endothelium-dependent) relaxation of corporal smooth muscle in the rabbit are probably caused by uraemia and subsequently, hyperthyroidism, hyperparathyroidism or low testosterone levels in CRF. These results also suggest that if vasoactive agents are to be used for treating erectile dysfunction in uraemic patients, direct-acting vasodilators and phosphodiesterase inhibitors will be useful.

Effect of chronic renal failure on the purinergic responses of corpus cavernosal smooth muscle in rabbits.

OBJECTIVE: To examine purinergic relaxation responses in chronic renal failure (CRF) in an experimental rabbit model, and thus evaluate the possible involvement of the purinergic system in erectile dysfunction with CRF. MATERIALS AND METHODS: The relaxant effects of ATP were measured in strips of corpus cavernosum smooth muscle taken from control and CRF rabbits. CRF was induced in New Zealand white rabbits as previously described. Penises were excised from CRF rabbits 4 weeks after inducing uraemia. In an organ bath the strips from controls and CRF rabbit corpus cavernosum were pre-contracted with phenylephrine and increasing doses of adenosine and ATP added. RESULTS: In the pre-contracted rabbit cavernosal tissue the relaxations induced by adenosine and ATP were unchanged in CRF. CONCLUSION: The lack of any relaxant effect of adenosine or ATP on the relaxation of cavernosal smooth muscle in rabbits with CRF might be because the relaxant effects of these agents are endothelium-independent and the endothelial purinergic receptor density was unchanged in CRF.