Lack of Cyclic Nucleotide Regulation of MBCQ-induced Relaxation of Rat Ileal Smooth Muscle.

Kaneda, Toshio; Yamamoto, Hideyuki; Azegami, Yoshihiro; Shimizu, Kazumasa; Urakawa, Norimoto; Nakajyo, Shinjiro

doi:10.1540/jsmr.39.47

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…However, at a concentration that induced half-maximum relaxation, Ro20-1724-increased cAMP content was less than that of the other inhibitors. We reported that MBCQ, a selective PDE 5 inhibitor, inhibits muscle contraction without changes in cAMP and cGMP content in ileal smooth muscle [12]. Therefore, it seems that Ro20-1724-induced relaxation may be partially involved in the cAMP-and cGMP-independent mechanism.…”

Section: Discussionmentioning

confidence: 89%

Effects of Various Selective Phosphodiesterase Inhibitors on Carbachol-Induced Contraction and Cyclic Nucleotide Contents in the Guinea Pig Gall Bladder

Kaneda

WATANABE

Shimizu

et al. 2005

The Journal of Veterinary Medical Science

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ABSTRACT. The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility and cyclic nucleotide contents in the guinea pig gall bladder were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), and zaprinast (type 5), inhibited CCh-induced contractions in a concentration-dependent manner. The rank order of potency for the gall bladder was Ro20-1724 > vinpocetine > EHNA >milrinone > zaprinast, which was different from that of the trachea, taenia coli, and aorta. In the presence of CCh (0.3 µM), vinpocetine, milrinone, and Ro20-1724 each increased cAMP content, but not cGMP. By contrast, zaprinast increased cGMP content, but not cAMP, and EHNA increased both cAMP and cGMP contents. These results suggest that vinpocetine-, milrinone-, and Ro20-1724-induced relaxation was correlated with cAMP, zaprinast-induced relaxation was correlated with cGMP, and that EHNA-induced relaxation was correlated with cAMP and cGMP in the guinea pig gall bladder. In conclusion, the effect of PDE inhibitors in the guinea pig gall bladder was different from those in smooth muscles, such as the trachea, taenia coli, and aorta. KEY WORDS: cAMP, cGMP, Gall bladder, PDE inhibitor.J. Vet. Med. Sci. 67 (7): [659][660][661][662][663][664][665] 2005 Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are important second messengers, and have been associated with smooth muscle relaxation [5]. These cyclic nucleotides are synthesized by adenylyl cyclase or guanylyl cyclase, and are degraded by phosphodiesterase (PDE). Currently, PDEs are classified into 11 families [3,6,23], and selective PDE inhibitors have been found [4]. It has been reported that the relaxation induced by these selective PDE (type 1-type 5) inhibitors is involved in the increases in cAMP and/or cGMP contents in vascular [14], tracheal [16], urinary [15,22], and intestinal smooth muscle [10,11]. Since PDE1 and 2 hydrolyze cAMP and/or cGMP [3], it is thought that type 1 and type 2 inhibitor-induced relaxations may be correlated with increases in cAMP and/or cGMP in smooth muscles. It has been reported that vinpocetine (type 1 inhibitor) induced relaxation in the rabbit aorta through the increase in cGMP content [1,7], and in the rat urinary bladder [15] and guinea pig taenia coli [10] through an increase in the cAMP content. There have been few reports indicating that relaxation induced by EHNA (type 2 inhibitor) is associated with the increases in the cyclic nucleotide contents of smooth muscle [9,11,13].Additionally, the relationship of relaxation induced by these selective inhibitors and cyclic nucleotides is less clear in the smooth muscle of the gastrointestinal tract. Barnette et al. [2] assessed the activity of PDE families and the relaxation induced by the PDE3, 4, and 5 inhibitors in canine colonic smooth muscle. They showed that PDE3 and 4 inhibitors decreased the hydrolysis of cAMP, that the PDE5 inhib...

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Section: Discussionmentioning

confidence: 89%

Effects of Various Selective Phosphodiesterase Inhibitors on Carbachol-Induced Contraction and Cyclic Nucleotide Contents in the Guinea Pig Gall Bladder

Kaneda

WATANABE

Shimizu

et al. 2005

The Journal of Veterinary Medical Science

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“…Phosphodiesterase 5, the target of sildenafil, with other components of the cGMP signalling cascade is primarily located in smooth muscle tissues, including the gastrointestinal tract. 4,5 This type of drug produces PDE5 inhibition, increasing intracellular concentrations of cGMP and enhancing NO-induced smooth muscle relaxation. 24 Therefore, substances that increase cellular levels of cGMP may lead to a reduced smooth muscle tone and inhibited responsiveness to contractile agonists.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] The smooth muscle cells of the gastrointestinal tract also contain cGMP and PDE5 enzyme. 4,5 Once inhibitory neurotransmitters, such as nitric oxide (NO) or atrial natriuretic peptide, are released, they increase intracellular cGMP levels, which decrease cytosolic Ca 2+ content, and smooth muscle relaxation occurs. 6,7 Recent evidence indicates that sildenafil modifies gastrointestinal motility both in animals and humans.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of sildenafil on rat duodenal contractility In vitro: Putative cGMP involvement

Araújo

Clemente

Graça

et al. 2005

Clin Exp Pharma Physio

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1. Sildenafil citrate (Viagratrade mark; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activity in vitro. 2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 micromol/L (95% confidence interval (CI) 2.0-55.3 micromol/L). 3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC(50) of 16.2 micromol/L (95% CI 9.5-27.6 micromol/L). Sildenafil produced significant additional relaxation of 25.2 +/- 8.1% of the CCh-induced contraction, beyond basal tone. 4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 micromol/L (95% CI 5.7-16.2 micromol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 micromol/L (95% CI 46.0-182.2 micromol/L) and 78.5 micromol/L (95% CI 37.1-166.3 micromol/L), respectively. 5. In preparations treated previously with methylene blue (10 micromol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 micromol/L (95% CI 23.9-63.4 micromol/L) and 43.8 micromol/L (95% CI 24.5-78.3 micromol/L), respectively. These values were significantly greater than those obtained with sildenafil alone. 6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segments in vitro. The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation.

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Sildenafil delays the intestinal transit of a liquid meal in awake rats

Graça¹,

Macedo²,

Palheta³

et al. 2008

Braz J Med Biol Res

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Sildenafil slows down the gastric emptying of a liquid test meal in awake rats and inhibits the contractility of intestinal tissue strips. We studied the acute effects of sildenafil on in vivo intestinal transit in rats. Fasted, male albino rats (180-220 g, N = 44) were treated (0.2 mL, iv) with sildenafil (4 mg/kg) or vehicle (0.01 N HCl). Ten minutes later they were fed a liquid test meal ( 99m 99m 99m 99m 99m technetium-labeled saline) injected directly into the duodenum. Twenty, 30 or 40 min after feeding, the rats were killed and transit throughout the gastrointestinal tract was evaluated by progression of the radiotracer using the geometric center method. The effect of sildenafil on mean arterial pressure (MAP) was monitored in a separate group of rats (N = 14). Data (medians within interquartile ranges) were compared by the Mann-Whitney U-test. The location of the geometric center was significantly more distal in vehicle-treated than in sildenafil-treated rats at 20, 30, and 40 min after test meal instillation (3.3 (3.0-3.6) vs 2.9 (2.7-3.1); 3.8 (3.4-4.0) vs 2.9 (2.5-3.1), and 4.3 (3.9-4.5) vs 3.4 (3.2-3.7), respectively; P < 0.05). MAP was unchanged in vehicletreated rats but decreased by 25% (P < 0.05) within 10 min after sildenafil injection. In conclusion, besides transiently decreasing MAP, sildenafil delays the intestinal transit of a liquid test meal in awake rats. Sildenafil citrate belongs to a class of compounds called phosphodiesterase (PDE) inhibitors. PDEs constitute a family of enzymes that hydrolyze cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanosine monophosphate, cGMP) and play a critical role in the modulation of the second messenger pathway (1). Sildenafil citrate is a selective PDE type 5 inhibitor widely used due to its therapeutic efficacy in human erectile dysfunction and pulmonary hypertension. It effectively blocks the PDE 5-mediated hydrolysis of cGMP inside vascular smooth muscle cells, relaxing the arterioles that supply the corpus cavernosum (2) and the lung parenchyma (3).Sildenafil increases the gastric resistance to injury by non-steroidal anti-inflammatory drugs (4), decreases the distal esophageal peristalsis (5), and inhibits the gastric emptying of test meals both in humans and rats (6,7), and decreases the contractility of isolated duodenal strips (8).Since the gastrointestinal transit rate results from a complex interplay between gastric tonus, distal stomach phasic activity and resistance and propulsion offered by the small intestine (9), we measured the effect of sildenafil on the small bowel intestinal transit of a liquid test meal in awake rats.

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Lack of Cyclic Nucleotide Regulation of MBCQ-induced Relaxation of Rat Ileal Smooth Muscle.

Cited by 4 publications

References 26 publications

Effects of Various Selective Phosphodiesterase Inhibitors on Carbachol-Induced Contraction and Cyclic Nucleotide Contents in the Guinea Pig Gall Bladder

Effects of Various Selective Phosphodiesterase Inhibitors on Carbachol-Induced Contraction and Cyclic Nucleotide Contents in the Guinea Pig Gall Bladder

Inhibitory effect of sildenafil on rat duodenal contractility In vitro: Putative cGMP involvement

Sildenafil delays the intestinal transit of a liquid meal in awake rats

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