The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β2-agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness (Emax) 91.33 ± 3.37%, P < 0.001], relaxed bronchi precontracted with ACh (Emax 94.62 ± 2.63%, pD2 4.84 ± 0.12, P < 0.001), and abolished the contraction induced by histamine. Analysis of interactions indicated a weak synergism between RPL554 and salbutamol (interaction index: 0.25 ± 0.06; BI Δeffect: 0.29 ± 0.11; dose equivalence: no synergism) but significant synergism between RPL554 and atropine (interaction index: 0.09 ± 0.07; BI Δeffect: 0.54 ± 0.09; dose equivalence: synergism for low concentrations) or glycopyrrolate (ACh: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.02; histamine: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.03). This study demonstrates that RPL554 relaxes human bronchi and that it can interact with a muscarinic receptor antagonist to produce a synergistic inhibition of ASM Tone. These results suggest that RPL554 may provide a novel treatment of airway diseases, either alone or in combination with antimuscarinic drugs.
Iñigo Sáenz De Tejada - One of the best experts on this subject based on the ideXlab platform.
-
regulation of human penile Smooth Muscle Tone by prostanoid receptors
British Journal of Pharmacology, 2002Co-Authors: J C Angulo, Pedro Cuevas, Jose M La Fuente, Jose M Pomerol, Eduardo Ruizcastane, Ana Puigvert, Sonia Gabancho, Argentina Fernandez, Peter Ney, Iñigo Sáenz De TejadaAbstract:We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular Smooth Muscle Tone. Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile Smooth Muscle Tone. TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC50 8.3+/-2.8 nM) and HPRA (EC50 6.2+/-2.2 nM), and the contractions produced by prostaglandin F(2alpha) at high concentrations (EC50 6460+/-3220 nM in HCCS and 8900+/-6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 microM). EP-receptors are responsible for prostanoid-induced relaxant effects in HCCS because only prostaglandin E1 (PGE1), prostaglandin E2 and the EP2/EP4-receptor agonist, butaprost, produced consistent relaxation of this tissue (EC50 93.8+/-31.5, 16.3+/-3.8 and 1820+/-1284 nM, respectively). In HPRA, both prostacyclin and PGE1 (EC50 60.1+/-18.4 and 109.0+/-30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC50 25.2+/-15.2 and 7050+/-6020 nM, respectively) caused relaxation, suggesting co-existence of IP- and EP-receptors (EP2 and/or EP4). In summary, endogenous production of prostanoids may regulate penile Smooth Muscle contractility by way of specific receptors. TP-receptors mediate contraction in HCCS and HPRA, while the relaxant effects of prostanoids are mediated by EP2- and/or EP4-receptors in HCCS and by EP- and IP-receptors in HPRA.
-
In Vivo Assessment of Trabecular Smooth Muscle Tone, its Application in Pharmaco-Cavernosometry and Analysis of Intracavernous Pressure Determinants
The Journal of Urology, 1995Co-Authors: Dimitrios Hatzichristou, Susie Kupferman, Swati Namburi, Daniel Udelson, Iñigo Sáenz De Tejada, Edoardo S. Pescatori, Irwin GoldsteinAbstract:AbstractA pharmaco-cavernosometry based clinical study was designed to define hemodynamic parameters consistent with complete trabecular Smooth Muscle relaxation, establish a methodology for overcoming incomplete trabecular Smooth Muscle relaxation, and determine under controlled conditions the contribution of venous outflow and arterial inflow to the steady-state equilibrium intracavernous pressure. Flow-pressure relationships were analyzed in 21 patients each of whom was assumed to have complete Smooth Muscle relaxation by virtue of the full, rigid and maintained erectile response following intracavernous vasodilator administration, which required intracavernous adrenergic agonists to achieve detumescence. Flow-to-maintain values increased linearly with intracavernous pressure while venous outflow resistance values were high and constant. Based on these relationships, trabecular Smooth Muscle Tone was assessed in 123 impotent patients. In 14 percent, 63 percent and 14 percent of the patients (112 of 123...
-
endothelium derived nitric oxide and cyclooxygenase products modulate corpus cavernosum Smooth Muscle Tone
The Journal of Urology, 1992Co-Authors: Kazem M Azadzoi, Irwin Goldstein, Michael L Brown, Richard A Cohen, Iñigo Sáenz De TejadaAbstract:AbstractRelaxation of penile corpus cavernosum Smooth Muscle is controlled by nerve and endothelium derived substances. In this study, endothelium-dependent relaxation of corporal Smooth Muscle was characterized and the role of arachidonic acid products of cyclooxygenase in endothelium-dependent relaxation was examined. Endothelium removal from rabbit corpora was performed by infusion with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate and was confirmed by transmission electron microscopy. Strips of human and rabbit corporal tissues were studied in the organ chambers for isometric tension measurement. The accumulation of cyclic guanosine monophosphate (cGMP) and the release of eicosanoids from corporal tissue was measured by radioimmunoassay and correlated to Smooth Muscle relaxation. Our study showed that relaxation of corpus cavernosum tissue to acetylcholine, bradykinin and substance P was endothelium-dependent; potentiated by indomethacin; and inhibited by NG-monomethyl-L-arginine, methyl...
-
endothelium derived nitric oxide and cyclooxygenase products modulate corpus cavernosum Smooth Muscle Tone
The Journal of Urology, 1992Co-Authors: Kazem M Azadzoi, Irwin Goldstein, Michael L Brown, Richard A Cohen, Noel N Kim, Iñigo Sáenz De TejadaAbstract:Relaxation of penile corpus cavernosum Smooth Muscle is controlled by nerve and endothelium derived substances. In this study, endothelium-dependent relaxation of corporal Smooth Muscle was characterized and the role of arachidonic acid products of cyclooxygenase in endothelium-dependent relaxation was examined. Endothelium removal from rabbit corpora was performed by infusion with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate and was confirmed by transmission electron microscopy. Strips of human and rabbit corporal tissues were studied in the organ chambers for isometric tension measurement. The accumulation of cyclic guanosine monophosphate (cGMP) and the release of eicosanoids from corporal tissue was measured by radioimmunoassay and correlated to Smooth Muscle relaxation. Our study showed that relaxation of corpus cavernosum tissue to acetylcholine, bradykinin and substance P was endothelium-dependent; potentiated by indomethacin; and inhibited by NG-monomethyl-L-arginine, methylene blue or LY83583. Relaxation to papaverine and sodium nitroprusside was endothelium-independent, and unaffected by NG-monomethyl-L-arginine. Relaxation to vasoactive intestinal polypeptide was partially endothelium-dependent; potentiated by indomethacin; attenuated by NG-monomethyl-L-arginine or methylene blue. The tissue level of cGMP was enhanced by acetylcholine and nitric oxide. Methylene blue inhibited both basal and drug-stimulated levels of cGMP. The release of eicosanoids was enhanced by acetylcholine and blocked by indomethacin. In conclusion, nitric oxide or a closely related substance accounts for the activity of endothelium-derived relaxing factor in the corporal tissue. Inhibition of the release of eicosanoids potentiates the relaxing effect of nitric oxide. Nitric oxide increases tissue cGMP which appears to modulate corporal Smooth Muscle relaxation.
Charles W Emala - One of the best experts on this subject based on the ideXlab platform.
-
agonism of the tmem16a calcium activated chloride channel modulates airway Smooth Muscle Tone
American Journal of Physiology-lung Cellular and Molecular Physiology, 2020Co-Authors: Jennifer Danielsson, George Gallos, Aisha S Kuforiji, Gene T Yocum, Yi Zhang, Dingbang Xu, Charles W EmalaAbstract:TMEM16A (anoctamin 1) is an important calcium-activated chloride channel in airway Smooth Muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have pr...
-
antagonists of the tmem16a calcium activated chloride channel modulate airway Smooth Muscle Tone and intracellular calcium
Anesthesiology, 2015Co-Authors: Jennifer Danielsson, George Gallos, Yi Zhang, Jose F Perezzoghbi, Kyra Bernstein, Matthew B Barajas, Satish Kumar, Pawan Sharma, Charles W EmalaAbstract:BACKGROUND: Perioperative bronchospasm refractory to β agonists continues to challenge anesthesiologists and intensivists. The TMEM16A calcium-activated chloride channel modulates airway Smooth Muscle (ASM) contraction. The authors hypothesized that TMEM16A antagonists would relax ASM contraction by modulating membrane potential and calcium flux. METHODS: Human ASM, guinea pig tracheal rings, or mouse peripheral airways were contracted with acetylcholine or leukotriene D4 and then treated with the TMEM16A antagonists: benzbromarone, T16Ainh-A01, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid, or B25. In separate studies, guinea pig tracheal rings were contracted with acetylcholine and then exposed to increasing concentrations of isoproterenol (0.01 nM to 10 μM) ± benzbromarone. Plasma membrane potential and intracellular calcium concentrations were measured in human ASM cells. RESULTS: Benzbromarone was the most potent TMEM16A antagonist tested for relaxing an acetylcholine -induced contraction in guinea pig tracheal rings (n = 6). Further studies were carried out to investigate the clinical utility of benzbromarone. In human ASM, benzbromarone relaxed either an acetylcholine- or a leukotriene D4-induced contraction (n = 8). Benzbromarone was also effective in relaxing peripheral airways (n = 9) and potentiating relaxation by β agonists (n = 5 to 10). In cellular mechanistic studies, benzbromarone hyperpolarized human ASM cells (n = 9 to 12) and attenuated intracellular calcium flux from both the plasma membrane and the sarcoplasmic reticulum (n = 6 to 12). CONCLUSION: TMEM16A antagonists work synergistically with β agonists and through a novel pathway of interrupting ion flux at both the plasma membrane and sarcoplasmic reticulum to acutely relax human ASM.
Luigino Calzetta - One of the best experts on this subject based on the ideXlab platform.
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P
-
effect of the mixed phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial Smooth Muscle Tone
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella MateraAbstract:The phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway Smooth Muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the Tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β2-agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness (Emax) 91.33 ± 3.37%, P < 0.001], relaxed bronchi precontracted with ACh (Emax 94.62 ± 2.63%, pD2 4.84 ± 0.12, P < 0.001), and abolished the contraction induced by histamine. Analysis of interactions indicated a weak synergism between RPL554 and salbutamol (interaction index: 0.25 ± 0.06; BI Δeffect: 0.29 ± 0.11; dose equivalence: no synergism) but significant synergism between RPL554 and atropine (interaction index: 0.09 ± 0.07; BI Δeffect: 0.54 ± 0.09; dose equivalence: synergism for low concentrations) or glycopyrrolate (ACh: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.02; histamine: BI Δeffect 0.46 ± 0.03, Berenbaum Δeffect 0.42 ± 0.03). This study demonstrates that RPL554 relaxes human bronchi and that it can interact with a muscarinic receptor antagonist to produce a synergistic inhibition of ASM Tone. These results suggest that RPL554 may provide a novel treatment of airway diseases, either alone or in combination with antimuscarinic drugs.
Satish Rattan - One of the best experts on this subject based on the ideXlab platform.
-
ca2 calmodulin mlck pathway initiates and rhoa rock maintains the internal anal sphincter Smooth Muscle Tone
American Journal of Physiology-gastrointestinal and Liver Physiology, 2017Co-Authors: Satish RattanAbstract:it is well known that Smooth Muscle contraction, whether spontaneous or following pharmacological stimulation, occurs in two phases: the initial phasic followed by the tonic phase ([1][1], [2][2], [5][3], [6][4], [11][5], [12][6], [14][7], [16][8], [17][9], [22][10], [23][11], [25][12], [33][13], [
-
nature of extracellular signal that triggers rhoa rock activation for the basal internal anal sphincter Tone in humans
American Journal of Physiology-gastrointestinal and Liver Physiology, 2015Co-Authors: Satish Rattan, Jagmohan Singh, Sumit Kumar, Benjamin PhillipsAbstract:The extracellular signal that triggers activation of rho-associated kinase (RhoA/ROCK), the major molecular determinant of basal internal anal sphincter (IAS) Smooth Muscle Tone, is not known. Usin...
-
3 hydroxymethyl coenzyme a reductase inhibition attenuates spontaneous Smooth Muscle Tone via rhoa rock pathway regulated by rhoa prenylation
American Journal of Physiology-gastrointestinal and Liver Physiology, 2010Co-Authors: Satish RattanAbstract:RhoA prenylation may play an important step in the translocation of RhoA in the basal internal anal sphincter (IAS) Smooth Muscle Tone. Statins inhibit downstream posttranslational RhoA prenylation by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition (HMGCRI). The role of statins in relation to RhoA prenylation in the pathophysiology of the spontaneously tonic Smooth Muscle has not been investigated. In the present studies, we determined the effect of classical HMGCRI simvastatin on the basal IAS Tone and RhoA prenylation and in the levels of RhoA/Rho kinase (ROCK) in the cytosolic vs. membrane fractions of the Smooth Muscle. Simvastatin produced concentration-dependent decrease in the IAS Tone (via direct actions at the Smooth Muscle cells). The decrease in the IAS Tone by simvastatin was associated with the decrease in the prenylation of RhoA, as well as RhoA/ROCK in the membrane fractions of the IAS, in the basal state. The inhibitory effects of the HMGCRI were completely reversible by geranylgeranyltransferase substrate geranylgeranyl pyrophosphate. Relaxation of the IAS Smooth Muscle via HMGCRI simvastatin is mediated via the downstream decrease in the levels of RhoA prenylation and ROCK activity. Studies support the concept that RhoA prenylation leading to RhoA/ROCK translocation followed by activation is important for the basal Tone in the IAS. Data suggest that the role of HMG-CoA reductase may go beyond cholesterol biosynthesis, such as the regulation of the Smooth Muscle Tone. The studies have important implications in the pathophysiological mechanisms and in the novel therapeutic approaches for anorectal motility disorders.
-
the internal anal sphincter regulation of Smooth Muscle Tone and relaxation
Neurogastroenterology and Motility, 2005Co-Authors: Satish RattanAbstract:Abstract Basal Tone in the internal anal sphincter (IAS) is primarily myogenic. Neurohumoral substances like angiotensin II may partially provide external signal for the basal Tone in the IAS. The sphincteric relaxation on the contrary is neurogenic by activation of non-adrenergic non-cholinergic (NANC) nerves that release nitric oxide (NO), vasoactive intestinal polypeptide (VIP) and perhaps carbon monoxide. Because of the presence of spontaneous Tone, the IAS offers an excellent model to investigate the nature of the inhibitory neurotransmission for NANC relaxation. Work from different laboratories in different species concludes that NO is the major contributor in the NANC relaxation. This may invoke the role of other inhibitory neurotransmitters such as VIP, working partly via NO. An understanding of the basic regulation of basal Tone in the IAS and nature of inhibitory neurotransmission are critical in the pathophysiology and therapeutic potentials in the anorectal motility disorders.