M. Zizzo - Academia.edu (original) (raw)

Papers by M. Zizzo

Journal of Physiology and Biochemistry, 2016

Dopamine (DA) acts as gut motility modulator, via D1-and D2-like receptors, but its effective rol... more Dopamine (DA) acts as gut motility modulator, via D1-and D2-like receptors, but its effective role is far from being clear. Since alterations of the dopaminergic system could lead to gastrointestinal dysfunctions, a characterization of the enteric dopaminergic system is mandatory. In this study, we investigated the role of DA and D1-and D2-like receptors in the contractility of the circular muscle of mouse distal colon by organ-bath technique. DA caused relaxation in carbacholprecontracted circular muscle strips, sensitive to domperidone, D2-like receptor antagonist, and mimicked by bromocriptine, D2-like receptor agonist. 7-Chloro-8-hydroxy-3-methyl-1phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390), D1-like receptor antagonist, neural toxins, L-NAME (nitric oxide (NO) synthase inhibitor), 2′-deoxy-N 6methyl adenosine 3′,5′-diphosphate diammonium salt (MRS 2179), purinergic P2Y1 antagonist, or adrenergic antagonists were ineffective. DA also reduced the amplitude of neurally evoked cholinergic contractions. The effect was mimicked by (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide (SKF-38393), D1-like receptor agonist and antagonized by SCH-23390, MRS 2179, or L-NAME. Western blotting analysis determined the expression of DA receptor proteins in mouse distal colon. Notably, SCH-23390 per se induced an increase in amplitude of spontaneous and neurally evoked cholinergic contractions, unaffected by neural blockers, L-NAME, MRS 2179, muscarinic, adrenergic, or D2-like receptor antagonists. Indeed, SCH-23390-induced effects were antagonized by an adenylyl cyclase blocker. In conclusion, DA inhibits colonic motility in mice via D2-and D1-like receptors, the latter reducing acetylcholine release from enteric neurons, involving nitrergic and purinergic systems. Whether constitutively active D1-like receptors, linked to adenylyl cyclase pathway, are involved in a tonic inhibitory control of colonic contractility is questioned.

Experimental evidence suggests that adenosine is involved in the regulation of gastrointestinal f... more Experimental evidence suggests that adenosine is involved in the regulation of gastrointestinal functions. In the present study we examined the influence of adenosine on the contractile activity of mouse duodenum longitudinal muscle. Reverse transcription-...

Angiotensin II (Ang II) is a newly discovered modulator of intestinal motility, mainly via activa... more Angiotensin II (Ang II) is a newly discovered modulator of intestinal motility, mainly via activation of excitatory AT1 receptors (AT1R). We demonstrated that during gut inflammation there is a recruitment of inhibitory AT2 receptors (AT2R) which would counteract the AT1R-induced effects. Our objective was to explore the consequence of AT2R activation in the pathogenesis of experimental colitis. Colitis was induced in rats by intrarectal administration of 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by macro- and microscopic scores, myeloperoxidase activity and inflammatory cytokine expression on day 6 after colitis induction. Colonic contractility was recorded in vitro. In a separate group of animals, the effects of 6-day intraperitoneal treatment with PD123319 (3 mg/kg) on colitis features were examined. Colon from DNBS-rats showed marked inflammation associated to a decrease of spontaneous and evoked mechanical activity. Ang II contractile response was reduced by the activation of inhibitory AT2 receptors. PD123319, AT2R antagonist, per se ameliorated colonic contractility. Inhibition of nitric oxide synthase or neural activity induced as well an increase of contractility in DNBS preparations. In such conditions PD123319 did not induce further effects. In DNBS rats daily i.p. treatment with PD123319, attenuated colitis severity, reducing body weight loss and incidence of diarrhoea and improving mechanical activity in vitro. In conclusion, during inflammation constitutively activated AT2 receptors via involvement of enteric nerves and NO would contribute to the reduction of muscle contractility. Blocking AT2R activation in vivo seems to improve some symptoms during intestinal inflammation, driving future study

... Tipologia: Proceedings. Citazione: ZIZZO, MG, LENTINI, L., MULE', FR, & SERIO, RM (2... more ... Tipologia: Proceedings. Citazione: ZIZZO, MG, LENTINI, L., MULE', FR, & SERIO, RM (2009). ... Paper presented at 60° Congresso annuale della Società Italiana di Fisiologia, SIENA. Autori: ZIZZO, MG; LENTINI, L; MULE', FR; SERIO, RM. ...

Since uracil nucleotide-preferring receptors, belonging to the P2Y receptor family and responding... more Since uracil nucleotide-preferring receptors, belonging to the P2Y receptor family and responding to either uridine triphosphate (UTP) or uridine diphosphate (UDP), have been proposed to be present at different cellular level in the gut, regulating various functions, we aimed to investigate whether their activation by uracil nucleotides may modulate the contractility of the intestinal muscle. Experiments were carried out in vitro, and the contractility of the longitudinal muscle from mouse ileum was recorded as changes of the isometric tension. UDP or UTP evoked a concentrationdependent, tetrodotoxin insensitive, contractile response. UDP effect was antagonized by suramin and by PPADS, P2 receptor antagonists, whilst UTP was antagonized only by PPADS. The responses of both nucleotides do not show cross-tachyphylaxis with responses to ATP. MRS 2758, P2Y6 receptor antagonist, antagonized only the effects induced by UDP. Thus, UDP and UTP would act via selective, non ATP-sensitive, rec...

BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in ... more BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in central nervous system (CNS) temporal differences occur in the maturation of different neurotransmitter systems (Goldman-Rakic & Brown, 1982, Ehrlich et al., 2013). Although significant advances have been made in understanding the modifications in CNS, only primarily descriptive studies about the changes taking place in enteric nervous system (ENS), main regulator of gastrointestinal (GI) functions, have been underway. As the other organ systems, digestive system is still developing and maturing after birth and thus it is possible to speculate that the changes in the chemical coding of ENS may occur with development. Studies about the postnatal maturation of enteric neurotransmitter systems could help to assess why drugs, able to modulate GI functions, may have diverse clinical effects at different ages. Serotonin (5-hydroxytryptamine or 5-HT), is an important enteric neurotransmitter in the GI tract (Gershon 2013). Neuronally-released 5-HT plays a crucial role in the regulation of several physiological functions, such as motility, secretion and visceral sensitivity (Gershon 2013; Baker 2005; Beattie & Smith 2008). Since serotoninergic system appears to undergo dramatic postnatal changes in CNS, in this study we aimed to assess if, in the enteric nervous system, 5-HT signalling may undergoes to postnatal maturation, using mouse duodenum as model. METHODS: Using a pharmacological approach, we examined, in vitro , the role of 5-HT signalling in the regulation of duodenal contractility in neonatal mice (2 days old) compared to the adults. RESULTS: 5-HT induced in both duodenal preparations a concentration-dependent muscular contraction, being its efficacy greater in duodenum from neonatal mice. Serotoninergic response was mediated by activation of muscular 5-HT receptors, antagonized by methysergide, nontarget 5-HT receptor antagonist, and of neural 5-HT 3 receptors, antagonized by ondasetron. In both preparations there was a major sensitivity of the postjunctional vs prejunctional receptors. In duodenum from neonatal mice pretreatment with atropine, muscarinic receptor antagonist, abolished neurally evoked serotoninergic contraction. Instead, in adult duodenum, in the presence of atropine, the response to 5-HT was converted in a muscular relaxation, abolished by L-NAME, a nitric oxide (NO) synthase inhibitor. L-NAME per se potentiated the 5-HT cholinergic contractile effects in adult preparations. Instead, L-NAME was ineffective in neonatal preparations. CONCLUSIONS: In mouse duodenum, 5-HT signaling undergoes to age-related changes. In both preparations, 5-HT induces contractile effects via activation of muscular receptors and neural 5-HT 3 receptors on cholinergic nerves to induce acetylcholine release. Contractile response to 5HT is detectable from birth, but there is a gradual decrease in efficacy with age and a concurrent recruitment of inhibitory nitrergic nerves. These changes may contribute to gut motility adaptation to cope with the dietary changes at weaning. REFERENCES Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch Pharmacol. (2008) ;377:181-203. Ehrlich DE, Ryan SJ, Hazra R, Guo JD, Rainnie DG. Postnatal maturation of GABAergic transmission in the rat basolateral amygdale J Neurophysiol.; (2013) 110:926-41. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. (2013) 20:14-21. Goldman-Rakic P, Brown R Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Dev Brain Res (1982) 4:339 \u2013 34

Journal of Physiology and Biochemistry, 2016

Dopamine (DA) acts as gut motility modulator, via D1-and D2-like receptors, but its effective rol... more Dopamine (DA) acts as gut motility modulator, via D1-and D2-like receptors, but its effective role is far from being clear. Since alterations of the dopaminergic system could lead to gastrointestinal dysfunctions, a characterization of the enteric dopaminergic system is mandatory. In this study, we investigated the role of DA and D1-and D2-like receptors in the contractility of the circular muscle of mouse distal colon by organ-bath technique. DA caused relaxation in carbacholprecontracted circular muscle strips, sensitive to domperidone, D2-like receptor antagonist, and mimicked by bromocriptine, D2-like receptor agonist. 7-Chloro-8-hydroxy-3-methyl-1phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390), D1-like receptor antagonist, neural toxins, L-NAME (nitric oxide (NO) synthase inhibitor), 2′-deoxy-N 6methyl adenosine 3′,5′-diphosphate diammonium salt (MRS 2179), purinergic P2Y1 antagonist, or adrenergic antagonists were ineffective. DA also reduced the amplitude of neurally evoked cholinergic contractions. The effect was mimicked by (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide (SKF-38393), D1-like receptor agonist and antagonized by SCH-23390, MRS 2179, or L-NAME. Western blotting analysis determined the expression of DA receptor proteins in mouse distal colon. Notably, SCH-23390 per se induced an increase in amplitude of spontaneous and neurally evoked cholinergic contractions, unaffected by neural blockers, L-NAME, MRS 2179, muscarinic, adrenergic, or D2-like receptor antagonists. Indeed, SCH-23390-induced effects were antagonized by an adenylyl cyclase blocker. In conclusion, DA inhibits colonic motility in mice via D2-and D1-like receptors, the latter reducing acetylcholine release from enteric neurons, involving nitrergic and purinergic systems. Whether constitutively active D1-like receptors, linked to adenylyl cyclase pathway, are involved in a tonic inhibitory control of colonic contractility is questioned.

Experimental evidence suggests that adenosine is involved in the regulation of gastrointestinal f... more Experimental evidence suggests that adenosine is involved in the regulation of gastrointestinal functions. In the present study we examined the influence of adenosine on the contractile activity of mouse duodenum longitudinal muscle. Reverse transcription-...

Angiotensin II (Ang II) is a newly discovered modulator of intestinal motility, mainly via activa... more Angiotensin II (Ang II) is a newly discovered modulator of intestinal motility, mainly via activation of excitatory AT1 receptors (AT1R). We demonstrated that during gut inflammation there is a recruitment of inhibitory AT2 receptors (AT2R) which would counteract the AT1R-induced effects. Our objective was to explore the consequence of AT2R activation in the pathogenesis of experimental colitis. Colitis was induced in rats by intrarectal administration of 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by macro- and microscopic scores, myeloperoxidase activity and inflammatory cytokine expression on day 6 after colitis induction. Colonic contractility was recorded in vitro. In a separate group of animals, the effects of 6-day intraperitoneal treatment with PD123319 (3 mg/kg) on colitis features were examined. Colon from DNBS-rats showed marked inflammation associated to a decrease of spontaneous and evoked mechanical activity. Ang II contractile response was reduced by the activation of inhibitory AT2 receptors. PD123319, AT2R antagonist, per se ameliorated colonic contractility. Inhibition of nitric oxide synthase or neural activity induced as well an increase of contractility in DNBS preparations. In such conditions PD123319 did not induce further effects. In DNBS rats daily i.p. treatment with PD123319, attenuated colitis severity, reducing body weight loss and incidence of diarrhoea and improving mechanical activity in vitro. In conclusion, during inflammation constitutively activated AT2 receptors via involvement of enteric nerves and NO would contribute to the reduction of muscle contractility. Blocking AT2R activation in vivo seems to improve some symptoms during intestinal inflammation, driving future study

... Tipologia: Proceedings. Citazione: ZIZZO, MG, LENTINI, L., MULE', FR, & SERIO, RM (2... more ... Tipologia: Proceedings. Citazione: ZIZZO, MG, LENTINI, L., MULE', FR, & SERIO, RM (2009). ... Paper presented at 60° Congresso annuale della Società Italiana di Fisiologia, SIENA. Autori: ZIZZO, MG; LENTINI, L; MULE', FR; SERIO, RM. ...

Since uracil nucleotide-preferring receptors, belonging to the P2Y receptor family and responding... more Since uracil nucleotide-preferring receptors, belonging to the P2Y receptor family and responding to either uridine triphosphate (UTP) or uridine diphosphate (UDP), have been proposed to be present at different cellular level in the gut, regulating various functions, we aimed to investigate whether their activation by uracil nucleotides may modulate the contractility of the intestinal muscle. Experiments were carried out in vitro, and the contractility of the longitudinal muscle from mouse ileum was recorded as changes of the isometric tension. UDP or UTP evoked a concentrationdependent, tetrodotoxin insensitive, contractile response. UDP effect was antagonized by suramin and by PPADS, P2 receptor antagonists, whilst UTP was antagonized only by PPADS. The responses of both nucleotides do not show cross-tachyphylaxis with responses to ATP. MRS 2758, P2Y6 receptor antagonist, antagonized only the effects induced by UDP. Thus, UDP and UTP would act via selective, non ATP-sensitive, rec...

BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in ... more BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in central nervous system (CNS) temporal differences occur in the maturation of different neurotransmitter systems (Goldman-Rakic & Brown, 1982, Ehrlich et al., 2013). Although significant advances have been made in understanding the modifications in CNS, only primarily descriptive studies about the changes taking place in enteric nervous system (ENS), main regulator of gastrointestinal (GI) functions, have been underway. As the other organ systems, digestive system is still developing and maturing after birth and thus it is possible to speculate that the changes in the chemical coding of ENS may occur with development. Studies about the postnatal maturation of enteric neurotransmitter systems could help to assess why drugs, able to modulate GI functions, may have diverse clinical effects at different ages. Serotonin (5-hydroxytryptamine or 5-HT), is an important enteric neurotransmitter in the GI tract (Gershon 2013). Neuronally-released 5-HT plays a crucial role in the regulation of several physiological functions, such as motility, secretion and visceral sensitivity (Gershon 2013; Baker 2005; Beattie & Smith 2008). Since serotoninergic system appears to undergo dramatic postnatal changes in CNS, in this study we aimed to assess if, in the enteric nervous system, 5-HT signalling may undergoes to postnatal maturation, using mouse duodenum as model. METHODS: Using a pharmacological approach, we examined, in vitro , the role of 5-HT signalling in the regulation of duodenal contractility in neonatal mice (2 days old) compared to the adults. RESULTS: 5-HT induced in both duodenal preparations a concentration-dependent muscular contraction, being its efficacy greater in duodenum from neonatal mice. Serotoninergic response was mediated by activation of muscular 5-HT receptors, antagonized by methysergide, nontarget 5-HT receptor antagonist, and of neural 5-HT 3 receptors, antagonized by ondasetron. In both preparations there was a major sensitivity of the postjunctional vs prejunctional receptors. In duodenum from neonatal mice pretreatment with atropine, muscarinic receptor antagonist, abolished neurally evoked serotoninergic contraction. Instead, in adult duodenum, in the presence of atropine, the response to 5-HT was converted in a muscular relaxation, abolished by L-NAME, a nitric oxide (NO) synthase inhibitor. L-NAME per se potentiated the 5-HT cholinergic contractile effects in adult preparations. Instead, L-NAME was ineffective in neonatal preparations. CONCLUSIONS: In mouse duodenum, 5-HT signaling undergoes to age-related changes. In both preparations, 5-HT induces contractile effects via activation of muscular receptors and neural 5-HT 3 receptors on cholinergic nerves to induce acetylcholine release. Contractile response to 5HT is detectable from birth, but there is a gradual decrease in efficacy with age and a concurrent recruitment of inhibitory nitrergic nerves. These changes may contribute to gut motility adaptation to cope with the dietary changes at weaning. REFERENCES Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch Pharmacol. (2008) ;377:181-203. Ehrlich DE, Ryan SJ, Hazra R, Guo JD, Rainnie DG. Postnatal maturation of GABAergic transmission in the rat basolateral amygdale J Neurophysiol.; (2013) 110:926-41. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. (2013) 20:14-21. Goldman-Rakic P, Brown R Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Dev Brain Res (1982) 4:339 \u2013 34