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F De Ponti

Publications and source records attributed to F De Ponti.

At least 55 records · Page 3Linked to original sources
PubMed1996

Adrenergic mechanisms in the control of gastrointestinal motility: from basic science to clinical applications.

Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut motility, blood flow, and mucosal transport. The present review is intended as a survey of key information on the relevance of adrenergic mechanisms modulating gut motility and will provide an outline of our knowledge on the distribution and functional role of adrenoceptor subtypes mediating motor responses. alpha1-Adrenoceptors are located postsynaptically on smooth muscle cells and, to a lesser extent, on intrinsic neurons; alpha2-adrenoceptors may be present both pre- and postsynaptically, with presynaptic auto- and hetero-receptors playing an important role in the modulation of neurotransmitter release; beta-adrenoceptors are found mainly on smooth muscle cells. From a clinical standpoint, adrenoceptor agonists/antagonists have been investigated as potential motility inhibiting (antidiarrheal/antispasmodic) or prokinetic agents, although at present their field of application is limited to select patient groups.

Adrenergic Agents↗
PubMed1996

Functional evidence of atypical beta 3-adrenoceptors in the human colon using the beta 3-selective adrenoceptor antagonist, SR 59230A.

The role of beta 3-adrenoceptors in human colonic circular smooth muscle was assessed in vitro by use of the beta 3-selective antagonist SR 59230A. Isoprenaline, in the presence of the selective beta-adrenoceptor antagonists CGP 20712A (beta 1) and ICI 118551 (beta 2), both at 0.1 microM, concentration-dependently relaxed the preparation (pEC50 = 5.22). This effect was potently and competitively antagonized by SR 59230A with a pA2 of 8.31, while its R,R enantiomer SR 59483A gave an apparent pKB of 6.21. Relaxation was likewise produced by CGP 12177A (pEC50 = 6.05), but not by BRL 37344. Although only one of these beta 3-selective agonists was effective, the remarkably high potency of SR 59230A as a stereospecific antagonist of non-beta 1 non-beta 2 relaxation of human colonic muscle by isoprenaline provides strong functional evidence of beta 3-adrenoceptors in that tissue.

Adrenergic beta-Agonists↗
PubMed1995

Tonic modulation of neurotransmitter release in the guinea-pig myenteric plexus: effect of mu and kappa opioid receptor blockade and of chronic sympathetic denervation.

We have studied the effects of mu- and kappa-opioid receptor blockade on endogenous acetylcholine and noradrenaline overflow from the myenteric plexus of the guinea-pig isolated colon. Cyprodime (putative mu-selective antagonist) and nor-binaltorphimine (kappa-selective antagonist) had a concentration-dependent facilitatory effect on both acetylcholine and noradrenaline overflow. Moreover, in colonic specimens obtained from sympathetically denervated animals, the effect of opioid antagonists on acetylcholine overflow was significantly higher with respect to normal preparations. Evidence is thus given in favour of an involvement of mu- and kappa-opioid receptor pathways in the tonic modulation of neurotransmitter release at the colonic level. Enhanced sensitivity to the effect of mu and kappa antagonists after chronic sympathetic denervation is strongly suggestive for the existence of a functional link between opioid and adrenergic pathways in this model.

Acetylcholine↗
PubMed1995

N-methyl-D-aspartate receptors modulate neurotransmitter release and peristalsis in the guinea pig isolated colon.

To assess the role of NMDA receptors in modulating neurotransmitter release in the myenteric plexus, we studied the effects of L-glutamic acid and NMDA on endogenous acetylcholine and noradrenaline overflow (assayed by HPLC) from the guinea pig isolated distal colon. L-Glutamic acid and NMDA enhanced electrically evoked acetylcholine and noradrenaline overflow and these effects were reversed by selective NMDA receptor antagonists. The possible functional significance of these findings was studied by measuring the efficiency of the colonic peristaltic reflex in the presence of NMDA receptor agonists. NMDA inhibited propulsion velocity at all concentrations tested, this effect being antagonized by (+/-)-2-amino-5-phosphonopentanoic acid and virtually abolished in sympathetically denervated animals. In conclusion, the inhibitory effect of NMDA on peristalsis, being almost entirely dependent on the integrity of sympathetic pathways, could be, at least in part, due to NMDA-induced noradrenaline release.

2-Amino-5-phosphonovalerate↗
PubMed1995

Inhibitory effects of SR 58611A on canine colonic motility: evidence for a role of beta 3-adrenoceptors.

1. In order to clarify whether atypical or beta 3-adrenoceptors can modulate canine colonic motility in vivo, we studied the effects of SR 58611A (a selective agonist for atypical beta-adrenoceptors) alone and after pretreatment with beta-adrenoceptor antagonists on colonic motility in the conscious dog. The gastrocolonic response (postprandial increase in motility) was monitored by means of electrodes and strain-gauge force transducers chronically implanted along the distal colon. In some experiments, heart rate was also measured. The possible role of beta 3-adrenoceptors in mediating the effects of SR 58611A was also tested in vitro in circular muscle strips taken from the canine distal colon. 2. Intravenous infusion of SR 58611A, ritodrine or isoprenaline at doses inducing the same degree of tachycardia inhibited the gastrocolonic response to a different extent, with SR 58611A and ritodrine being more effective than isoprenaline. 3. In a dose-response study, SR 58611A was more potent in inhibiting colonic motility than in inducing tachycardia: the ED35 values for inhibition of colonic motility and induction of tachycardia were 23 and 156 micrograms kg-1, i.v., respectively. 4. The inhibitory effect of SR 58611A 100 micrograms kg-1, i.v., on the gastrocolonic response was reversed by alprenolol (non-selective beta-adrenoceptor antagonist), but resistant to CGP 20712A (beta 1-adrenoceptor antagonist) or ICI 118551 (beta 2-adrenoceptor antagonist). 5. In vitro, SR 58611A concentration-dependently relaxed circular muscle strips, an effect that was competitively antagonized by alprenolol with a pA2 value of 7.1, but resistant to CGP 20712A (100 nM), ICI 118551 (100 nM) or tetrodotoxin (1 microM). 6. The present study provides strong functional evidence for a role of atypical or beta 3-adrenoceptors in the modulation of canine colonic motility both in vivo and in vitro by an inhibitory effect most likely at the smooth muscle level.

Adrenergic beta-Agonists↗
PubMed1995

Functional evidence for the presence of beta 3-adrenoceptors in the guinea pig common bile duct and colon.

To determine the existence of beta 3-adrenoceptors in functional assays in isolated preparations for which data are lacking, we compared the effects of SR 58611A, a selective beta 3-adrenoceptor agonist, and isoprenaline in the guinea pig common bile duct, distal colon and urinary bladder. SR 58611A and isoprenaline relaxed the common bile duct (EC50: 6.85 and 0.41 mumol/l, respectively). The effect of SR 58611A was resistant to CGP 20712A, ICI 118551, propranolol and tetrodotoxin, but was antagonized by alprenolol (pA2 = 6.86), while the effect of isoprenaline was antagonized by CGP 20712A, ICI 118551, propranolol and alprenolol (pA2 = 7.04, in the presence of propranolol to saturate beta 1- and beta 2-adrenoceptors). In colonic preparations, SR 58611A and isoprenaline relaxed circular muscle strips (EC50: 5.48 and 0.49 mumol/l, respectively). The effect of SR 58611A was resistant to CGP 20712A, ICI 118551, propranolol and tetrodotoxin, but was antagonized by alprenolol (pA2 = 7.01). The effect of isoprenaline was resistant to CGP 20712A, but was antagonized by ICI 118551, propranolol and alprenolol (pA2 = 6.88, in the presence of propranolol). In urinary bladder strips, SR 58611A had no effect, whereas isoprenaline reduced resting tone (EC50:0.87 mumol/l), an effect antagonized by alprenolol (pA2 = 8.14). These data provide functional evidence for the presence of beta 3-adrenoceptors in the guinea pig common bile duct and colon, but not in the urinary bladder. At the concentrations used, the effect of SR 58611A was probably mediated solely by activation of beta 3-adrenoceptors located on smooth muscle cells, whereas the effects of isoprenaline were due to beta 3- and also to beta 1-and/or beta 2-adrenoceptor activation.

Adrenergic alpha-Agonists↗
PubMed1994

Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon.

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Effect of food on the bioavailability of pidotimod in healthy volunteers.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) is a dipeptide-like molecule with immunostimulating activity in animals and in men. According to a cross-over randomized study design, 12 healthy volunteers received pidotimod both as 800 mg sachets and 800 mg ampoules after fasting and after a standard meal. The intake of a standard meal before pidotimod administration, either as sachet or as ampoule, reduced the bioavailability of the drug, probably due to an interference at the absorption level. After eating, the time of maximum plasma level was significantly longer than that observed after fasting, while AUC values and the maximum concentration were reduced by 50%. On the contrary, the pharmacokinetics after absorption phase were not influenced by food: as a matter of fact, half-life and MRT did not differ significantly when the drug was taken after fasting or after a standard meal. Finally, the two formulations used in this study resulted bioequivalent.

Adult↗
PubMed1993

Calcium-channel blockers and gastrointestinal motility: basic and clinical aspects.

Several calcium-channel blockers currently in use for the treatment of cardiovascular disorders have recently been tested for their effects on gastrointestinal motility. The rationale for this approach centers on the concept that calcium-channel blockers are at least as potent in inhibiting intestinal smooth muscle as in relaxing vascular smooth muscle. This review will give an outline of the most recent findings on the role of calcium and calcium channels in smooth muscle and neuronal function in the digestive system. It will also consider the mechanisms by which calcium-channel blockers may affect gastrointestinal motility and assess potential clinical applications in gastroenterology. The main goal for researchers in this field will be the development of gut-selective agents, with no cardiovascular side effects.

Animals↗
PubMed1993

Inhibition of endogenous acetylcholine release by blockade of voltage-dependent calcium channels in enteric neurons of the guinea-pig colon.

The effects on acetylcholine release from the guinea-pig colon of the N-type calcium channel blocker omega-conotoxin GVIA (omega-conotoxin), the L-type calcium channel blocker nifedipine and the putative blocker of T-type channels, flunarizine, have been investigated. Endogenous basal acetylcholine release and electrically (1 Hz, 1 ms, 450 mA)-evoked overflow in the presence of cholinesterase inhibitor were studied. omega-Conotoxin (1-10 nM) and nifedipine (0.03-3 microM) dose-dependently inhibited basal and electrically-evoked acetylcholine release. Maximal inhibition of basal or electrically-evoked acetylcholine release was about 40% for nifedipine and about 75% for omega-conotoxin. The potency of nifedipine was inversely related to the external calcium concentration: its EC50 value in low-calcium medium (0.5 mM) was as low as 12 nM. Flunarizine inhibited acetylcholine release only at concentrations higher than 0.2 microM. Our results are consistent with an involvement of N- and L-type calcium channels in the control of the endogenous acetylcholine release from the guinea-pig colon.

Acetylcholine↗
PubMed1993

Immunological adverse effects of anticonvulsants. What is their clinical relevance?

Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

Antibody Formation↗
PubMed1992

Motility of rabbit proximal colon. Relevance of cholinergic pathways and role of different muscarinic receptor subtypes.

To better define the physiologic relevance of the cholinergic muscarinic input to the rabbit colon and the role of different muscarinic receptor subtypes, we studied the effects of atropine, telenzepine (MI antagonist) and DF594 (M3 antagonist) on colonic motility in eight conscious rabbits fitted with bipolar electrodes and strain gauges along the proximal colon. In some experiments, the chronotropic and mydriatic effect of the pharmacological agents were also assessed. Two main patterns of spike activity were identified: short spike bursts (SSBs), which were usually stationary, and long spike bursts (LSBs), which were usually propagated. Both myoelectrical patterns were dose-dependently inhibited by atropine (0.06-4 mumol/kg). Atropine, at the doses of 2-4 mumol/kg, abolished both myoelectrical and mechanical activity. Telenzepine (0.008-0.125 mumol/kg) dose-dependently inhibited migrating LSBs without significant effect on SSBs. Higher doses (0.25-0.5 mumol/kg) inhibited both LSBs and SSBs. DF594 (0.06-2 mumol/kg) dose-dependently inhibited both migrating LSBs and SSBs. The three antimuscarinic agents, at doses that inhibited colonic spike activity by approximately 80% (equiactive doses), behaved as follows on heart rate and pupil diameter: atropine induced tachycardia and mydriasis, telenzepine had no effect, and DF594 induced slight mydriasis with no effect on heart rate. We conclude that spontaneous motility in the rabbit proximal colon depends on a muscarinic excitatory input. M3 receptors are involved in the control of both LSBs and SSBs, while M1 receptors play an important role in the regulation of LSBs. The development of selective antimuscarinic drugs, acting on a given motility pattern and with minimal side effects, may offer new perspectives in the treatment of functional bowel motor disorders.

Action Potentials↗