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Biomedical subjects

F De Ponti

Publications and source records attributed to F De Ponti.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effect of calcium channel blockers on postprandial gastrointestinal motility in the dog.

We have compared the ability of nifedipine and lacidipine, a new 1,4-dihydropyridine, to interfere with postprandial gastrointestinal motility. Five conscious dogs, fitted with 8 bipolar electrodes along the gastrointestinal tract, were studied. Gastrointestinal spike activity was evaluated by means of a computer system. Lacidipine (8 micrograms kg-1) was administered as an i.v. bolus immediately followed by a 10 micrograms kg-1 h-1 i.v. infusion for 3 h, starting 30 min before a standard meal. This dose of lacidipine decreased systolic blood pressure by approximately 20%. Nifedipine was used at equihypotensive doses (30 micrograms kg-1 i.v. bolus followed by 300 micrograms kg-1 h-1 i.v. infusion). Lacidipine had no effect on either gastric or intestinal postprandial spike activity. Nifedipine significantly delayed the appearance of the fed pattern and reduced the number of spikes in the small bowel, while it had no effect on gastric spike activity. We conclude that equihypotensive doses of lacidipine and nifedipine differ in their effects on the gastrointestinal tract, lacidipine having a better cardiovascular selectivity profile than nifedipine, and that the sensitivity to nifedipine varies in different parts of the gut.

Animals↗
PubMed1992

Interaction between (-)naloxone and morphine in modifying superoxide generation from human granulocytes.

The effect of the opioid agonist morphine and of the (-) and (+) stereoisomers of the antagonist naloxone were studied on superoxide generation from human granulocytes. Morphine or naloxone had no effect on basal or phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide generation. Combined equimolar (-)naloxone and morphine concentrations (0.1 pM-0.1 microM) inhibited PMA-stimulated superoxide generation, while combined (+)naloxone and morphine had no effect. The stereospecific effect of naloxone suggests the involvement of opioid receptors. Thus, inhibition of superoxide generation by combined (-)naloxone and morphine could result from the unmasking of non opioid effects of morphine. It is suggested that the opioid control of oxidative metabolism in human granulocytes could involve multiple receptors mediating opposite effects.

Adult↗
PubMed1991

Pharmacological activity and safety of trandolapril (RU 44570) in healthy volunteers.

The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of wash-out. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.

Adult↗
PubMed1991

Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle. 4. A facilitatory effect of Bay K 8644 on both the efficiency of the peristaltic reflex and the nonadrenergic, non-cholinergic (NANC) nerve-mediated relaxation could be observed at concentrations at least 10 fold lower than those required to affect ACh release or smooth muscle. 5. It is concluded that the effects of Ca2+ channel blockers on neurotransmitter release may be relevant to their effects on the gastrointestinal motor function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Effect of iron succinyl-protein complexes on gastrointestinal motility in the fasting dog.

Studying the gastrointestinal motor effects of iron compounds may help to elucidate the mechanism originating the gastrointestinal side effects of frequently reported during martial therapy. The aims of the present study were: (1) to examine the gastrointestinal motor effects of ferrous sulfate (reference compound) and (2) to compare its effects with those of two iron succinyl-protein complexes (ITF 1096 and ITF 282, an iron-albumin and iron-casein complex, respectively). In 6 fasting, conscious dogs, fitted with 8 bipolar electrodes and 3 strain-gauge force transducers along the gastrointestinal tract, gastrointestinal motor activity was recorded. Ferrous sulfate and iron succinyl-protein complexes were administered by an orogastric tube at two dose levels: the lower and higher dose levels were approximately equivalent to 10 and 30 mg/kg as Fe, respectively. In control experiments, 154 mM NaCl, ITF 211 (succinylated albumin) and ITF 297 (succinylated casein) were used. Administration of 154 mM NaCl did not affect gastrointestinal motility nor did it disrupt migrating motor complex (MMC) cycling. ITF 1096 and ITF 282, only at the higher dose, lengthened the MMC period and increased intestinal, but not gastric spike activity. The effects of ITF 211 and ITF 297 were similar to those of ITF 1096 and ITF 282. Ferrous sulfate, at the lower dose, lengthened the MMC period; the higher dose disrupted MMC cycling and induced intense, irregular spike bursts in the stomach and in the small bowel, accompanied, in 3 out of 6 dogs, by a prolonged tonic contraction of the upper small bowel. Four out of 6 dogs vomited after the higher dose of ferrous sulfate. No vomiting was observed with any of the other treatments. We conclude that ITF 1096 and ITF 282 have a markedly better gastrointestinal tolerability than ferrous sulfate.

Animals↗
PubMed1991

Physiopharmacology of the peristaltic reflex: an update.

The peristaltic reflex is one of the simplest models which can be used to study the function of enteric neurons by recording intestinal motor activity. Peristalsis consists of a coordinated, aborally propagating motor activity which requires the functional integrity of receptor pathways, excitatory and inhibitory neural pathways and neuromuscular junctions. Luminal distension elicits polarized responses: an ascending excitatory response (ascending contraction) and a descending inhibitory response (descending relaxation). The present paper reviews the most recent acquisitions on the neural pathways and neurotransmitters involved in the regulation of the peristaltic reflex.

Humans↗
PubMed1990

Pharmacokinetics of the total triterpenic fraction of Centella asiatica after single and multiple administrations to healthy volunteers. A new assay for asiatic acid.

A new HPLC assay method was used to investigate the pharmacokinetics of asiatic acid after oral administration of the total triterpenic fraction of Centella asiatica in single doses (30 or 60 mg) and after a 7-day treatment (30 or 60 mg twice daily). Twelve healthy volunteers received each treatment following a randomized cross-over design with trials separated by a 3-week interval. The time of peak plasma concentration was not affected by dosage difference or by treatment scheme. Differences in peak plasma concentration and area under the concentration vs. time curve from 0 to 24 h (AUC0-24) calculated after 30 or 60 mg administration (single dose) were accounted for by the different dose regimen. However, after chronic treatment with both 30 and 60 mg, peak plasma concentrations, AUC0-24 and half-life were significantly higher than those observed after the corresponding single dose administration. This phenomenon could be explained by a metabolic interaction between asiatic acid and asiaticoside, which is transformed into asiatic acid in vivo.

Administration, Oral↗
PubMed1990

Effects of a new 1,4-dihydropyridine, lacidipine, on gastrointestinal motility and other gastrointestinal functions.

Lacidipine is a new 1,4-dihydropyridine calcium entry blocker endowed with slow onset of action and potent and long-lasting antihypertensive activity. This study investigated the effect of lacidipine on some gastrointestinal functions, mainly gastrointestinal motility, in rats and dogs. In fasting conscious dogs chronically fitted with electrodes and strain gauges along the small bowel, lacidipine (12 micrograms/kg i.v. bolus or 10 micrograms/kg/h for 3 h) did not modify the migrating motor complex pattern or intestinal spike activity. In the rat, lacidipine proved less active (ED 50 greater than 100 mg/kg p.o.) than nitrendipine (ED 50 = 31 mg/kg p.o.) in inhibiting gastric emptying of a liquid meal, whereas the opposite was true after a solid meal (ED 50 = 10.9 and 35.0 mg/kg p.o., respectively). Lacidipine inhibited fecal pellet output at lower doses (ED 50 = 14.8 mg/kg p.o.) than nitrendipine (ED 50 = 40.1 mg/kg p.o.). On histamine-induced gastric acid secretion, the effect of 100 micrograms/kg i.v. lacidipine was moderate (maximum inhibition 45%). The gastrointestinal effects displayed by lacidipine appear at doses at least 5 and 50 times as high as those affecting blood pressure after intravenous and oral administration, respectively. Thus, lacidipine is unlikely to cause noteworthy unwanted effects on the gastrointestinal tract.

Animals↗
PubMed1989

Inhibitory effects of calcium channel blockers on intestinal motility in the dog.

Calcium channel blockers are now widely used for the treatment of cardiovascular disorders. However, data concerning their effects on intestinal motility in vivo are still rather fragmentary. Therefore, we evaluated the effects of three prototype calcium channel blockers (nifedipine, verapamil and diltiazem) on intestinal motility in five fasting, conscious dogs fitted with electrodes and strain-gauges along the small bowel. The myoelectric data were analyzed by a recently developed and validated computer program which allows accurate monitoring of intestinal spike activity. The mechanical data were analyzed by calculating a motility index. After recording of at least two migrating motor complexes (control), an i.v. infusion of one of the following calcium channel blockers was maintained for 3 h: 0.29 or 0.87 mumol/kg per h nifedipine, 1.02 or 2.04 mumol/kg per h verapamil and 1.11 or 2.22 mumol/kg per h diltiazem. Nifedipine 0.29 mumol/kg per h significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. The higher dose suppressed migrating motor complex cycling and almost completely abolished both spike and mechanical activities. The two doses of verapamil had effects similar to those of the two doses of nifedipine. Both doses of diltiazem significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. We conclude that all the agents tested, apart from their well known cardiovascular effects, also have a profound inhibitory effect on intestinal motility in vivo, the order of potency being nifedipine greater than verapamil greater than diltiazem. The search for more selective calcium channel blockers for the treatment of intestinal motor disorders with minimal cardiovascular effects is warranted.

Animals↗
PubMed1989

Relaxatory responses of canine proximal stomach to esophageal and duodenal distension. Importance of vagal pathways.

The viscerovisceral reflex control of gastric tone remains poorly characterized. We have previously demonstrated physiological variations in gastric tone that occur during fasting and after feeding. These variations are neurally regulated. We have now compared the reflex mechanisms modulating gastric tone that are elicited by esophageal or duodenal distension in fasted, conscious dogs. To determine the pathways involved in these reflexes, we combined the technique of vagal blockade (by cooling the supradiaphragmatic vagi isolated within a surgically implanted cooling jacket) with the administration of autonomic drugs. Gastric tone was measured as the air volume within an intragastric bag maintained at a constant, low pressure by an electronic barostat. Standardized distensions were performed by means of an inflatable balloon-catheter positioned either in the mid-esophagus (in three dogs) or in the distal duodenum (in three dogs). A profound and consistent gastric relaxation was induced by distension of either the esophagus (247 +/- 21 ml delta volume, P less than 0.05) or the duodenum (238 +/- 29 ml, P less than 0.05). Supradiaphragmatic vagal cooling abolished the gastric relaxatory response to duodenal distension and significantly reduced, but did not completely suppress, the response to esophageal distension. Neither cholinergic stimulation (intravenous bethanechol) nor adrenergic blockade (combined intravenous phentolamine and propranolol) had any significant effect on either gastric relaxatory response. Combined adrenergic and cholinergic (intravenous atropine) blockade induced gastric relaxation, but failed to suppress the gastric responses. We conclude that both esophageal and duodenal distension elicit gastric relaxation by a noncholinergic vagal mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[3H]acetylcholine release from the guinea-pig distal colon: comparison with ileal [3H]acetylcholine release and effect of adrenoceptor stimulation.

To study cholinergic function in the guinea-pig colon, resting and electrically evoked 3H release after preincubation with [3H] choline has been compared in colonic and ileal myenteric plexus preparations. Fractional spontaneous colonic 3H release was significantly higher than ileal 3H release, while the reverse was true for electrically evoked 3H outflow. Electrically evoked 3H outflow in the colon was linearly related to stimulation frequency (0.2-3 Hz range) and current intensity (300-600 mA range), while 3H outflow per pulse was inversely related to stimulation frequency. Electrically evoked 3H outflow was prevented in Ca2(+)-free solution, indicating that it probably mirrored neuronal exocytotic [3H]acetylcholine release. Both noradrenaline and clonidine concentration-dependently inhibited electrically evoked 3H outflow, clonidine being more potent but less efficacious than noradrenaline. For both noradrenaline and clonidine, the potency and efficacy for inhibition of 3H outflow were close to the values previously reported for the inhibition of electrically evoked endogenous acetylcholine output from colonic preparations. In conclusion, these data indicate that 3H release after incubation with [3H]choline is a valid alternative to measurement of endogenous acetylcholine output to study colonic cholinergic neuronal function in the guinea-pig.

Acetylcholine↗
PubMed1989

Effect of beta-casomorphins on intestinal propulsion in the guinea-pig colon.

beta-Casomorphins are a family of opioid peptides originally isolated from beta-casein. In view of a possible physiological significance of these milk-derived compounds, the effects of bovine beta-casomorphin-5 (beta-CM-5), beta-casomorphin-4 (beta-CM-4) and D-Ala2-beta-casomorphin-4-NH2 (D-Ala2-beta-CM-4-NH2) have been investigated on the peristaltic reflex in the guinea-pig isolated colon and compared with morphine. beta-CM-5 and D-Ala2-beta-CM-4-NH2 each dose-dependently inhibited the velocity of propulsion of an intraluminal bolus; beta-CM-4 was ineffective. IC50 values were 0.30, 5.21 and 0.29 microM for morphine, beta-CM-5 and D-Ala2-beta-CM-4-NH2, respectively. The potency ratios vs morphine were 0.06 and 0.96 for beta-CM-5 and D-Ala2-beta-CM-4-NH2, respectively. Blockade of the peristaltic reflex by beta-CM-5 or D-Ala2-beta-CM-4-NH2 was reversed by the opioid antagonist naloxone. D-Ala2-beta-CM-4-NH2 also dose-dependently inhibited resting acetylcholine output (IC50 = 5.69 microM; potency ratio vs morphine: 0.63). In conclusion, certain beta-casomorphins inhibit intestinal propulsion and cholinergic neurotransmission in the guinea-pig colon, probably by acting at opioid receptors.

Acetylcholine↗
PubMed1989

Inhibitory effects of DF 594, a new antispasmodic agent, on intestinal motility in the dog.

DF 594, 11-(N-methylnipecotyl)-6,11-dihydro-5H-pyrido[2,3-b]-1,5-benzod iazepin-5-one hydrochloride, is a new antimuscarinic compound endowed with high affinity for intestinal muscarinic receptors and showing potent inhibitory effects on intestinal motility. This study investigated the intestinal motor effects of DF 594 in fasting, conscious dogs, chronically fitted with electrodes and strain gauges along the small bowel. In a first series of experiments, we assessed the antispasmodic activity of the compound by comparing the ability of intravenous DF 594 or atropine to antagonize the stimulatory effect of bethanechol (100 micrograms/kg s.c.). ED50 values for inhibition of bethanechol-stimulated contractions were 13.9 (8.8-21.8) and 4.0 (1.8-8.7) micrograms/kg for DF 594 and atropine, respectively. In a second series of experiments, we evaluated the effects of intravenous DF 594 and atropine on the migrating motor complex (MMC), monitoring heart rate as well. Similarly to atropine (30-100 micrograms/kg), DF 594 (100-300 micrograms/kg) blocked the further migration of an ongoing MMC and significantly delayed the onset of the following MMC. Unlike atropine, DF 594 had only a minor effect on heart rate at the highest dose tested (300 micrograms/kg). These data indicate that DF 594 is an effective antispasmodic agent at doses lower than those required to interfere with the MMC and is also less likely than atropine to induce cardiac side effects.

Animals↗
PubMed1988

Quantitative analysis of intestinal electrical spike activity by a new computerized method.

We developed a computerized method that allows quantitative analysis of intestinal spike activity. This method was tested for a series of measurements in six fasting conscious dogs, fitted with bipolar electrodes chronically implanted along the small intestine. Data were stored on 8-channel tape recordings and digitized before computer processing. Spike detection was accomplished by means of a discriminant function able to differentiate spikes from non-spikes (e.g. artifacts) on the basis of six parameters. Computer analysis allowed accurate spike recognition (probability of incorrect classification less than 6%). Spike activity during fasting was monitored by calculating, during each phase of the migrating myoelectric complex, the following parameters per unit of time (30 s): number of spikes, percentage of spiked slow waves and number of spikes per spiked slow wave. Results were given both in tabular and graphical form. This method provides a research tool for a better quantitation of intestinal spike activity.

Action Potentials↗
PubMed1987

Depressant action of oxybutynin on the contractility of intestinal and urinary tract smooth muscle.

Experiments were carried out in-vitro using segments of guinea-pig ileum, taenia caeci, ureter and detrusor. In the ileum, oxybutynin (30, 100 nM) competitively antagonized acetylcholine-induced contractions but did not alter those induced by histamine. Higher concentrations of oxybutynin (up to 10 microM) induced a non-competitive depression of responses to both agonists and caused a parallel shift to the right of the Ca2+-induced contractions in taenia caeci strips bathed in a Ca2+-free, high-K+ medium. In the ureter, oxybutynin (1-10 microM) impaired rhythmic muscular contractions in normal medium and after CaCl2 addition in Ca2+-free medium. Similarly to verapamil (10, 30 microM), oxybutynin (10, 30 microM) depressed both the cholinergic and non-adrenergic, non-cholinergic components of the electrically-induced contractions of detrusor strips. It is concluded that oxybutynin has anticholinergic properties and, at higher concentrations, exerts a direct spasmolytic activity possibly mediated by blockade of the transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Acetylcholine↗
PubMed1987

Reflex gastric relaxation in response to distention of the duodenum.

Using a newly developed gastric barostat, we studied the effect of duodenal distention on gastric tone in a chronic canine model. In the conscious, fasted dogs, duodenal distention for 15 s consistently induced a marked gastric relaxation (delta intragastric volume = 226 +/- 23 ml). This response could be induced repeatedly without evidence of fatigue. Neither bethanechol nor combined phentolamine and propranolol infused intravenously had any significant effect on gastric relaxation in response to duodenal distention. To investigate the pathway of this duodenogastric mechanism, in four dogs we isolated the vagal nerves at the supradiaphragmatic level within an implanted cooling jacket. During intravenous infusion of bethanechol (used as a cholinergic background to maintain base-line gastric tone), supradiaphragmatic vagal blockade by cooling abolished the gastric relaxatory response to duodenal distention (delta intragastric volume = 11 +/- 5 ml during vagal blockade vs. 194 +/- 36 after vagal rewarming; P less than 0.05). This effect of acute and reversible vagal blockade by cooling was also mimicked by bilateral surgical vagotomy. We conclude that a nonadrenergic, noncholinergic mechanism participates in gastric relaxation induced by duodenal distention. This mechanism is mediated by the vagus nerve.

Animals↗
PubMed1986

Inhibitory action of capsaicin on cholinergic responses induced by GABAA agonists in the guinea-pig ileum.

Pretreatment of the guinea-pig ileum with capsaicin resulted consistently in depression of the neurogenic cholinergic contractions induced by the GABAA receptor agonists 3-aminopropane sulphonic acid (3-APS) and muscimol. Since capsaicin acts mainly by releasing and depleting substance P from its stores in intestinal nerves, it is likely that substance P plays a role in the response caused by GABAA-mimetic compounds, On the whole, our results suggest that excitatory responses to 3-APS and muscimol result from both direct and indirect activation of intrinsic intestinal cholinergic neurons innervating smooth muscle cells.

Animals↗