Aldosterone receptor antagonists--how cardiovascular actions may explain their beneficial effects in heart failure.

Historically, aldosterone receptor antagonists (ARA) have been classified as 'potassium sparing diuretics'. However, the positive effect of spironolactone, the most extensively studied ARA, on morbidity and mortality observed in humans suffering cardiac insufficiency could not be explained by the renal effect of the drug alone, and a pivotal clinical study has led to extensive research. Many experimental studies have demonstrated that ARA have previously unexpected beneficial effects on the cardiovascular system including reduction in remodelling of the vascular smooth muscle cells and myocytes and improvement of endothelial cell dysfunction in heart failure. These effects improve vascular compliance and slow down the progression of left ventricular dysfunction and end-organ damage. Furthermore, aldosterone receptor blockade also restores the baroreceptor reflex, improving heart rate variability in heart failure in humans. Some of these effects have been demonstrated in dog models of cardiac disease and so justified further investigation of the potential benefit of ARA in dogs with congestive heart failure (CHF). Positive effects of spironolactone on morbidity and mortality appear to have been seen in studies conducted in dogs suffering from naturally occurring CHF. In addition, eplerenone has been shown to have benefits in canine models of heart failure. The precise mechanisms by which ARA produce these beneficial effects in dogs remain to be determined but this group of drugs clearly provide therapeutic actions out-with their diuretic effects.

Comparative effects of mu and kappa opiate agonists on the cecocolic motility in the pony.

The electrical and mechanical activity of the large intestine and its response to administration of opiate mu and kappa agonists were assessed from electrodes and inductograph coils chronically implanted on the cecocolic segment in six ponies given a diet of hay and concentrates. Before the drugs were given, migrating complexes propagating from the cecum into the colon occurred at the rate of 1.5 to 16/hour. During this propulsive activity, the cecocolic sphincter opened and closed allowing the outflow of cecal contents and preventing the backflow of colic contents. Each pony was used as its own control and was given fentanyl (0.01 and 0.05 mg/kg of body weight, IV) and U50488H (0.1 and 0.5 mg/kg, IV) at weekly intervals. The mu agonist fentanyl elicited a marked phase of inhibition of the propulsive activity and a closure of the cecocolic sphincter that lasted one to two hours depending on the dose. The kappa agonist U50488H induced an inhibition of the short spiking activity, i.e. of the resting muscle tone. It did not disturb the occurrence of migrating complexes nor that of the openings of the cecocolic sphincter. These kappa compounds may be drugs of choice to alleviate visceral pain in colic stases without inducing delay of transit unlike mu compounds.

Peripheral opioid receptors mediate gastrointestinal secretory and motor effects of dermorphin N-terminal tetrapeptide (NTT) in the dog.

Dermorphin N-terminal-tetrapeptide-amide (NTT) increased both basal and pentagastrin- or histamine-induced secretion in conscious dogs chronically implanted with both gastric fistulae and Heidenhain pouches. These excitatory effects were significantly prevented by the opioid receptor antagonists naloxone and N-methyl-levallorphan-methanesulphonate. In conscious dogs fitted with electrodes and strain-gauges in different parts of gastrointestinal tract, a premature phase III of the migrating myoelectric complex (MMC) in the duodeno-jejunum was triggered by NTT, while the activity of the antrum was not significantly modified. Further, the peptide enhanced the contractile activity of both proximal and distal portions of the colon, including a long-lasting period of increased muscle tone on the distal colon. Either naloxone or N-methyl-levallorphan-methanesulphonate completely prevented motor effects of NTT on gastrointestinal tract. It is concluded that NTT displays significant opiate-like activity on gastric acid secretion and intestinal motility of the dog by activating peripheral mu opioid receptors.

Cholinergic modulation of the release of serotonin in the gastric interstitial fluid. An in vivo study in rabbits.

Dialysis fibers chronically implanted into the gastric submucosa of rabbits allowed us to simultaneously (a) collect an interstitial fluid dialysate in which 5-hydroxytryptamine concentrations were measured, and (b) locally perfuse drugs such as acetylcholine, neostigmine, and atropine, which stimulated the release of 5-hydroxytryptamine. The effect of acetylcholine was not blocked by atropine but was blocked by hexamethonium. Furthermore, 5-hydroxytryptamine concentrations in the interstitial fluid were lower when acetylcholine and hexamethonium were injected together than when hexamethonium was injected alone. We conclude that acetylcholine stimulates the release of 5-hydroxytryptamine into the gastric interstitial fluid by acting on nicotinic receptors, and has inhibitory effects by stimulating the muscarinic receptors.

Comparative effects of opiate agonists on proximal and distal colonic motility in dogs.

The colonic motility index was measured in dogs, by using strain-gauge transducers, before and after administration of opiate agonists. Fentanyl, a mu-compound, ethylketazocine (EKC), a kappa-compound, and [D-Ala2,Leu5]enkephalin (DADLE), a delta-agonist, were administered by intravenous (i.v.) or intrathecal (i.t.) routes. Fentanyl (2-10 nmol X kg-1 i.v.) induced a dose-related period of hyperactivity characterized by an increase in both tone and frequency of contractions in the distal portion of the colon, whereas a period of hypomotility following a short-lived period of increased activity was elicited on the proximal colon. Fentanyl (0.1, 0.2 nmol X kg-1 i.t.) had inhibitory effects on both proximal and distal colon. Small doses of EKC (2-4 nmol X kg-1) administered i.t. or larger doses (20-40 nmol X kg-1 i.v.) inhibited colonic motility for a dose-related duration, the effects of EKC being more marked on the distal colon than on the proximal colon. The administration of DADLE, 1-2 nmol X kg-1 i.t., and 40-20 nmol X kg-1 i.v., inhibited and stimulated the colonic contractions, respectively, in both proximal and distal colon. The results demonstrated that the colonic opiate-mediated responses may vary according to the route of administration, the portion of the colon studied and the opioid agonist used. Opiate agonists when administered centrally show a tendency to modulate colonic activity in a similar way whatever the type of agonist.

Neurotensin-induced colonic motor responses in dogs: a mediation by prostaglandins.

The effects of systemic infusion of neurotensin (NT) were studied in four dogs fitted with strain-gauge transducers implanted on the ascending and descending colon. The motility index of the colon was enhanced for the duration of the 20 min NT infusion (20 pmol X kg-1 X min-1). Such stimulation was comparable to the colonic motor response elicited by feeding, i.e. the gastrocolic reflex. A period of hypomotility, lasting 40-90 min, occurred after either feeding or completion of NT infusion. Pretreatment with prostaglandin synthetase inhibitors, ketoprofene (KTP) and acetylsalicylic acid (ASA), reduced the magnitude of both the NT- and meal-induced hypermotility responses. The results suggest that the ability of NT to increase colonic motility may involve prostaglandin synthesis and that endogenous prostaglandin may exert a physiologic effect on colonic motor response to feeding. Moreover, these findings support a possible role for NT as one of the mediators involved in the non-neural mediation of the gastrocolic reflex.

Colonic motor responses in the pony: relevance of colonic stimulation by opiate antagonists.

The electrical and mechanical activity of the digestive tract and its response to the administration of opiate agonists and antagonists was assessed from electrodes and strain gauges chronically implanted on the jejunum and the cecocolonic segments in 3 ponies given a diet of hay and concentrates. Before the drugs were given, 10 to 17 migrating myoelectric complexes/day were recorded on the small intestine, and a rhythmic motor activity (base line) was observed on the proximal portion of the colon at the rate of 3.5 to 6.6/hour. Propagated contractions from the proximal to the distal portion of the colon occurred at the rate of 1.5 to 2.3/hour. Each pony was used as its own control and was given morphine (0.5 or 1 mg/kg of body weight, IV) or fentanyl (0.01 or 0.05 mg, IV) at weekly intervals. After an early phase of inhibition of the overall activity that lasted from 0.5 to 3 hours, depending on the dose, the resting muscle tone of the colonic activity was increased for a dose-dependent period. Propagated contractions only reappeared at the end of this 2nd phase. The opiate antagonist naloxone (0.5 mg/kg, IV) elicited a marked propulsive activity on the left replicated colonic segment, characterized by an increase in the number of propagated contractions. The N-methyl-quaternary analog of naloxone (methylnaloxone, which presumably entails selective action at opiate receptors outside the CNS) was also effective, indicating peripheral effects at the dosage level used (0.5 mg/kg, IV). Seemingly, an inhibitory opioid system exists in the control of colonic motor function in ponies and the possible usefulness of opiate antagonists to relieve hypomotility resulting in colonic impaction and constipation.

Opioid control of the ruminant stomach motility: functional importance of mu, kappa and delta receptors.

In sheep, the subcutaneous (SC) or intracerebroventricular (ICV) administration of the mu-type opioid agonists, fentanyl and morphine, evokes a blockade of the cyclic contractions of the reticulum. A similar inhibition of forestomach motility was recorded following the administration of the two enkephalin analogs, D-Ala2-Met5-enkephalinamide (DAMA) and D-Ala2-D-Leu5-enkephalin (DADLE) which are mixed mu - delta opioid agonists. In contrast, the reticular contractions were enhanced by the SC or ICV administration of the kappa type agonist, ethylketazocine (EKC) and U - 50 488 H. The proximal duodenum motor activity was transiently increased resulting in the occurrence of a phase III-like activity by these opioid agonists, regardless of the subtypes. The effects of the opioid agonists on reticular motility were prevented by the injection of naloxone but not by the quaternary parent compound methylnaloxone which does not cross the blood-brain barrier. The duodenal motor effects elicited by the opioid agonists were antagonized by both naloxone and methylnaloxone. The results suggest that the inhibition of the ruminant stomach motility is centrally mediated by mu - delta type opioid agonists and are consistent with opposite effects from kappa type opioid agonists. The stimulatory effect of peptide and non-peptide opioid agonists on the duodenum may result in part from direct opioid receptor-mediated actions on smooth muscle.

Changes in 5-HIAA and 5-HT levels in lumbar CSF following morphine administration to conscious dogs.

Monoamine metabolites in the lumbar cerebrospinal fluid were measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) in 6 conscious dogs after administration of morphine. The concentrations of dopamine and its metabolites exhibited only small variations whereas a significant increase in serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) occurred after a latency of 5 min and culminated after 1 h. The increased release of 5-HT and 5-HIAA and behavioral changes (restlessness, sialorrhea) induced by morphine were prevented by administration of naloxone or nalorphine.

The cyclic motor activity of the ovine gut: its reset at a faster rhythm.

In adult sheep, the frequency of the migrating motor complexes (MMC) was increased by the duodenal administration of methysergide, but not affected by other 5-HT1 or 5-HT2 antagonists. This reset of the MMC pattern at a faster rhythm suggests a selective action on the enteric neuronal serotoninergic mechanism modulating the pacing of the gut cyclic motor activity.

Involvement of serotonergic mechanisms in initiation of small intestine cyclic motor events.

Continuous mechanical and electrical activity recordings of the gastroduodenal junction and duodenum were performed in conscious sheep receiving pharmacologic agents delivered intraduodenally before and after nerve section. Sheep on a normal diet regimen exhibited cyclic periods of maximal activity (phase III of the migrating myoelectric complex) on the duodenum or in-series contractions on the duodenal bulb recurring at a frequency of 13/24 hr and more after nerve section. Among the variety of agents triggering in intact animals premature phases of maximal activity, methysergide, when administered locally, was found to increase the number of complexes to a frequency of 24/24 hr, even when extrinsic nerve supply was removed. The results suggest that in the ovine model the mechanism of cycling of the motor events involved serotonergic myenteric neurons located in the duodenal bulb. The data were consistent with the regulation of the enteric biological clock via 5HT neural receptors mediating inhibition.

Influence of bran on bioavailability of chloramphenicol administered orally to pigs.

The present study was undertaken to determine if bran added to a fiber-free diet (milk) would modify the absorption of orally administered chloramphenicol (cmp) compared with that observed on a standard concentrates diet in pig. The plasma chloramphenicol level was maximal (0.47 +/- 0.26 microgram/mL), 3.5 h after a meal of concentrates containing 8 g of chloramphenicol palmitate; this highest concentration represented only 30% of that observed 12 h after a meal of substituted milk and 14% of the maximal plasma concentration of chloramphenicol detected 14 h after a milk meal when supplemented with bran (100 g). Over 24 h, the plasma availability of chloramphenicol with the three tested diets represented, respectively, 11.4% (concentrates), 17.2% (milk), and 74.1% (milk + bran) of that obtained for intravenous administration; similar oral--caecal transit times were observed for these three diets. It was concluded that the presence of bran in the regimen strongly increases the intestinal absorption of chloramphenicol palmitate, with the lowest rate of absorption on standard concentrates, and it is tempting to speculate that this increase is due to a more rapid intestinal hydrolysis by an increased pancreatic lipase activity on bran.

[The motoricity cycle of the small intestine]. / Le cycle moteur de l'intestin grêle.

The electrical spike activity of the small intestine at the gastroduodenal junction occurs as migrating myoelectric complexes (MMCs), initiated regularly at intervals of 90-100 min. in the adult sheep and of 20-30 min. in the neonate. This ultradian rhythm, generated by the enteric nervous system, may become identical in the adult and in the neonate, by the use of methysergide which interacts with 5-HT myenteric neurones. The results suggest a postnatal development of a serotoninergic inhibitory system, involved in the control of the basic rest-activity cycle of the small intestine.

Nature of the effects of bran on digestive transit time in pigs.

Transit time of digesta, faecal volatile fatty acids (VFA) excretion and faecal output were measured in four pigs (initially of 90 kg live weight) fitted with chronic catheters inserted into the caecum. Each pig was given a basal milk diet (20 g/kg live weight per d) for 30 d and then received successively four further treatments: the basal diet with bran (100 g/d), the bran-supplemented diet with a daily administration of neomycin (100 mg/kg orally and 100 mg/kg intracaecally), the basal diet with continuous intracaecal infusion of either saline (9 g sodium chloride/l) or with VFA solution (100 mM/h) at the same rate. The mean retention time of the polyvinyl chloride marker was reduced from 98.6 h on the milk diet to 64.3 h on the milk + bran diet. This transit time was not significantly modified by neomycin treatment. Daily faecal excretion of VFA was significantly affected by the diet: the addition of bran induced a 167% increase from the milk diet; neomycin treatment reduced VFA excretion with the bran-supplemented diet from 11.3 mM/d to 6.3 mM/d whereas during VFA infusion, excretion levels were twice those of the basal diet. Infusion of VFA solution on the milk diet induced an 11% increase in transit time, without any change in faecal output and dry matter. In conclusion, it is suggested that the decrease in transit time associated with bran supplementation is mediated by direct mechanical factors rather than fermentation products, including VFA.

[Inhibitory role of the opioid system in the initiation of rumination in sheep]. / Rôle inhibiteur du système opiacé dans le déclenchement de la rumination chez le mouton.

Major movements of the reticulo-rumen occur approximately once per minute as a result of periodic vagal motor discharges from "gastric centres" located in the medulla oblongata. During rumination evoked by stroking the interior wall of the reticulum or caused by the injection (bolus) of catecholamines, an additional contraction of the reticulum occurs at the time of regurgitation before the normal biphasic contraction. In sheep, the intravenous (IV) and intracerebroventricular (ICV) administration of naloxone at the doses of 0.1 mg/kg and 10 micrograms/kg respectively, enhances the occurrence of rumination caused by adrenaline. Morphine has opposite effects. Rumination can also be induced by catecholamines in sheep under naloxone regardless of the coarseness of the diet and during eating. The results suggest the involvement of an inhibitory opioid system in the central regulation of rumination and then in the occurrence of reticular contractions linked to regurgitation.