E. Molina

Action of some natural polypeptides on the longitudinal muscle of the guinea pig ileum.

The structure--activity relationship of some natural tachykinins was investigated in the longitudinal muscle of the guinea pig ileum. The order of potency was eledoisin greater than uperolein greater than substance P greater than phyllomedusin greater than physalaemin. This ratio of activity is different from that observed in other experimental conditions, and in different in vivo or in vitro preparations; it is suggested that the N-terminal part of the molecule of the tachykinins plays a role in determining the degree of potency of these compounds.

Histamine receptors in the guinea pig ileum.

SummaryHistamine and some related compounds acting selectively on H2-or H1-receptors were tested for their ability to contract the guinea pig ileum, in the usual whole ileum preparation and in the longitudinal muscle preparation. The concentrations elicited by histamine in both kinds of preparations were not potentiated by cimetidine or metiamide and were not inhibited by administration of H2 receptor selective agonists in doses which were subthreshold for contracting the guinea pig ileum; higher doses of the H2 agonists could actually potentiate the effect of histamine. The results obtained suggest that H2 receptors with relaxing effect do not occur in the guinea pig ileum or at least that they are not involved in the contraction of the longitudinal muscle layers. The possibility that a sub-type of H2 receptors with properties different from those of the “classical” H2 receptors so far known, exists in the guinea pig ileum, cannot be excluded.

Regional differences in motor responsiveness to antimuscarinic drugs in rabbit isolated small and large intestine

The pirenzepine-related analogue, nuvenzepine, and the antagonists selective for the three muscarinic receptor subtypes 4-DAMP (M1 and M3 receptors), pirenzepine (M1 receptors), methoctramine (M2 receptors) have been tested on rabbit isolated small and large intestinal regions provided with spontaneous motor activity. The employed drugs differently affected intestinal motility patterns. The ileum pendular movements as well as the proximal colon and taenia coli tone, spike amplitude and frequency were concentration-dependently inhibited by the compounds here employed. Their pIC50 values followed the rank order of potency generally reported for the involvement of the M3 muscarinic receptors (4-DAMP > or = atropine > nuvenzepine > or = pirenzepine > methoctramine). Unlike nuvenzepine and the other antimuscarinics assayed, the M1 selective antagonist pirenzepine, at nanomolar concentrations, was able to enhance the proximal taenia coli motility patterns suggesting that a M1-inhibitory pathway might operate in the physiological modulation of taenia coli motility. At variance with longitudinal ileum and colon contractile activity, proximal circular colon motility was resistant to muscarinic as well as to alpha 1-, H1-, 5-HT-blockade indicating that NANC neuronal mechanisms could act at this level. In summary, these data provide evidence that, at intestinal level, nuvenzepine is almost completely devoid of reliable M1-linked effect thus possessing a different pharmacological selectivity at muscarinic receptor subtypes with respect to pirenzepine. Furthermore, it emerges that rabbit spontaneous small and large intestinal motility is probably driven by different physiological mechanisms regional-related. The peculiar circular colon refractoriness deserves further studies to be extended to the human tissue.

Muscarinic M1 and M3 receptor antagonist effects of a new pirenzepine analogue in isolated guinea-pig ileal longitudinal muscle-myenteric plexus

The new pirenzepine analogue DF 545 has been tested for its muscarinic M1 and M3 receptor antagonist properties in guinea-pig longitudinal muscle-myenteric plexus preparations. McN-A-343-induced inhibition of twitch contractions was taken as a parameter for muscarinic M1 receptor activation while electrical and acetylcholine-induced contractions were considered as a model for muscarinic M3 receptor stimulation. An unexpected contractile effect evoked by McN-A-343 was also investigated. In contrast to pirenzepine, DF 545 only weakly counteracted the M1-mediated McN-A-343 inhibitory effect but blocked M3-related twitch- or acetylcholine-stimulated responses with a 2-fold higher affinity than pirenzepine. Therefore, in this preparation, our findings suggest that DF 545 does not share the selectivity profile exhibited by pirenzepine at ileal muscarinic receptors. Studies on the McN-A-343 contractile effect provide evidence that this agonist may interact with ileal muscarinic effector sites in a different way from other cholinergic agents.

Neuroendocrine and behavioural responses to opioid receptor-antagonist during heroin detoxification: relationship with personality traits

The present study investigated clinical, cardiovascular and neuroendocrine consequences of rapid opioid detoxification (ROD) in heroin-dependent individuals, affected, or not, by comorbid antisocial personality disorder (ASPD). Thirty-two patients underwent ROD and subsequent treatment with daily naltrexone: 3 days detoxification procedures were performed utilizing clonidine, baclofen, oxazepam and ketoprofene, without anaesthesia. Withdrawal symptoms, mood changes, cardiovascular indexes (heart rate, blood pressure), norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH) and cortisol (CORT) were evaluated during naloxone–naltrexone administration on the second day of detoxification treatment. The patients were divided into two groups following DSM-IV criteria for ASPD. Group A comprised 14 ASPD patients and group B comprised 18 patients without ASPD. Slight and transient withdrawal symptoms and mood changes were demonstrated on the second day in the whole sample of patients, in association with a significant, but moderate, elevation of heart rate, blood pressure, NE (two-fold), EPI (five-fold), ACTH (two-fold) and CORT (two-fold) plasma levels, in response to opioid receptor-antagonist administration. When evaluated separately in ASPD (group A) and non-ASPD patients (group B), significantly higher withdrawal symptoms and mood changes, heart rate, blood pressure, NE, ACTH and cortisol levels were observed in ASPD subjects. By contrast, no differences were found in EPI responses to naloxone–naltrexone administration between group A and B patients. The significant differences demonstrated in clinical and neuroendocrine responses to opioid receptor-antagonist administration, in relation to personality traits, could be due to reduced alpha-adrenergic receptor sensitivity, which was previously reported in ASPD, with a possible impairment of clonidine action. Our study suggests that a detailed diagnostic assessment before detoxification procedure may help to predict treatment outcome.

Functional comparison between nuvenzepine and pirenzepine on different guinea pig isolated smooth muscle preparations

The antimuscarinic agents nuvenzepine and pirenzepine were tested on four guinea pig isolated smooth muscle preparations in order to better investigate the existence of differences in the functional activities of such antagonists, as suggested by previous reports. The effects of both compounds were compared to those of atropine. Nuvenzepine showed a four-fold higher affinity than pirenzepine in competitively antagonizing acetylcholine-induced contractions on isolated ileal musculature (pA2 = 7.08 +/- 0.15) and on longitudinal ileum dispersed cells (pA2 = 7.11 +/- 0.19). By contrast, unlike pirenzepine which was ineffective, nuvenzepine inhibited histamine-induced ileal motor activity in a dualistic manner, behaving as an irreversible competitive H1 antagonist (pA2 = 5.02 +/- 0.11). Nuvenzepine was almost equipotent to pirenzepine in competitively preventing bethanechol-induced gall-bladder contractions (pA2 = 7.23 +/- 0.16) and it displayed a four-fold higher potency than pirenzepine in blocking vagal-stimulated tracheal constrictions (pIC50 = 6.77 +/- 0.06). Both compounds were definitely less potent than atropine. On the whole, these findings indicate that, on the selected preparations, nuvenzepine substantially shares the antimuscarinic properties of pirenzepine but it is also endowed with a (weak) H1-blocking action. Furthermore, based on some observations, the presence in gallbladder smooth muscle of muscarinic receptors distinguishable from those of ileum could be speculated.

Comparison of the effects of of structurally different H2-antagonists on acid and pepsin activity stimulated by dimaprit in conscious cats

In the present study the effects of three structurally different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) have been investigated on gastric acid and pepsin secretion of eight cats provided with cannulated gastric fistulas. The maximum pepsin output obtained from a set of complete dose-response curves of dimaprit was not statistically different from basal vaules.In the presence of the H2-antagonists, while the gastric acid secretion indeced by diparit was competitively antagonized, the pepsin secretion was differently affected. The data obtained on pepsin activity with cimetidine and ranitidine were quite similar to the control values. By contrast, oxemtidine induced a significant increase. The results suggest a very weak involvement of the H2-receptors in pepsin activity and that oxmetidine performance could not be attributable to an H2-receptor block.

Spasmogenic activity of some choleretic drugs on the rat pylorus

Summary Substances endowed with specific choleretic effect as well as compounds having a choleretic action only as a side-effect provoked a strong contraction on the gastroduodenal junction of the anaesthetized rat. This property is shared with other substances capable of increasing the duodenal content like cholecystokinin and secretin. It was suggested that the pyloric contraction is unrelated to unspecific spasmogenic activities but it is connected to the possible prevention of a regurgitation of alkaline juice into the stomach. The meaning and the interest of the present observations are discussed.