L. Zappia

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.

Inhibition of Gastric Acid Secretion by Adenosine Receptor Stimulation in the Rat

The effects of adenosine and its metabolically stable derivative L-phenylisopropyladenosine (L-PIA), acting mainly on A1 receptors, on gastric acid secretion were studied in the rat. Although inactive by intraduodenal route, subcutaneous adenosine significantly inhibited acid secretion. This inhibition, however, was not dose-dependent. On the contrary, L-PIA was able to decrease dose-dependently acid output by both subcutaneous and intraduodenal route, its ED50 being 0.11 mg/kg subcutaneously and 0.24 mg/kg intraduodenally. The inhibitory effect of L-PIA was reduced by prior administration of theophylline. These results suggest that activation of A1-receptors inhibits acid secretion in the rat.

Antisecretory and antiulcer effect of the H2-receptor antagonist famotidine in the rat: comparison with ranitidine.

1 The effects of the new H2‐receptor antagonist famotidine, administered orally, on gastric secretion and emptying as well as on experimentally‐induced gastric and duodenal ulcers were studied in the rat. Ranitidine was used as a reference compound. 2 Both compounds inhibited acid secretion in a dose‐dependent manner. Calculated ED50 values were 0.80 and 6.84 mg kg−1 for famotidine and ranitidine, respectively. However, the duration of the antisecretory action was the same for both drugs. 3 The effect of the two drugs, administered at equiactive antisecretory doses, on gastric emptying was different. Ranitidine significantly accelerated the emptying rate whereas famotidine had no effect. 4 Famotidine reduced, in a dose‐dependent manner, ulcer incidence in stomachs of dimaprit‐treated rats and in duodena of cysteamine‐treated animals with a potency respectively 2 and 7 times higher than that of ranitidine. 5 Famotidine is therefore an effective antisecretory and untiulcer compound. Its potency, but not its efficacy, is higher than that of ranitidine. Moreover, the duration of the antisecretory action is virtually the same for both drugs.

Histamine receptors in the guinea‐pig duodenum

Guinea‐pig duodenum contracted by histamine or by acetylcholine was relaxed dose‐dependently by a series of H2‐receptor selective agonists namely dimaprit, impromidine, clonidine and tolazoline. This relaxation was not neurally mediated since it was not modified by tetrodotoxin nor was it exerted through sympathetic receptors because it was not modified by pretreatment with propranolol or phentolamine. Apparently it was connected with the H2‐receptor stimulation more than to peculiarities of the single compounds. However a series of H2‐blockers (metiamide, cimetidine, ranitidine or oxmetidine) were unable to counteract the effect of the H2‐agonists or the relaxant effect of histamine in the presence of chlorpheniramine. This peculiar situation seems to indicate the existence of anomalous H2‐receptors, susceptible to the action of the agonists but not to that of the antagonists.

Histamine receptors in the human ureter

The occurrence of histamine H1- and H2-receptors in the human ureter was studied by means of relatively selective agonists and antagonists of both kinds of receptors. Isolated preparations of small strips of human ureters removed during surgery were used. Histamine and the H1-agonist 2-aminoethylthiazole contracted the ureter in a dose-dependent fashion whereas the H2-agonists dimaprit and impromidine were ineffective. The H1-antagonist chlorpheniramine shifted to the right the dose-response curves to histamine and to 2-aminoethylthiazole with the kinetics of the competitive antagonism. Conversely the H2-antagonists cimetidine, metiamide and tiotidine potentiated the effect of histamine by a factor of 3 though high concentrations had to be used (25 - 30 micrograms/ml). Both H1 and H2-antagonists were not able to modify the basal tone and/or motility showed by ureteral strips. All the above data suggested that H1-receptors are predominant in the human ureteral muscle and the contraction induced by their stimulation completely mask the effect of the H2-receptors stimulation. Since H2-agonists were ineffective in basal conditions and H2-antagonists potentiated the effect of histamine which is spasmogenic, we may suggest that H2-receptors are less numerous than H1-receptors and their stimulation cause a slight relaxation of the ureteral muscle. This situation is not uncommon in other smooth muscle system (e.g. respiratory system and gastrointestinal tract).

Antimuscarinic activity of telenzepine on isolated human urinary bladder: No role for m1-muscarinic receptors

1. The antimuscarinic activity of the selective M1-blocking drug, telenzepine, was investigated on the isolated human urinary bladder, contracted with exogenous muscarinic agonists and with field stimulation. 2. Telenzepine (3 x 10(-8)-10(-5) M) concentration-dependently shifted to the right the dose-response curves of bethanechol, acetylcholine and McN-A343, and partially depressed the electrically-evoked twitch responses. 3. pA2 values of telenzepine against bethanechol and McN-A343 were very close. 4. McN-A343 did not modify twitch responses elicited by field stimulation up to 10(-5) M. 5. The lack of muscarinic M1 receptors in human detrusor muscle is confirmed.

Evidence against the temperature-dependent interconversion of histamine H1- and H2-receptors in the guinea-pig ileum

1 The possible temperature‐dependent interconversion of histamine H1‐ and H2‐receptors in the guinea‐pig ileum suggested from previous studies was re‐investigated by use of new and selective H2‐receptor agonists and antagonists. 2 Chlorpheniramine, an H1‐blocker, caused a rightward shift of the cumulative histamine dose‐response curve at both 37°C and 12°C. Conversely cimetidine and tiotidine, two H2‐receptor blockers, were ineffective at both temperatures. Metiamide behaved as a non competitive antagonist at 12°C but only in very high concentrations. 3 Dimaprit and impromidine, two selective H2‐receptor agonists, were inactive at both 37°C and 12°C when given alone, whereas at both temperatures they elicited the already described relaxation of the contractions induced by histamine. 4 Similar results were obtained on the guinea‐pig whole ileum and on the longitudinal muscle strip: this indicates a lack of interference of the circular smooth muscle. 5 Our results allow us to conclude that no temperature‐dependent interconversion of histamine H1‐ and H2‐receptors occurs in the guinea‐pig ileum.

Effects of rociverine on the human ureter: in vivo and in vitro experimental study

An in vitro and in vivo study was conducted to verify the effects of rociverine--a new spasmolytic agent--on peristalsis in the human ureter. In vitro (human ureter strips), rociverine exerted a spasmolytic activity both on the baseline motility and on the spasm induced by direct contractants (eledoisin, KCl) or by histamine. It may therefore be concluded that rociverine is a predominantly myotropic spasmolytic. In the in vivo study, conducted in patients with cutaneous ureterostomy, the drug showed a marked inhibitory effect on the amplitude and frequency of the ureteral rhythmic spikes, without affecting the baseline tone.

Action of substance P and its natural analogs on the circular muscle of the guinea pig ileum

Abstract Substance P and its natural analogs were tested for their activity on the circular muscle of the guinea pig ileum taking into account the possible role of these peptides in the regulation of intestinal peristalsis. All of the peptides examined were found to be less potent (from 2 to 10 times) in contracting the circular than the longitudinal muscle. The order of “potency” was the following: kassinin = eledoisin > uperolein > physalaemin > phyllomedusin = substance P. The order of “efficacy” was: kassinin > eledoisin > uperolein > phyllomedusin > physalaemin > substance P. Thus considering both the threshold dose (potency) and the maximum effect (efficacy) substance P appeared to be the less effective peptide. The hypothesis may be suggested that guinea pig substance P, so far not identified, is more closely related from a chemical and a pharmacological point of view to one of the above tachykinins than to bovine substance P used in our experiments. Since all these peptides possess a common C-terminal part in their molecules, the importance of the N-terminal part (which is different in the various peptides) must be emphasized.