R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum.

5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 24924 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 X 10(-7) M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 +/- 7% at 3 X 10(-7) M for cisapride and 36 +/- 6% for BRL 24924, also at 3 X 10(-7) M. R 50 595 (10(-7)(-3) X 10(-7) M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 +/- 3.2% at 3 X 10(-8) M. The effects of 5-HT were completely abolished at a concentration of 3 X 10(-7) M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way.(ABSTRACT TRUNCATED AT 250 WORDS)

Uncertainties in extreme surge level estimates from observational records.

Ensemble simulations with a total length of 7540 years are generated with a climate model, and coupled to a simple surge model to transform the wind field over the North Sea to the skew surge level at Delfzijl, The Netherlands. The 65 constructed surge records, each with a record length of 116 years, are analysed with the generalized extreme value (GEV) and the generalized Pareto distribution (GPD) to study both the model and sample uncertainty in surge level estimates with a return period of 104 years, as derived from 116-year records. The optimal choice of the threshold, needed for an unbiased GPD estimate from peak over threshold (POT) values, cannot be determined objectively from a 100-year dataset. This fact, in combination with the sensitivity of the GPD estimate to the threshold, and its tendency towards too low estimates, leaves the application of the GEV distribution to storm-season maxima as the best approach. If the GPD analysis is applied, then the exceedance rate, lambda, chosen should not be larger than 4. The climate model hints at the existence of a second population of very intense storms. As the existence of such a second population can never be excluded from a 100-year record, the estimated 104-year wind-speed from such records has always to be interpreted as a lower limit.