Like the vehicle, tegaserod find more (1 mg?kg?1) failed to alter MBF and MVC during the 140 min observation period post injection (Figure 4C,D). MAP and HR did not significantly change after injection of alosetron and tegaserod, while, after administration of vehicle, MAP and HR decreased with a delay of some 125 min (Table 4). Table 4 Effect of acute i.v. injection of vehicle, alosetron and tegaserod on MAP and HR of non-fasted rats during a prolonged period of time (140 min) Effects of i.d. injection of alosetron and tegaserod (study 3) The aim of study 3 was to test whether alosetron and tegaserod are able to modify CBF and vascular conductance after acute i.d. administration.

In addition, the ability of the vascular recording techniques to pick up vasodilator effects was tested with clonidine, a drug with proven oral bioavailability that has been found to increase gastric mucosal vascular conductance in a sustained manner (Holzer and Painsipp, 2001). In view of its GI bioavailability in humans (50�C60%), the highest dose of alosetron used in study 1 (0.3 mg?kg?1) was selected for i.d. injection. The dose of tegaserod chosen for i.d. administration was 30 mg?kg?1 because the oral bioavailability of this drug in humans is only about 10% (Rivkin, 2003; Evans et al., 2007). Once baseline recordings of the cardiovascular parameters (Table 1) had been made, vehicle, alosetron or tegaserod was administered i.d., whereafter post-injection recordings were taken for 90 min. Following i.d. injection of clonidine (0.

03 mg?kg?1), MAP, HR, MBF and CBF (measured by laser Doppler flowmetry) decreased, whereas MVC, and CVC in particular, increased to a significant extent, with these changes being sustained throughout the observation period (Figure 5). Figure 5 Time-dependent effects of i.d.-injected vehicle and clonidine (0.03 mg?kg?1) on (A) mean arterial blood pressure (MAP), (B) heart rate (HR), (C) mesenteric blood flow (MBF), (D) mesenteric vascular conductance (MVC), (E) colonic blood … Throughout the observation period, i.d. injection of vehicle, alosetron (0.3 mg?kg?1) or tegaserod (30 mg?kg?1) failed to alter MAP, CBF and CVC (Table 5). The HR also remained unchanged, except that there was a late increase of this parameter following vehicle or tegaserod administration (Table 5). Alosetron led to a delayed fall of MBF, which was statistically significant when compared with the pre-injection baseline value (Figure 6A).

Relative to vehicle, however, neither alosetron nor tegaserod caused a significant change of MBF and MVC (Figure 6A,B). Table 5 Effect of acute i.d. injection of vehicle, alosetron and tegaserod on MAP, HR, CBF and CVC of fasted Brefeldin_A rats Figure 6 Time-dependent effects of i.d.-injected vehicle, alosetron (0.3 mg?kg?1) and tegaserod (30 mg?kg?1) on (A) mesenteric blood flow (MBF) and (B) mesenteric vascular conductance (MVC). The basal values of the cardiovascular …