A meta-analysis of 29 clinical studies on
tegaserod revealed an imbalance of cardiovascular ischemic events in patients treated with drug versus placebo. Because increased platelet activity is known to attribute to cardiovascular events, we examined the presence of
serotonin receptor type 4 (5-HT₄) receptors and the effects of
tegaserod on in vitro aggregation of human platelets. Blood samples were obtained from 20 healthy volunteers and 20 subjects with
irritable bowel syndrome with
constipation. Samples of whole blood-
citrate mixtures were incubated with different
tegaserod concentrations mimicking human Cmax values (10 nM), 3.3 times, and 10 times Cmax for at least 1 hour. Conventional plasma platelet aggregation was induced by
adenosine diphosphate,
collagen,
thrombin receptor activating peptide,
epinephrine, and
serotonin plus
adenosine diphosphate. Gene expression analyses targeting 5-HT₄ and
serotonin receptor type 2 receptors were carried out using human platelet
RNA. The presence of 5-HT₄ receptor
protein was investigated by Western blot analysis using membrane fractions from human platelets. Preincubation with
tegaserod resulted in mild but statistically significant increases in platelet aggregation induced by
adenosine diphosphate,
collagen,
epinephrine, or
serotonin, mostly at supratherapeutic concentrations of
tegaserod. The effects were comparable using thrombocytes obtained from healthy volunteers and patients with
irritable bowel syndrome with
constipation. Expression analysis revealed that
mRNA encoding both 5-HT₄ and
serotonin receptor type 2 receptors was present in human platelets. The expression of 5-HT₄ receptor
mRNA was approximately eightfold lower than
serotonin receptor type 2 receptor
mRNA. Results from Western blot analyses examining the presence of 5-HT₄ receptor
protein in human platelets were in agreement with the findings of the
mRNA expression analysis. In platelets harvested from normal persons and patients with
irritable bowel syndrome with
constipation and exposed in vitro to
tegaserod, we detected small but statistically significant concentration-dependent increases in induced platelet aggregation. The relationship of these in vitro effects to clinical cardiovascular ischemic events is presently unclear. Western blot analysis findings suggest the presence of 5-HT₄ receptor
protein on human platelets. Further investigations on the potential role of 5-HT₄ receptors in human platelets may be warranted.