1 The e ects of 5-hydroxytryptamine (5-HT) in rat cardiac preparations were studied. 5-HT up to 10 mM failed to a ect contractility in papillary muscles. However, in electrically driven (1 Hz) left atria 5-HT exerted a positive inotropic e ect that started at 1 mM and attained its maximum at 10 mM (312+50% of predrug value, n=8). 2 5-HT 10 mM stimulated the content of inositol-1,4,5-trisphosphate but not of cyclic AMP in rat left atria. 3 Plasma and serum levels of 5-HT amounted to about 0.3 mM and 15 mM, respectively. 4 The selective 5-HT 4 receptor antagonists GR 125487 (10 nM and 1 mM) and SB 203186 (1 mM) did not attenuate the positive inotropic e ect of 5-HT in rat left atria. In contrast, the 5-HT 2 receptor antagonist ketanserin (5 nM, 50 nM, 1 mM) resulted in a concentration-dependent diminution of the positive inotropic e ect of 5-HT in rat left atria. 5 Reverse transcriptase polymerase chain reaction with speci®c primers detected mRNA of the 5-HT 2A receptor in rat atria and ventricles, while expression of the 5-HT 4 receptor was con®ned to atria. 6 It is suggested that the positive inotropic e ect of 5-HT in electrically driven rat left atria is mediated by ketanserin-sensitive 5-HT 2A receptors and not through 5-HT 4 receptors.

We studied the mRNA expression and function of 5-hydroxytryptamine (5-HT) receptors as well as their signal transduction in right atrial tissue from patients undergoing cardiac surgery and right ventricular tissue from human donor hearts. In isolated, electrically driven strips from human right atrium, 5-HT exerted concentration-dependent positive inotropic effects (EC(50) value = 0.10 +/- 0.01 microM) and hastened relaxation (positive lusitropic effect). The 5-HT(4) receptor antagonists SB203186 or GR125487 antagonised these effects. 5-HT (2 microM) increased the content of cyclic adenosine monophosphate (cAMP) from 6.86 +/- 1.36 to 19.1 +/- 2.45 pmol/mg protein (n = 6, p < 0.05) but did not alter the tissue content of inositol-1,4,5-trisphosphate (IP(3)). With reverse transcription polymerase chain reaction, mRNAs coding for the 5-HT(4) receptor splice variants 5-HT(4(a)), 5-HT(4(b)) and 5-HT(4(c)) were detected in human right atrium and right ventricle. 5-HT(2A) mRNA only was measurable in human atrium. Expression level of total 5-HT(4) receptor mRNA in the right ventricle amounted to 41% (n = 5-8) of that in the right atrium. 5-HT (2 microM) increased the atrial phosphorylation states of phospholamban to 168% at serine-16 and to 150% at threonine-17 (n = 4; p < 0.05) and of the inhibitory subunit of troponin to 150% (n = 6; p < 0.05). In conclusion, the positive inotropic and lusitropic effects of 5-HT in electrically driven human right atria are mediated via 5-HT(4) receptors. These effects are accompanied by and probably due to an increase in cAMP content and the subsequent elevation of the phosphorylation state of Ca(2+) regulatory proteins.