Inotropic effects of prokinetic agents with 5-HT(4) receptor agonist actions on human isolated myocardial trabeculae.
OBJECTIVE
Besides acting as gastrointestinal prokinetic agents, 5-hydroxytryptamine(4) (5-HT(4)) receptor agonists can induce positive inotropism in human isolated atrium, but not in ventricles. We pharmacologically evaluated the gastroprokinetic 5-HT(4) receptor agonists tegaserod, prucalopride, R199715, cisapride, the cisapride metabolite norcisapride, and the 5-HT(3) receptor agonist MKC773 on human isolated myocardial trabeculae, and compared their effects with those induced by 5-HT and 5-methoxytryptamine (5-MeOT).


METHODS
Atrial and ventricular trabeculae were paced and changes in contractile force were studied in the absence or presence of the 5-HT(4) receptor antagonist GR113808. Partial agonism was assessed using 5-HT(4) receptor agonists as antagonists against 5-HT. To test the contribution of L-type calcium channels, the inotropic responses to 5-HT and 5-MeOT were studied in the absence or presence of verapamil.


RESULTS
Like 5-HT and 5-MeOT, cisapride and tegaserod, but not prucalopride, R19971 and MKC-733, induced concentration-dependent positive inotropic responses on atrial trabeculae, which were abolished by GR113808. The L-type calcium channel blocker verapamil attenuated inotropic responses to 5-HT and 5-MeOT. None of the agonists affected the contraction of left ventricular trabeculae. Concentration response curves to 5-HT were shifted to the right in the presence of prucalopride, cisapride, tegaserod and R199715, but not MKC-773.


CONCLUSIONS
We conclude that (i) inotropic responses to 5-HT and 5-MeOT seem to depend on L-type calcium channels, (ii) tegaserod and cisapride behave as partial 5-HT(4) receptor agonists, while prucalopride, norcisapride and MKC-733 cause no significant effects on human atrial trabeculae, (iii) R199715 seems to behave as a 5-HT(4) receptor antagonist.
Div. of Pharmacology, Metabolic and Vascular Diseases, Dept. of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
Wenxia
W
Chai
Kayi Y
KY
Chan
René
R
de Vries
Antoon J
AJ
van den Bogeardt
Joris H
JH
de Maeyer
Jan A J
JA
Schuurkes
Carlos M
CM
Villalón
Pramod R
PR
Saxena
A H Jan
AH
Danser
Antoinette
A
MaassenVanDenBrink
D008735:5-Methoxytryptamine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002648:Child; D020117:Cisapride / Q000494:pharmacology; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D055815:Young Adult
D001572:Benzofurans; D015220:Calcium Channels; D005765:Gastrointestinal Agents; D007211:Indoles; D011725:Pyridines; D011812:Quinuclidines; D058828:Serotonin 5-HT4 Receptor Agonists; D012702:Serotonin Antagonists; D013449:Sulfonamides; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; C482040:Pumosetrag; D012701:Serotonin; D008735:5-Methoxytryptamine; C105050:tegaserod; D020117:Cisapride; C082871:GR 113808