Investigation of the mechanism by which ketanserin prolongs the duration of the cardiac action potential.
Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.
Le Grand
B
B
Division of Cardiovascular Diseases, Centre de Recherche Pierre Fabre, Castres, France.
Talmant
J M
JM
Rieu
J P
JP
Patoiseau
J F
JF
Colpaert
F C
FC
John
G W
GW
D000200:Action Potentials / Q000187:drug effects; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000662:Amphetamines; D010880:Piperidines; D015221:Potassium Channels; D012702:Serotonin Antagonists; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C034177:pirenperone