Both beta-adrenergic receptor stimulation and cardiac tissue type have important roles in elucidating the functional effects of I(Ks) channel blockers in vitro.
BACKGROUND
Conflicting results associated with the use of I(Ks) blockers on the action potential duration (APD) have raised a question as to whether the variable results arise from the use of different cardiac tissues, beta-adrenergic stimulation, or by the "selectivity" of the chosen I(Ks) blockers.


METHODS
We used the highly selective I(Ks) blocker (-)-[3R, 4S] chromanol 293B [(-) chromanol] to mimic drug-induced long QT1 in isolated rabbit Purkinje fibers, papillary muscles, and ventricular trabeculae using the conventional microelectrode technique.


RESULTS
I(Ks) block with (-) chromanol at 1 x 10(-5) M did not significantly change the APD at different stimulation rates in all three cardiac tissues. Isoproterenol (Iso:1 x 10(-7) M) shortened APD(90), and (-) chromanol (1 x 10(-5) M) largely prevented this shortening in isolated papillary muscles at 1 Hz [-3% with Iso combined (-) chromanol group versus -16% with iso group; p<0.05] and also at 2 Hz (+7% versus -25% with Iso group; p<0.05), but did not significantly prevent this shortening in isolated Purkinje fibers. In isolated trabeculae, (-) chromanol combined with Iso significantly prolonged the APD(90) by 15% at 1 Hz (versus -10% with Iso group; p<0.05) and by 5% at 2 Hz (versus -11% with Iso group; p<0.05).


CONCLUSIONS
Our study shows that only during beta-adrenoceptor stimulation, pharmacological inhibition of the I(Ks) current plays an important role in the APD recorded from isolated ventricular trabeculae and papillary muscles, but not from Purkinje fibers. These results indicate that the APD prolonging effects of I(Ks)channel blockers during beta-adrenergic receptor stimulation can only be detected from isolated rabbit papillary muscles and ventricular trabeculae, but not Purkinje fibers.
Lu
H R
HR
Center of Excellence for Cardiovascular Safety Research, Johnson and Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutical N.V. B-2340, Beerse, Belgium.
Vlaminckx
E
E
Van De Water
A
A
Gallacher
D J
DJ
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000503:physiopathology; D008839:Microelectrodes; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000166:cytology / Q000502:physiology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D002839:Chromans; D004338:Drug Combinations; D026902:Potassium Channel Blockers; D011943:Receptors, Adrenergic, beta; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D007545:Isoproterenol