Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender.
As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (I(K1)) and slow delayed (I(Ks)) rectifier cardiac K(+) currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I(K1) with BaCl(2), (ii) selective block of I(Ks) with (-) chromanol 293B under basal conditions and (iii) selective block of I(Ks) during beta-adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl(2) (10 microM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 microM (-) chromanol 293B did not change the APD in fibres from female and male dogs. During beta-adrenoceptor stimulation with 0.1 microM isoproterenol, an APD prolonging effect of (-) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (-) chromanol 293B. In conclusion, our findings confirm that beta-adrenoceptor stimulation is one condition where there may be an increased role of I(Ks) in action potential repolarisation. Gender differences in the autonomic modulation of I(Ks) could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias.
Abi-Gerges
Najah
N
Safety Pharmacology Department, Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG. Najah.AbiGerges@astrazeneca.com
Small
Ben G
BG
Lawrence
Chris L
CL
Hammond
Tim G
TG
Valentin
Jean-Pierre
JP
Pollard
Chris E
CE
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial / Q000379:methods; D002712:Chlorides / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012737:Sex Factors; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D017609:Barium Compounds; D002712:Chlorides; D002839:Chromans; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C024986:barium chloride; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D007545:Isoproterenol