title: Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits.
abstract: Slow delayed rectifier potassium current (IKs) is important in action potential (AP) repolarization and repolarization reserve. We tested the hypothesis that there are sex-specific differences in IKs, AP, and their regulation by β-adrenergic receptors (β-AR's) using whole-cell patch-clamp. AP duration (APD90) was significantly longer in control female (F) than in control male (M) myocytes. Isoproterenol (ISO, 500 nM) shortened APD90 comparably in M and F, and was largely reversed by β1-AR blocker CGP 20712A (CGP, 300 nM). Inhibition of IKs with chromanol 293B (10 μM) resulted in less APD prolongation in F at baseline (3.0 vs 8.9 %, p < 0.05 vs M) and even in the presence of ISO (5.4 vs 20.9 %, p < 0.05). This suggests that much of the ISO-induced APD abbreviation in F is independent of IKs. In F, baseline IKs was 42 % less and was more weakly activated by ISO (19 vs 68 % in M, p < 0.01). ISO enhancement of IKs was comparably attenuated by CGP in M and F. After ovariectomy, IKs in F had greater enhancement by ISO (72 %), now comparable to control M. After orchiectomy, IKs in M was only slightly enhanced by ISO (23 %), comparable to control F. Pretreatment with thapsigargin (to block SR Ca release) had bigger impact on ISO-induced APD shortening in F than that in M (p < 0.01). In conclusion, we found that there are sex differences in IKs, AP, and their regulation by β-AR's that are modulated by sex hormones, suggesting the potential for sex-specific antiarrhythmic therapy.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL 35294, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xun
authors.initials: X
authors.lastname: Ai
authors.forename: Robert A
authors.initials: RA
authors.lastname: Oster
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pogwizd
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000172:deficiency*; D006352:Heart Ventricles / Q000166:cytology / Q000294:innervation; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009919:Orchiectomy; D010052:Ovariectomy; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012737:Sex Factors; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D051668:Delayed Rectifier Potassium Channels; D012739:Gonadal Steroid Hormones; D026902:Potassium Channel Blockers; D011943:Receptors, Adrenergic, beta; D011188:Potassium